WO2021205083A2 - Composition for the prevention or treatment of covid-19 - Google Patents

Composition for the prevention or treatment of covid-19 Download PDF

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Publication number
WO2021205083A2
WO2021205083A2 PCT/FR2021/000037 FR2021000037W WO2021205083A2 WO 2021205083 A2 WO2021205083 A2 WO 2021205083A2 FR 2021000037 W FR2021000037 W FR 2021000037W WO 2021205083 A2 WO2021205083 A2 WO 2021205083A2
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Prior art keywords
bht
dose
sars
sod
gsh
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PCT/FR2021/000037
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French (fr)
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WO2021205083A3 (en
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Jolanda Spadavecchia
Mario GIOUSUÈ BALZANELLI
Murielle DERRIEN
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Finindsutria Srl
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Publication of WO2021205083A2 publication Critical patent/WO2021205083A2/en
Publication of WO2021205083A3 publication Critical patent/WO2021205083A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/324—Boswellia, e.g. frankincense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates generally to a novel composition for the treatment of infections by a coronavirus and more particularly Covid-19, infection by SARS-CoV-2.
  • Coronaviruses are part of the Nidovirales order, the Coronaviridae family and the Coronavirinae subfamily which includes 4 genera: alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus. Coronaviruses infect a wide variety of hosts, including many species of birds and mammals, including humans. Alphacoronaviruses and betacoronaviruses circulate among mammals, gammacoronaviruses and deltacoronaviruses infect birds and mammals.
  • lineage A to which the human coronaviruses HKU1 and OC43 belong
  • lineage B to which SARS-CoV (stands for Severe Acute Respiratory Syndrome Coronavirus) belongs
  • lineage C to which the human coronavirus belongs.
  • MERS-CoV Middle East Respiratory Syndrome Coronavirus
  • D lineage to which the bat coronaviruses HKU4 and HKU5 belong, close to MERS-CoV.
  • SARS-CoV SARS viras or SARS virus
  • the epidemic has spread to various countries (Vietnam, Hong-Kong, Singapore, Thailand and Canada) from an initial outbreak which appeared in China in the last quarter of 2002.
  • the severity of this disease is such that its mortality rate was around 3 to 6%.
  • Genomic sequences of this coronavirus have thus been obtained, in particular those of the Urbani isolate (Genbank no. access AY274119.3 and A. MARRA et al., Science, May l, 2003, 300, 1399-1404) and the isoiat of Toronto (Tor2, Genbank accession no AY 278741 and A. ROTA et al. Science, 2003, 300, 1394-1399).
  • SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging in 2019 in China, belongs, like the SARS virus, to the SARSr-CoV species (Severe acute respiratory syndrom-relaied Coronavirus ⁇ , in the subgenus Sarbecovirus, in the genus Betacoronavirus and the family Coronaviridae TM.
  • SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging in 2019 in China, belongs, like the SARS virus, to the SARSr-CoV species (Severe acute respiratory syndrom-relaied Coronavirus ⁇ , in the subgenus Sarbecovirus, in the genus Betacoronavirus and the family Coronaviridae TM.
  • SARS-Cov or SARS-Cov-2 are enveloped single-stranded RNA viruses of positive polarity. They have a morphology typical of coronaviruses with in particular the halo of protein protuberances ("Spike” or spicule) which gave them their name (“crown virus”) (Fields, B. N, In Rnipe, D. M, & In Howley, PM (2013). Fields virology. Philadelphia: Wolters Kluwer Health / Lippincott Williams & Wilkins). The size of the SARS-Cov-2 genome is approximately 30 kilobases. The proximal origin of SARS-CoV-2.
  • each coronaviras affects only one species. However, these viruses can cross the species barrier. This may well be the case with SARS-CoV-2, which is believed to be from a bat or pangolin coronaviras.
  • SARS-CoV-2 binds to the angiotensin converting enzyme 2 (ACE2) receptor (Zhang, H., Penninger, JM, Li, Y. et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS- CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46, 586-590 (2020). https://doi.om/10.1007/s00134-020-05985-9 ); LACE2 is an angiotensin II cell receptor converting enzyme.
  • ACE2 angiotensin II cell receptor converting enzyme
  • AT2 alveolar epithelial cells located in the pulmonary alveoli, but also in the esophagus, in the upper and stratified epithelial cells, in the absorbing enterocytes of the ileum and the colon and in the pancreas.
  • the diseases or symptoms (Covid-19) caused by these SARS-Co-2-type coronaviras can range from the absence of symptoms, to a cold accompanied by fever, body aches, sore throat, rhinorrhea (damage to the gastrointestinal tract "upper "), Or even cause more serious symptoms such as severe acute respiratory syndrome observed in patients infected with SARS-Cov-1, (epidemic in 2003), MERS-CoV, epidemic in 2012), or even suffering from Covid-19 as observed in 2020.
  • the warning signs of these aggravations are nausea, vomiting, diarrhea (damage to the “lower” gastrointestinal tract).
  • Symptoms of an acute respiratory infection are observed in 20 to 30% of patients. Kidney and intestinal damage have also been observed in some patients about 10% and patients with pre-existing chronic diseases as well as the elderly are more likely to develop severe forms which can lead to death. This virus kills about 1% to 10% of infected people regardless of age or ethnicity.
  • a treatment based on a combination of an antibiotic associated with an anti-inflammatory drug, or associated with hydroxychloroquine (Gautret et al. (2020) Hydroxy chloroquine and azithromycin as a treatment of COVID-19: result of an open label non randomized clinical trial.
  • the compound 2,6-di-tert-butyl-4-methylphenol has known antiviral properties but its efficacy on coronaviruses, in particular the SARS-Cov-2 coronaviruses, has never been suggested and even less demonstrated.
  • BHT 2,6-di-tert-butyl-4-methyl-phenol
  • the invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus SARS-CoV-2.
  • the invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2, by virucidal activity or. decontaminating.
  • a coronavirus such as SARS-CoV-2
  • the invention also relates to:
  • BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS ).
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with NATTOKINASE.
  • BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswe solutionia Serrata (BS), advantageously in a pharmaceutical formulation intended for oral administration.
  • NAC N-acetylcysteine
  • BS Boswe solutionia Serrata
  • BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswe resolutionia Serrata
  • BS BS
  • Nattokinase advantageously in a galenic formulation intended for oral administration.
  • the invention relates to nattokinase for the prevention and / on the treatment infection with a coronavirus such as SARS-CoV-2, on a composition comprising nattokinase for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2.
  • the invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2.
  • BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), and a combination of these compounds.
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • BHT for its use according to the invention, characterized in that the BHT is also combined with Adenosine TriPhosphate (ATF).
  • ATF Adenosine TriPhosphate
  • BHT for its use according to the invention characterized in that BHT is used at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 rng to 100 mg, from 100 rng to 900 mg, from 300 mg to 500 mg, advantageously at a dose of 0.1 mg / kg to ig / kg, from 1 mg / kg to 0.1 g / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 900tng / kg; from 300 mg / kg to 500 mg / kg by weight.
  • the BHT for its use according to the invention characterized in that the BHT is administered at least orally, and intravenously, sublingually, rectally, by inhalation, depending on the symptoms, to bring the BHT into contact with the SARS- Cov-2.
  • BHT for its use according to the invention, characterized in that BHT is administered 1 to 3 times per day, advantageously from 1 to 3 times per day for at least 5 days to at least 14 days.
  • BHT for its use according to the invention, characterized in that BHT is administered to individuals with or without symptoms of Covid-19.
  • BHT for its use according to the invention, characterized in that BHT is administered to an individual infected with SARS-Cov-2 exhibiting at least one symptom chosen from cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances. intestinal, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
  • BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms chosen from cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration. and / or by inhalation.
  • the invention relates to 2,6-di-tert-butyl-4-methyl-phenol (BHT) alone or in combination with at least one other dietary supplement for its use in the prevention and / or treatment of infection. by a SARS-CoV-2 coronavirus (Covid-19).
  • a food supplement can be, for example, SOD ⁇ Zn, Cu and or Mg, CAT, GSH ATP, N AC, BS.
  • a food supplement can be, for example, SOD ⁇ Zn, Cu and or Mg, CAT, GSH ATP, NAC, BS, NATTOKINASE.
  • the invention relates to BHT for its use as a medicament for the prevention or treatment of infections with betacoronaviruses, in particular SARS-CoV-2.
  • drug is understood to mean a compound or a composition having a direct or indirect antiviral effect.
  • the invention also relates to BHT combined with another antioxidant, and / or an anti-inflammatory, to a composition comprising BHT combined with another antioxidant, and / or an anti-inflammatory, to dosage formulations of these.
  • the invention relates to BHT characterized in that it is combined with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS), advantageously in a galenic formulation intended for oral administration.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • a compound of formula (I) (I: 2,6-di-tert-hutyl-4-R-phenol) or wherein R is CH3 (BHT), 0-CH3 (BG1), CH2-OH (BG2), COOH (BG3), or CHO (BG4) alone, or in combination according to the invention was very effective in preventing or treating symptoms of Covid-19.
  • R is CH3 or 2,6-di-tert-butyl-4-methyl-phenol (BHT) is very effective for preventing or treating the symptoms observed during Covid-19.
  • compositions according to the invention are administered, preferably by the oral route, to patients presenting no symptoms, or presenting at least 1 symptom among (fever, fatigue, headache, rhinorrhea, dry cough, stiffness, respiratory discomfort, insufficiency. respiratory; diarrhea, nausea, vomiting, dizziness) or at least 2 symptoms including respiratory failure and at least one of (fever, fatigue, headache, rhinorrhea, dry cough, body aches, respiratory discomfort, respiratory failure) ; diarrhea, nausea, vomiting, dizziness).
  • BHT BHT
  • compositions according to the invention can be administered by any one of all the routes of administration according to the invention, or a combination of routes of administration, to all the patients or persons susceptible to. be infected with the SARS-Cov2 virus or infected with SARS-Cov-2,
  • compositions according to the invention can be administered: preferably orally,
  • intrarectal and / or oral preferably oral and intrarectal route in patients presenting signs of infection of the intestine (nausea, diarrhea, presence of virus in the nose, in the faeces),
  • the invention also relates, according to one aspect, to BHT for preventing and / or treating Covid-19, characterized in that it is combined with another antioxidant, in particular with a compound selected from Catalase (CAT), Su- peroxide dismutase (SOD), gluthation (GSH), and a combination of these compounds, advantageously to another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds, or also to another antioxidant selected from N acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds.
  • CAT Catalase
  • SOD Su- peroxide dismutase
  • GSH gluthation
  • ATP adenosine triphosphate
  • the invention also relates, according to one aspect, to BHT characterized in that it is combined with another antioxidant, in particular with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), glutha- tion ( GSH), and a combination of these compounds, advantageously with another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds, or alternatively to another antioxidant selected from N acetylcysteine (NAC), Catalyst (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds.
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH glutha- tion
  • ATP adenosine triphosphate
  • NAC N acetylcysteine
  • CAT Catalyst
  • BHT combined with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), BS and a combination of these compounds, advantageously with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP), BS and a combination of these compounds, or to another antioxidant selected from N acetyicysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD) , gluthation (GSH), adenosine triphosphate (ATP), BS and a combination of these compounds.
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH adenosine triphosphate
  • BS a combination of these compounds
  • compositions according to the invention can be used for the prevention or treatment of an infection by an enveloped virus, a parasite having a lipid bilayer (enveloped).
  • the present invention also relates to BHT alone or in combination with an anti-inflammatory, for example Boswellia Serrata, to prevent or treat Covid-19.
  • an anti-inflammatory for example Boswellia Serrata
  • the present invention relates to NATTOKINA SE for preventing or treating the symptoms and coagulation problems (formation of clots) linked to a viral infection, preferably linked to covid-19.
  • the invention also relates, according to one aspect, to BHT for preventing and / or treating Covid-19, characterized in that it is combined with another antioxidant selected from one of the following compounds: NAC, CAT, SOD , ATP, GSH and a combination of these associated compound (s) and an anti-inflammatory, advantageously, BS.
  • the invention relates to BHT for its use according to the invention characterized in that the BHT is further combined with Adenosine TriPhosphate (ATP).
  • ATP Adenosine TriPhosphate
  • the invention relates to BHT for its use according to the invention characterized in that the BHT is used at a dose (x) of 0.1 mg to 10g, from 1 mg to 1g, from 10 mg 800 mg, from 100 mg at 90Qmg, from 300mg to 500 mg.
  • the dose (x) can be per kg body weight.
  • the invention relates to BHT for its use according to the invention characterized by the use of a dose of 1 to 3 times per day.
  • the invention relates to BHT for its use according to the invention characterized by use for at least 5 days to at least 28 days, for at least 5 days to at least 14 days, for at least 5 days to at least 10 days .
  • the invention relates to BHT for its use according to the invention characterized in that BHT is administered to individuals with or without symptoms of Covid-19.
  • the invention relates to BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 who may or may not have at least one symptom of cough, dyspnea, fatigue, sore throat, disorders. gastrointestinal, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
  • an individual infected with SARS-Cov-2 is meant an individual in whom specific viral sequences of SARS-Cov-2 are detectable, at least by PCR in a sample taken either from the nose, or from a sample of blood, or in a faeces sample.
  • the invention relates to BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a pharmaceutical formulation. suitable for intravenous and / or inhalation administration.
  • compositions according to the invention are administered orally to all patients and persons likely to be infected with the virus.
  • the compositions according to the invention are administered:
  • intrarectal and / or oral preferably oral and intrarectal in patients showing signs of infection of the intestine (nausea, diarrhea, presence of virus in the nose, in the faeces) ,
  • Figure 1 Measurement of the infectious titers of SARS-CoV-2 at 24 hours post-infection, on cells treated with diluent (control), BHT alone or a combination of BHT and (NAC or BS or both NAC and BS) , reported to the infectious titer of infected and untreated control cells.
  • the infectious titers were obtained by infection technique by limiting dilution and calculation by the method of Reed and Muench.
  • Figure 2 Measurement of the IC50 (concentration necessary to obtain 50% of normalized viral production) of the compounds tested (A- Control B-BHT, C-BHT- NAC, D-BHT- BS) on VeroE6 cells infected with co- ronavirus SARS-COV-2.
  • the infectious titers were obtained by infection technique by limiting dilution and calculation by the method of Reed and Muench.
  • FIG. 3A Measure of antiviral efficacy of the compounds tested (A-BHT, B- BHT-NAC, C-BHT-BS D-BHT-NAC-BS) and FIG. 3B.
  • A549 infected with the SARS-COV-2 coronavirus The infectious titers were obtained by technique of infection by limiting dilution and calculation by the method of Reed and Muench. Normalized viral production is measured alongside cell viability, depending on the concentration of compounds used.
  • Figure 4A Measure of antiviral efficacy of the compounds tested (A-BHT, B- BHT-NAC, C-BHT-BS D-BHT-NAC-BS) and FIG. 3B.
  • A- diluent, B-NAC, C-BS human intestinal epithelial cells expressing angiotensin-converting enzyme 2 (ACE2) and protease TMPRSS2, infected with the SARS-COV-2 coronavirus:
  • ACE2 angiotensin-converting enzyme 2
  • TMPRSS2 protease TMPRSS2 coronavirus
  • Figure 4A Measure of antiviral efficacy of the compounds tested (A- BHT, B- BHT-CAT, C-BHT-GSH, D-BHT- SOD, E-BHT-CAT-SOD-GSH-ATP (all)) and Figure 4B A - diluent, B-CAT, C-GSH, D-SOD, E- ATP; F- ail) on human intestinal epithelial cells expressing angiotensin converting enzyme 2 (ACE2) and protease TMPRSS2, infected with the SARS-COV-2 coronavirus: Infectious titers were obtained by technique of infection by limiting dilution and calculation by the method of Reed and Muench. The normalized viral production is measured in parallel with the viability of the cells, as a function of the concentration of compounds used.
  • ACE2 angiotensin converting enzyme 2
  • TMPRSS2 protease
  • Figure 6 Anti-viral activity of BHT on target cells without decontamination: the quantity of RNA measured at 48 hours comprises the inoculum.
  • Product 1 and Product 2 include BHT, vs Remdesivir positive control tested in parallel.
  • the present invention relates to BHT, for its use in the prevention and / or treatment of an infection with the coronavirus SARS-CoV-2 (Covid-19).
  • the present invention relates to a composition comprising BHT and an excipient or diluent for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19).
  • the present invention relates to a pharmaceutical composition comprising BHT and a pharmaceutical excipient suitable for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19).
  • the present invention relates to a food composition
  • a food composition comprising BHT and an excipient suitable for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19).
  • the invention relates to BHT or a composition comprising BHT, for its use as an antiviral for the prevention or treatment of infections by betacoronaviruses, in particular SARS-CoV-2,
  • BHT is very effective in particular for preventing and / or treating COVID-19 but also for the prevention and / or treatment of Coronavirus infections, more specifically betacoronavirus, such as SARS-Cov, MERS-Cov, SARS-Cov -2.
  • the present invention relates to BHT, for its use for the prevention and / or treatment of infections with Coronavirus, more precisely with betacoronavirus, such as SARS-Cov, MERS-Cov, SARS-Cov-2 ,
  • BHT alone or in combination with at least one other compound for its use in the prevention and / or treatment of infection with a beta-coronavirus, preferably capable of causing severe acute syndrome, SARS-Cov, MERS -Cov, SARS-Cov-2, or any isolate of these viruses is an aspect of the present invention.
  • BHT alone or in combination with at least one other compound, for its use in the prevention and / or the treatment of an infection by a betacoronavirus, preferably, capable of causing a severe acute syndrome, and exhibiting at least 70% identity, at least 80% identity, at least 90% identity, at least 96% identity, and up to 100% sequence identity with the sequence of a SARS-Cov, or MERS-Cov, or SARS-Cov-2, or any isolate of these viruses, is an aspect of the present invention, preferably SARS-Cov-2 or any isolate of SARS-Cov-2.
  • BHT alone or in combination with at least one other compound, for its use in the prevention and / or treatment of infection with SARS-Cov-2, or any isolate of this virus listed described and closed the day before the day of filing of this request: https://www.ncbi.nlm.nih.gov/gen - bank / sars-cov-2-seqs /
  • SARS-CoV-2 coronavirus an isolate of this virus, such as those identified and sequenced in Italy (MT066156, or MT008022, MT008023, or any other emerging beta coronavirus of the SARS type, responsible for the pandemic in 2020.
  • SARS-Cov-2 isolate that can potentially induce Covid-19 (disease) is referred to as SARS-Cov-2 in this study.
  • SARS-Cov-2 infection can in particular be established by performing at least one detection and / or viral titration from respiratory samples, or faeces or by assaying specific antibodies to circulating SARS-CoV-2. in the blood. Detection of this specific virus in infected individuals is carried out by conventional diagnostic methods, in particular molecular biology (PCR), well known to those skilled in the art.
  • PCR molecular biology
  • infection with the SARS-CoV-2 coronavirus is meant the fact that an organism, for example a human, has cells which have been infected with a SARS-CoV-2 coronavirus, or viral sequences of SARS-CoV-2 detectable by polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • Covid-19 the disease observed in patients infected with SARS-Cov-2
  • SARS-Cov-2 the disease observed in patients infected with SARS-Cov-2
  • dyspnea difficulty breathing in 31% to 55% of patients
  • anosmia total loss of smell in 10% to 15% of cases 89 ; anosmia is a frequent manifestation in viral infections, ageusia (loss of taste) has been reported by your Covid-19 patients,
  • Diarrhea or abdominal pain appear one or two days before the respiratory problems, especially in the elderly.
  • Acute respiratory distress is observed in 30% of cases, myocarditis in 10% of cases and bacterial over-infection: in 10% of cases a significant release of cytokine responsible for secondary hemophagocytic lymphohistiocytosis (cytokine shock) can result in death, is observed.
  • treatment refers to combating infection with the SARS-CoV-2 coronavirus in an organism. Thanks to the administration of at least one composition according to the invention, the infectious titre in the organism can decrease compared to that taken previously from the same patient, and preferably the virus will no longer be detectable in the organism. the body.
  • treatment also designates the act of reducing at least one of the symptoms associated with the viral infection (acute respiratory syndrome, fever, headache, diarrhea, vomiting, renal failure, cough, etc.).
  • the compositions according to the invention are also intended for use in the prevention of infection by SARS-CoV-2.
  • prevention denotes the fact of preventing, or at least reducing the probability of bility of onset of infection in a human or animal organism by SARS-CoV-2.
  • compositions according to the invention may be of the food or pharmaceutical type intended to be administered to a human being.
  • suitable pharmaceutical vehicle denotes vehicles or excipients, ie compounds not exhibiting any specific action on the infection considered here. These vehicles or excipients are pharmaceutically acceptable, which means that they can be administered to an individual without generating significant deleterious effects.
  • the invention relates in one aspect to a compound of formula 2,6-di-tert-butyl-4-R-phenol or where R is CH3 or for the prevention and / or treatment of betaCoronavirus infections, in particular Covid-19.
  • R is CH3 (BHT), R is OCH3 (BG1), R is CH20H (BG2), R is COOH (BG3), are particularly useful for the prevention or treatment of symptoms related to the infection with betacoronaviruses, in particular the coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or Covid-19.
  • a compound of formula I preferably R is COOH, CHO, CH2-OH, CO-CH3 for its use in the prevention and / or treatment of infection by SARS-Cov, MERS-Cov, SARS-Cov- 2 is one aspect of the present invention.
  • a composition comprising a compound of formula (I) can be used for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly symptoms linked to SARS-Cov- 2, for the prevention or treatment of Covid-19.
  • SARS severe acute respiratory syndrome
  • BG1 is combined with a compound selected from N-acetyl cysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • BG2 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid- 19.
  • SARS severe acute respiratory syndrome
  • BG3 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid- 19.
  • SARS severe acute respiratory syndrome
  • BG4 is combined with a compound selected from N-acetyl cysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • BG1 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • BG2 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • BG3 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • BG4 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
  • SARS severe acute respiratory syndrome
  • PURPOSE Butylated hydroxy toluene, BHT or 2,6-di-tert-butyl-4-methylphenol is a molecule obtained by synthesis. It results from the reaction between p-cresol and isobutylene. This phenolic derivative contains a labile hydrogen which can be transferred to any oxidizable fatty substance. BHT is considered as an anti-oxidant as effective as vitamin E. Initially patented in 1947 for applications in the rubber industry, the classification of this additive is in the category of ingredients "generally recognized as safe" ( FAT).
  • BHT is also known as an antiviral agent acting on viruses such as the herpes virus or the polio virus (US4350707A).
  • Document US7696330B2 suggests BHT as a possible excipient in a composition intended to treat SARS-Cov, but BHT has never been described as an active principle, much less an anti-virus anti-SARS-Cov active principle, or anti-SARS-Cov-2.
  • beta-coronavirus infection such as SARS-Cov-2, SARS-Cov, or even MERS-Cov has never even been suggested.
  • the inventors have identified the antiviral activity of BHT on SARS-Cov-2, in particular when BHT is used with another compound.
  • the first results suggest that BHT alone markedly decreases the symptoms induced by this virus.
  • BHT reduces the infectious viral load.
  • BHT BHT-Cov2
  • a food supplement BHT-Cov2
  • its use to prevent or treat Covid-19 is particularly interesting.
  • the present invention relates to a composition for its use in the prevention and / or treatment of an infection by the coronavirus SARS-CoV-2 (Covid-19), characterized in that it comprises, in a suitable pharmaceutical carrier, a compound of formula 2,6-di-tert-butyl-4-methylphenol (BHT),
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • the present invention relates to a composition for its use in the prevention and / or treatment of a infection with the coronavirus SARS-CoV-2 (Covid-19), characterized in that it comprises, in an appropriate pharmaceutical vehicle, a compound BG1 or BG2 or BG3 or BG4.
  • the daily dosage of BHT may vary from 0.01 to 1000 mg / kg in adults per day.
  • the compositions contain 0.01; 0.05; 0.1; 0.5: 1.0; 2.5; 5.0; 10.0: 15.0: 25.0; 50.0; 100; 250.0. ; 500.0; 700.0; 800.0; 900.0; 1000.0; 1500.0; 2000.0; 3000.0; 4000.0 or 5000.0 mg / kg of BHT according to the invention.
  • the maximum oral dose of BHT is 1 g / kg by weight. http: //www.scc-que- bec .org / wp-content / uploads / 2017/08 / BHT-Marilou-N adeau-2016.pdf.
  • a composition according to the invention contains from about 0.01 mg to about 5000 mg of BHT, according to the invention, preferably from 1 mg to about 1000 mg of BHT, more preferably 300 mg or 500 mg of BHT.
  • An effective amount of BHT, alone or in a composition according to the invention is provided at a dosage level ranging from 0.0002 mg / kg to about 2 g / kg of body weight per day, in particular about 0.001. mg / kg to 900 mg / kg body weight per day; 75 to 400 mg / kg body weight per day, or 0.3 mg / kg body weight per day.
  • BHT is administered at a dose of 300 mg (or 500 mg) 3 times a day, in an individual weighing between 40 to 60 kg, or 500 mg 3 times a day_ ⁇ 200 mg, in an individual weighing between 61 at 90 kg, ⁇ 100 mg 3 times a day, or for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days.
  • the duration of treatment, the doses, the injection routes (po, in, sl, iv) will be evaluated according to the evolution of the symptoms of Covid-19.
  • These doses correspond to an anti-SARS-Cov-2 activity of BHT used as a drug.
  • a drug is any substance or composition presented as having curative or preventive properties with regard to human or animal diseases.
  • the BHT or the BHT in a composition comprising the BHT according to the invention can be used at a concentration of between 0.01 ⁇ M and 200 ⁇ M, or at a concentration of 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 20.0 ⁇ M.
  • the BHT or the BHT in a composition comprising the BHT according to the invention can be used at a concentration of between 0.01 mM and 200 mM, or at a concentration of 0.01; 0.05; 0.1; 0.5; 1.0: 2.5; 5.0; 10.0; 15.0; 20.0 mM.
  • New compositions comprising BHT and another antioxidant.
  • the invention also relates to novel compositions comprising BHT, another antioxidant, and an anti-inflammatory.
  • quercetin is particularly preferred.
  • the present invention relates to quercetin for the treatment or prevention of Covid-19.
  • the present invention relates to quercetin for the treatment or prevention of Covid-19, used at a dose of 200 mg three times a day.
  • the present invention relates to quercetin and BHT for the treatment or prevention of Covid-1; Quercetin at a dose of 200 mg three times a day in combination with BHT at a dose of 250 mg 1 to 3 times a day,
  • the present invention also relates to glutathione for the prevention or treatment of Covid-19,
  • the present invention also relates to N acetylcyteine associated with glutathione for the prevention or treatment of Covid-19.
  • the present invention also relates to Boswellia Serrata (with at least 40% of boswellic acids relative to the total weight) for the prevention or treatment of Covid-19,
  • the present invention relates to CASPEROME (R) for the prevention or treatment of Covid-19
  • the present invention also relates to N acetylcytein and Boswellia serrata (with at least 40% of boswellic acids relative to the total weight ) for the prevention or treatment of Covid-19
  • the present invention also relates to SOD for the prevention or treatment of Covid-19, SOD in combination with Zn, Cu, Mg,
  • the present invention also relates to CAT for the prevention or treatment of Covid-19,
  • the present invention also relates to GSH, in particular sublinthion (300mg) for the prevention or treatment of Covid-19,
  • the present invention also relates to ATP for the prevention or treatment of Covid-19,
  • the present invention also relates to SOD + CAT + GSH + ATP for the prevention or treatment of Covid-19.
  • the present invention also relates to mattokinase for the prevention or treatment of Covid-19,
  • BHT 2,6-di-tert-butyl-4-methyl-phenol
  • composition or kit comprising quercetin and BHT
  • BHT for its use according to the invention, characterized in that the BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS), and / or nattokinase, advantageously in a galenic formulation intended for oral administration.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • nattokinase advantageously in a galenic formulation intended for oral administration.
  • BHT 2,6-di-tert-butyl-4-methyl-phenol
  • active ingredients selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT ), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and. a combination of these active ingredients.
  • An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus
  • An active ingredient selected from Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dis- mutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • An active ingredient selected from N-acetylcysteine (NAC), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or the treatment of an infection with a SARS-CoV-2 coronavirus.
  • NAC N-acetylcysteine
  • CAT Catalase
  • SOD Superoxide dis- mutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • An active principle selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Super- oxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active principles, for prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • SOD Super- oxide dismutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • An active principle selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), Adenosine triphosphate (ATP), and a combination of these active principles, for prevention and / or the treatment of an infection with a SARS-Co V-2 coronavirus,
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dismutase
  • ATP Adenosine triphosphate
  • An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • An active principle selected from 2,6-di-tert-butyl-4-methyl-phenol (BHT), N-acetylcysteine (NAC), Bos- wellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD) ), gluthation (GSH), Adenosine triphosphate (ATP), a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
  • BHT 2,6-di-tert-butyl-4-methyl-phenol
  • NAC N-acetylcysteine
  • BS Bos- wellia Serrata
  • BS Nattokinase
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • BHT 2,6-di-tert-butyl-4-methyl-phenol
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • ATP Adenosine triphosphate
  • Composition comprising an active principle according to claim 1 or a kit comprising one month two active principle according to claim 1 or 2 and an acceptable excipient.
  • composition or kit according to claim 3 comprising BHT
  • composition or kit according to Claim 4 characterized in that the BHT is at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 100 mg to 900 mg, from 300 mg to 500 mg, advantageously administered at a dose of 0.1 mg / kg to Ig / kg, from 1 mg / kg to 0.1 g / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 90 mg / kg ; from 300 mg / kg to 500 mg / kg by weight; or again advantageously administered at a dose of 0.1 mg / individual to Ig / individual from 1 mg / individual to 0.1 g / individual, from 10 mg / individual to 800 mg / individual, from 100 mg / individual to 900 mg / individual: from 300 mg / individual to 500 mg / individual; or even more advantageously administered per day at a dose of 0.1 mg / individual to 1 g / individual of 1 mg / in dividu at O.lg
  • These doses can be administered for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, the length of time can be doubled or tripled, even quadrupled or multiplied by 5, 6, 7, 8, 9, 10, 11, 12.
  • composition or kit according to the invention characterized in that BS is administered to an individual at a dose of 250 mg, Acethylcysteine at a dose of 100 mg, BHT is at a dose of 150 mg, in combination with 'vegetable oil, the composition or the kit being adminsitré twice a day for 30 days,
  • composition or kit according to the invention characterized in that SOD is administered orally to an individual at a dose of 100 mg, Acethylcysteine at a dose of 50 mg, BHT is at a dose of 250. mg, in combination with vegetable oil, Nattokinase is administered at a dose of 50 mg, gluthation is administered at a dose of 50 mg, the composition or the kit being administered every 12 hours for 21 days .
  • composition or kit according to the invention characterized in that the SOD is administered orally to an individual at a dose of 100 mg, TAcethylcysteine at a dose of 50 mg, BHT is at a dose of 250 mg, in combination - National with vegetable oil, Nattokinase is administered at a dose of 50 mg, gluthation is administered at a dose of 50 mg, the composition or the kit being administered every 8 hours for 14 days.
  • composition or kit for its use according to any one of the preceding embodiments, characterized in that the BHT is further combined with TAdenosine Triphosphate (ATP).
  • ATP TAdenosine Triphosphate
  • BHT for its use according to one of the preceding embodiments, characterized in that the BHT is combined with Nattokinase and / or TAdenosine TriPhosphate (ATP).
  • BHT for its use according to the invention characterized in that the BHT is used at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 100 mg to 900 mg, from 300 mg to 500 mg, advantageously at a dose of 0.1 mg / kg to Ig / kg, from 1 mg / kg to 0. Ig / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 900 mg / kg; from 300 mg / kg to 500 mg / kg by weight.
  • BHT for its use according to the invention, characterized in that the BHT is administered at least by the oral route, and by the intravenous, sublingual, rectal route, by inhalation, to bring the BHT into contact with the SARS-Cov-2 from the start of contact.
  • BHT for its use according to the invention characterized in that the BHT is administered 1 to 3 times per day, advantageously from 1 to 3 times per day for at least 5 days to at least 14 days.
  • BHT for its use according to the invention, characterized in that the BHT is administered to individuals who may or may not have symptoms of Covid-19.
  • BHT for its use according to the invention, characterized in that the BHT is administered to an individual infected with SARS-Cov-2 exhibiting at least one symptom chosen from cough, dyspnea, fatigue, sore throat, gastrointestinal disorders, pain intestinal, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
  • BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms selected from cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration and / or by inhalation.
  • the present invention relates to a composition
  • a composition comprising BHT and an (other) anti-oxidant and a pharmaceutically acceptable carrier.
  • Antioxidants are molecules that have the property of preventing harmful chain reactions caused by free radicals.
  • BHT is considered an antioxidant, like SOD, CAT, G SH and NA C,
  • Antioxidant is understood to mean antioxidant molecules
  • CAT catalase
  • thioredoxin redox protein which acts as an antioxidant, essential for mammals
  • NAC is also considered as an antioxidant, it activates the production of GSH by cells.
  • Nattokinase (EC 3.4.21,62) which has fibrynolytic activity, (enzyme derived from a Japanese food called nattô. Nattô is produced by fermentation by adding the bacterium Bacillus natto, which also produces the enzyme, with boiled soy).
  • Quercetin or quercetol of formula 3,3 ', 4', 5,7-pentahydroxy-2-phenylchromén-4-one or 2- (3,4-dihy-droxyphenyl) -3,5,7-trihydroxy- 4H-chromen-4-one is an organic compound of the flavonoid family, more precisely of the flavonol subgroup. It is a secondary metabolite present in some plants
  • the antioxidants according to the invention are: Butylated hydroxytoluene, or 2,6-di-Ar / -butyl-4-methylphenol - (B HT) (antiviral, antioxidant), Glutathione (GSH): 2-amino acid- 5- ⁇ [2 - [(carboxymethyl) amino] - 1 - (mercaptomethyl) -2-oxoethyl] amino ⁇ -5 -oxopentanoic acid.
  • the GSH used in the prevention or treatment of Covid-19 is reduced glutathione, N-acetylcysteine or acetylcysteine (C 5 H 9 NO 3 S or R) - N-acetyl-L-cysteine) ( MAC) which is a lively nonessential acid, and stimulates the production of glutathione.
  • SOI Superoxide Dismutase
  • Cataiase is a heme oxidoreductase with classification EC No. 1.11.1.6.
  • Adenosine triphosphate is a nucleotide of the formula: [[(2R, 3S, 4R, 5R) -5- (6-aminopurin-9-yl) -3,4- dihydroxyoxolan-2-y!] Methoxy- hydroxyphosphoryl] phosphono hydrogen phosphate ATP potentiates the effects of anti-oxidants.
  • the antioxidants according to the invention combined with BHT can advantageously be GSH, CAT, SOD, or GSH, CAT SOD and N AC;
  • compositions according to the invention comprising SOD are optionally supplemented with Copper, Zinc, Magnesium, advantageously with Zinc.
  • Oxidative stress can have various origins: exogenous (atmospheric pollution, nanoparticles, etc.) or endogenous (energy metabolism). Often neglected, this last category is nonetheless significant.
  • cells need ATP, produced by the mitochondria. However, this production of ATP generates reactive oxygen species. The more cells are called upon, the more they manufacture ATP and generate oxidative stress.
  • Providing ATP without generating oxidative stress in the presence of BHT and SOD, CAT, GSH further improves the antiviral performance of the composition according to the invention on SARS-Cov-2.
  • the antioxidants according to the invention are advantageously GSH, CAT, SOD or GSH, CAT SOD and NAC, whether or not associated with ATP.
  • GSH glutination
  • BHT can also be combined according to the invention with an anti-inflammatory, preferably with Boswellia Serratata (BS).
  • BS Boswellia Serratata
  • Boswellia Serrata is a plant from which incense originates and produces. It is also known as Indian oli-banum, salai guggul, and sallaki in Sanskrit. Although anti-inflammatory drugs are strongly discouraged in the case of Covid-19, BS surprisingly acts, probably on the level of IL-6 that is generated in patients and the initiator of the cytokine storm. . https: /7dumas.ccsd.cnrs.fr/dumas-01845371/document
  • BHT in combination with BS is to be prescribed orally for a Covid-19 patient suffering from nausea or diarrhea.
  • Boswellia Fort titrated at 65% bosweilic acids is particularly interesting, Boswellia serrata is well known and described for example in document WO2011114350 or also in Gupta I, Gupta V, et al. Effects of Boswellia serrata gum resin in patients with bronchial asth- ma: results of a double-blind, placebo-controlled, 6-week clinical study./itir J Med Res 1998 Nov 17; 3 (11): 511-4, incorporated by reference.
  • the BS described in WO2011114350_ is particularly suitable for the formulations according to the invention, in particular the formulations suitable for the route of administration iv, si, by inhalation.
  • the BS according to the invention comprises at least
  • the product Casperome (R) is particularly advantageous for the invention.
  • BHT is combined with a compound selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine TriPhosphate (ATP), or with two of these compounds , or three of these compounds, or four of these compounds or five of these compounds.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH gluthation
  • ATP Adenosine TriPhosphate
  • BHT is combined with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS). BHT is combined with Boswellia Serrata (BS) for an oral dosage formulation.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • BHT is combined with Boswellia Serrata (B) as prepared and described in document, WO2011114350A3, advantageously, for an intravenous dosage formulation.
  • BHT for its use according to the invention is characterized in that it is combined with N-acetylcysteine and with GSH.
  • BHT for its use according to the invention is characterized in that it is combined with N-acetylcysteine and with BS.
  • compositions according to the invention comprise any one of the following combinations:
  • BHT, NAC BHT, GSH; BHT, SOD; BHT, CAT; BHT, AIT; BHT, BS;
  • BHT NAC, GSH; BHT, NAC, SOD; BHT, NAC, CAT; BHT, NAC, ATP; BHT, NAC, BS;
  • BHT GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS;
  • BHT SOD, CAT; BHT, SOD, ATP; BHT, SOD, BS;
  • BHT BHT, CAT, ATP; BHT, CAT, BS;
  • BHT NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT, NAC, GSH, BS;
  • compositions according to the invention comprise Time any of the following combinations:
  • BHT NAC
  • BHT GSH
  • BHT SOD
  • BHT CAT
  • BHT ATP
  • BHT BS
  • BHT N VI TÜ;
  • BHT GSH, SOD, NATTO; BHT, GSH, CAT, NATTO; BHT, GSH, ATP, NATTO; BHT, GSH, BS, NAT-TO;
  • BHT SOD, CAT, NATTO
  • BHT SOD, ATP, NATTO
  • BHT SOD, BS, NATTO
  • BHT BHT, CAT, ATP, NATTO
  • BHT BHT, CAT, BS, NATTO
  • the invention relates to BHT or any of the molecules named BG1, BG2, BG3 or BG4 combined with nattokinase (NATTO) for the prevention or treatment of Covid-19.
  • Nattokinase is a potent fibrinolytic agent
  • Nattokinase is an enzyme which helps to activate the breakdown of clots.
  • Nattokinase is an enzyme produced by the fermentation of natto, a traditional Japanese condiment. Natto comes from boiled soy beans which are seeded with a certain type of probiotic bacteria (Bacilius subtilis) lice to ensure fermentation.
  • Bactus subtilis probiotic bacteria
  • NATTOKINASE is used for the prevention or treatment of COVID-19, preferably at a dose of 50 mg per individual per dose or 50 mg / kg / day or 50 mg / kg / dose.
  • NATTOKINASE is used for the prevention or treatment of CO-VID-19, preferably at a dose of 100 mg per individual per intake or 100 mg / kg / day or 100 mg / kg / intake.
  • the invention relates to a preferably pharmaceutical composition
  • a preferably pharmaceutical composition comprising at least one active principle selected according to the invention from, BHT, BG1, BG2, BG3, BG4, SOD, CAT, GSH, ATP, BS, NATTO, a combination of these principles active ingredients and an excipient which is pharmaceutically acceptable if it is intended for the pharmaceutical composition.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising in a suitable pharmaceutical vehicle the BHT according to any of the combinations comprising the BHT according to the invention.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-ert-butyl-4-methyl-phenol and N-acetylcysteine (NAC) and either Boswellia Serrata (BS) or the GSH.
  • NAC N-acetylcysteine
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-tert-butyl-4-methyl-phenol and Nattokinase.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-tert-butyl-4-methyl-phenol and Nattokinase and N-acetylcysteine (NAC).
  • a pharmaceutical composition comprising in a suitable pharmaceutical carrier Natokinase and N-acetylcysteine (NAC) and either Boswellia Serrata (BS) or GSH.
  • NAC N-acetylcysteine
  • BS Boswellia Serrata
  • GSH GSH
  • a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and Boswellia Serrata (BS).
  • BS Boswellia Serrata
  • a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and GSH.
  • a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and BS and GSH.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2, 6-di-tert-butyl-4-methyl-phenol and a combination of SOD, CAT, GSH and ATR.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of formula 2,6-di-tert-butyl-4-methyl-phenol and a combination of Nattokinase, SOD, CAT, GSH and ATP.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and ATP.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and SOD, preferably SOD2.
  • a pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and CATALASE.
  • a pharmaceutical composition in the form of a kit comprising at least two of the active agents selected from BHT or BG1, or BG2 or BG2 or BG4, and nattokinase or ATP.
  • the vehicles which are pharmaceutically acceptable can in particular be isotonic, sterile saline solutions (monosodium or disodium phosphate, sodium, potassium, decalcium or magnesium chloride or the like, or mixtures of such salts), or dry compositions, in particular lyophilized, which, depending on the case, sterilized water or physiological serum, allow the constitution of injectable solutions.
  • sterile saline solutions monosodium or disodium phosphate, sodium, potassium, decalcium or magnesium chloride or the like, or mixtures of such salts
  • dry compositions in particular lyophilized, which, depending on the case, sterilized water or physiological serum, allow the constitution of injectable solutions.
  • compositions suitable for injectable use include sterile aqueous solutions or dispersions; formulations comprising sesame oil, peanut oil or an aqueous solution of propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the vehicle should be sterile and fluid as long as there is syringe ease. It must be stable under the conditions of manufacture and storage and must be preserved from the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising BHT as the free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • the dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • BHT (or compound BH1 to BG4) for its use according to the present invention can be formulated in a composition in neutral form or in salt form.
  • Pharmaceutically acceptable salts include salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases such.
  • the carrier can also be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.) , their appropriate mixtures and vegetable oils.
  • polyol eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.
  • the proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion and using surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium carbonate, sodium sorbic acid, thimerosal, etc.
  • isotonic agents for example sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example aluminum monostearate and preferably gelatin.
  • composition according to the invention by acting on the viral membranes, makes it possible to disrupt the virus as soon as it comes into contact with the composition and therefore to significantly reduce the “inoculum” and therefore to reduce the probability of dissemination of the virus in the virus. organism and that of host-to-host transmission.
  • composition according to the invention is that it does not contain any product harmful to the organism.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent along with several of the other ingredients listed above, as needed, followed by filtration sterilization.
  • the dispersions according to the invention are prepared by incorporating the sterilized agents of the present invention in a sterile vehicle which contains the basic dispersion medium and the other required ingredients from those listed above.
  • a sterile vehicle which contains the basic dispersion medium and the other required ingredients from those listed above.
  • typical preparation methods are vacuum drying and lyophilization techniques which yield a powder of BHT or BHT in combination of the present invention, plus any ingredient. or additional desired excipient from sterile filtered solution.
  • aqueous solutions For parenteral administration in an aqueous solution, the solution should be appropriately buffered if necessary and the liquid diluent should first be made isotonic with a sufficient amount of saline or glucose.
  • aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be used will be known to those skilled in the art.
  • Certain variations in dosage will necessarily occur depending on the condition of the subject being treated. In all cases, the person responsible for administration will determine the appropriate dose for each subject, the appropriate vehicle, the duration of treatment, the route (s) of injection (po, in, si, iv), evaluated in depending on the evolution of the symptoms of Covid-19.
  • a suppository of the present invention can be prepared by melt mixing a fatty acid tri-glyceride, an oil base consisting of a combination of one or more fatty acid glycerides at 4 0. -18, and if necessary, powders insoluble in the triglycerides of fatty acids, adding thereto the BHT alone or in the combination according to the invention, mixing and uniformly stirring the resulting mixture, and filling the mixture in a container, mold or the like, and cooling and solidifying the filling.
  • the method of mixing is not specifically limited.
  • composition according to the invention characterized in that the BHT is used at a dose of between 0.01 g / kg / day and 0.50 g / kg / day, preferably between 0.10 g / kg 0.25 g / kg / day.
  • composition according to the invention characterized in that the BHT is used at a dose of 300 mg to 500 mg or at a dose of 0.25 g / kg of body mass /) our, preferably at a dose ranging from 10 mg at the maximum dose of 0.25 g / kg (body weight) / day.
  • composition according to the invention characterized in that the BHT is used at a dose of between 0.01 mg / kg / day and 0.5 mg / kg / day, preferably between 0.1 mg / kg 0.250 mg / kg / day.
  • the pharmaceutical composition according to the invention is characterized in that the BHT is used at a dose of 300 mg or at a dose of 500 mg or at a dose of 0.25 mg / kg in weight / day. , preferably at a dose ranging from 10 mg to the maximum dose of 0.25 mg / kg in weight / day.
  • composition according to the invention characterized by an administration! to 12 times per day, preferably 1 to 5 times per day, more preferably 1 to 3 times per day.
  • composition according to the invention characterized in that it is administered at least 2 consecutive days, at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, at least 10 consecutive days, at least 15 consecutive days, at least 21 consecutive days, at least 28 consecutive days, for at least 1 month, for at least 2 months.
  • composition according to the invention characterized in that it is in a galenic form suitable for oral administration.
  • the combinations according to the invention are used for the prevention and / or treatment of infections with Coronavirus, advantageously with betacoronaviras, and more advantageously by S ⁇ RS-Cov, MERS-Cov, CO-VID-19, and more advantageously again the Covid-19.
  • a pharmaceutical composition according to the invention can be characterized in that it is used in the prevention and / or the treatment of an infection by a coronavirus, advantageously a betacoronavims, more advantageously SARS-CoV-2.
  • the invention relates to novel compositions characterized by comprising, in a vehicle suitable pharmaceutical, a compound of the formula 2,6-di-tert-butyl-4-methylphenol (BHT) and any of the antioxidants or dietary supplements selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), Glutathione (GSH), adenosine triphosphate (ATP) and Bowellia Serrata (BS) and a combination of these antioxidants or dietary supplements.
  • BHT 2,6-di-tert-butyl-4-methylphenol
  • the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adenosine triphosphate (ATP) and Bo-wellia Serrata (BS). , a combination of these compounds, for the prevention or treatment of Covid-19.
  • NAC N-acetylcysteine
  • CAT Catalase
  • SOD Superoxide dismutase
  • ATP adenosine triphosphate
  • BS Bo-wellia Serrata
  • the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Superoxide dismutase (SOD), GSH, adenosine triphosphate (ATP) and Bowellia Serrata (BS), a combination of these. compounds, for the prevention or treatment of Covid-19.
  • NAC N-acetylcysteine
  • SOD Superoxide dismutase
  • GSH adenosine triphosphate
  • ATP adenosine triphosphate
  • BS Bowellia Serrata
  • the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), GSH, adenosine triphosphate (ATP) and Bowellia Serrata (BS), a combination of these compounds. , for the prevention or treatment of Covid-19.
  • NAC N-acetylcysteine
  • CAT Catalase
  • GSH GSH
  • ATP adenosine triphosphate
  • BS Bowellia Serrata
  • the present invention relates to BHT, combined with a compound selected from N-aeetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), GSH and Bowella Serrata (BS), a combination of these compounds.
  • NAC N-aeetylcysteine
  • CAT Catalase
  • SOD Superoxide dismutase
  • GSH GSH
  • Bowella Serrata a combination of these compounds.
  • the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adenosine triphosphate (ATP) GSH, a combination of these compounds, for the prevention or treatment of Covid-19.
  • NAC N-acetylcysteine
  • CAT Catalase
  • SOD Superoxide dismutase
  • ATP adenosine triphosphate
  • the present invention relates to BHT, combined with a compound selected from Catalyst (CAT), Superoxide dismutase (SOD), GSH, adenosine triphosphate (ATP) and Bowella Serrata (BS), a combination of these. compounds, for the prevention or treatment of Covid-19.
  • CAT Catalyst
  • SOD Superoxide dismutase
  • GSH GSH
  • ATP adenosine triphosphate
  • BS Bowella Serrata
  • BHT of a composition comprising: BHT, NAC: BHT, GSH; BHT, SOD; BHT, CAT; BHT, ATP; BHT, BS; BHT, NA C, GSH; BHT, NAC, SOD; BHT, NAC, CAT; BHT, NAC, ATP; BHT, NAC, BS; BHT, GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS; BHT, SOD, CAT; BHT, SOD, ATP; BHT, SOD, BS; BHT, CAT, ATP; BHT, CAT, ATP; BHT, CAT, BS; BHT, ATP, BS; BHT, NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT NAC, GSH, BS: BHT, NAC, GSH, SOD; BHT, CAT;
  • BHT NAC, GSH; BHT, NAC, SOD; BHT NAC, CAT; BUT, NAC, ATP; BHT, NAC, BS;
  • BHT GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS;
  • BHT SOI
  • CAT BHT, SOD, ATP
  • BHT SOD, BS:
  • BHT BHT, CAT, ATP; BHT, CAT, BS;
  • BHT NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT, NAC, GSH, BS;
  • said composition for its use as cited above is characterized in that it comprises a combination of at least two of the following compounds: NAC, BS, GSH.
  • composition may, according to other embodiments, in particular comprise all the possible combinations of BHT with any one of the compounds, NAC, GSH, SOD, CAT, ATP BS, and combinations of said compounds.
  • the pharmaceutical composition for its use according to the invention comprises at least one effective amount of BHT.
  • the pharmaceutical composition for its use according to the invention comprises at least one effective amount of NAC.
  • the pharmaceutical composition for its use according to the invention comprises at least an effective amount of BS.
  • the pharmaceutical composition for its use according to the invention comprises at least an effective amount of GSH.
  • the pharmaceutical composition for its use according to the invention comprises at least an effective amount of SOD.
  • the pharmaceutical composition for its use according to the invention comprises at least one effective amount of CAT.
  • the pharmaceutical composition for its use according to the invention comprises at least one effective amount of ATP.
  • the pharmaceutical composition for its use according to the invention comprises at least one effective amount of NATTOKINASE.
  • the pharmaceutical composition for its use according to the invention comprises at least an effective amount of quercetin.
  • an effective amount is meant according to one aspect within the meaning of the invention (for a combination) an amount of compound, alone or with BHT in an undereffective amount, relative to the control (p ⁇ 0.049). , suffi- health to significantly inhibit (p ⁇ 0.05 t or ki2 test) the proliferation and / or replication of the SARS-Cov-2 coronavirus, and / or the development of viral infection within the organism, and / or the appearance of symptoms representative of a severe stage of Covid-19. This inhibition can be quantified, for example by measuring the viral titer as presented in the examples of the present application.
  • a therapeutically effective amount of BHT is meant a sufficient amount of BHT, to reduce the frequency and / or the intensity of a symptom induced by SARS-Cov-2 with respect to the frequency and / or the intensity of the symptom measured initially and without treatment or / and still being able to reduce the viral load of SARS-Cov-2 measured or evaluated in a specific place of the organism (nose, mouth, throat, pulmonary exudate, rectum ) or viraemia (viral load in the blood) - measured initially without treatment with a reasonable benefit / risk ratio applicable to any medical treatment.
  • "therapeutically effective amount" of BHT is the amount reducing by at least 10% to 20% the frequency and / or intensity of a symptom induced by SARS-Cov-2 (and / or) or the viral load, more preferably at least 30%, even more preferably at least 50%.
  • the level of therapeutically effective dose specific to a particular subject will depend on various factors including the nature and severity of the symptom, viral load, specific activity of BHT, specific composition used, age, the subject's body weight, general health, sex and diet; the time of administration, the route of administration and the duration of treatment; other drugs that may be used.
  • antiviral activity or “antiviral action” are understood to mean an action on the virus or on its infected target cells, in particular the faction of inhibiting the replication cycle of the virus or its ability to infect. and to replicate in host cells, this antiviral effect being obtainable by modulating a number of genes in target cells.
  • antiviral activity or “antiviral action” are understood to mean an action of BHT or of the compositions according to the invention on one symptom or more symptoms in individuals infected with SARS-Cov. -2; more generally, one symptom or several symptoms in individuals infected with a coronavirus potentially capable of inducing acute respiratory distress.
  • the expression “antiviral activity” or “anti-viral action” outfits is understood to mean an action of BHT or of the compositions according to the invention on the percentage of individuals infected with SARS-Cov-2.
  • Antiviral activity means, for example, a reduction in viral load, normalization of fever (return to normal body temperature, i.e. around 37 ° C plus or minus 0.5 ° C, normalization of blood gases, return to normal appearance. normal bowel movements, stop nausea, decrease coughing, decrease IL-6 in the blood.
  • composition for its use according to the invention comprises BHT and / or another antioxidant and that it can therefore also comprise other active compounds, in addition to the appropriate pharmaceutical vehicle.
  • BHT and another antioxidant, another anti-inflammatory, or mixtures thereof, can be used in therapy alone, or in combination with at least one other active agent.
  • They may be compounds making it possible to improve the activity of these compounds, or else other active agents known for a particular activity.
  • additional active compounds may be chosen from the pharmaceutical classes of agents cited in application WO 2015/157223, namely from antibacterial agents, antiparasitic agents, neurotransmission inhibitors, estrogen receptor inhibitors, inhibitors of DNA synthesis and replication, protein maturation inhibitors, kinase pathway inhibitors, cytoskeletal inhibitors, lipid metabolism inhibitors, anti-inflammatory agents, ion channel inhibitors, inhibitors for apoptosis and cathepsin inhibitors.
  • These active compounds may in particular be chosen from antibacterial agents, ion channel inhibitors, immunosuppressive agents and antiviral agents.
  • an antiviral agent mention may be made, for example, of acyclovir and hydroxychloroquine.
  • the pharmaceutical composition for its use in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus further comprises T ATP.
  • the pharmaceutical composition for its use in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus comprises, BHT and, in addition to a combination of at least two compounds chosen from G SH, CAT SOD, NAC, at least one other antiviral agent.
  • an antiviral agent denotes a compound which acts on a virus, by inhibiting and / or slowing down and / or preventing the associated viral infection.
  • Antiviral agents are classified into different categories based on their mode of action. We can cite in particular:
  • nucleotide analogs which interfere with or stop the synthesis of DNA or RNA; as well as inhibitors of enzymes involved in DNA or RNA synthesis (helicase, replicase);
  • RNA viruses such as protease inhibitors, helicase inhibitors, and inhibitors of cell entry of the virus.
  • SARS-CoV-2 in target cells.
  • the pharmaceutical composition is characterized in that the other antiviral agent is chosen from the following compounds: ribavirin, an interferon, or a combination of the two.
  • an interferon or “interferon” is understood to mean a compound belonging to the family of interferons, which are glycoproteins secreted by cells of the immune system.
  • Interferons are a family of small protein molecules with a molecular weight of about 15,000 to 21,000 dations. Three major classes of interferons have been identified: alpha, beta and gamma. These 3 main classes are not themselves homogeneous and can group together several different molecular species of interferon. More than 14 genetically different human alfa interferons have been identified.
  • the interferon used will be a recombinant polypeptide, synthesized in the laboratory.
  • interferon used will be recombinant interferon afa-2b, the efficacy of which on viral replication in vitro and in vivo has been demonstrated.
  • antiviral agents are commercially available, and their conditions of use are described in reference works such as The Vidal Dictionary.
  • the pharmaceutical composition for its use according to the invention will consist of a combination of active agents as mentioned above, and a suitable pharmaceutical vehicle.
  • a medicament is understood to mean any substance or composition presented as having curative or preventive properties with regard to human or animal diseases.
  • the pharmaceutical composition will consist of one of the combinations of compounds as mentioned above, and a suitable pharmaceutical vehicle.
  • the invention also relates to the products according to the invention, dosages of the products according to the invention, dosages of the products according to the invention, advantageous routes of administration of the products according to the invention, for the prevention and / or treatment of Covid-19.
  • compositions for the use according to the present invention are suitable for oral (po), sublingual, inhalation, subcutaneous, intramuscular, intravenous (iv), transdermal, ocular or rectal, advantageously oral, iv and by inhalation.
  • the products or compositions according to the invention are administered by at least one route of administration or by several routes of administration, to all patients or persons liable to be infected with the SARS-Cov2 virus.
  • the products or the compositions according to the invention can be administered:
  • intrarectal and / or oral intragastric, sublingual
  • signs of infection of the intestine nonausea, diarrhea, presence of virus in the nose, in the faeces
  • the composition for its use according to the invention is characterized in that it is in a galenic form intended for administration by inhalation.
  • Inhalation refers to absorption through the respiratory tract. It is in particular a method of absorbing compounds for therapeutic purposes, certain substances in the form of gas, micro-droplets or powder in suspension.
  • compositions by inhalation that is to say by the nasal and / or oral, or rectal routes is well known to those skilled in the art.
  • the dosage form considered here is therefore chosen from: a powder, an aqueous suspension of droplets or a solution under pressure.
  • BHT alone or in combination for use against Covid-19 according to the invention can be characterized by: a galenic formulation suitable for oral administration (sublingual, per os); a dosage formulation suitable for administration by inhalation, a dosage formulation suitable for intravenous administration, a dosage formulation suitable for intrarectal administration, preferably oral administration to all individuals showing symptoms or no symptoms , and more preferably oral administration for patients suffering from at least one intestinal disorder and still more preferably intravenous or inhalation administration for patients suffering from severe acute respiratory syndrome, and still more preferably intravenous and via administration. inhalation for patients with severe acute respiratory syndrome.
  • BHT for its use against Covid-19 characterized by use in an individual infected or not with Covid-19 and not showing any symptoms, advantageously in a galenic formulation suitable for oral and rectal administration .
  • BHT for its use against Covid-19 according to the invention characterized by use in an individual infected with S ⁇ RS-Coe-2 exhibiting symptoms such as cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a dosage formulation suitable for oral administration.
  • BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration and / or by inhalation.
  • BHT at a dose of 300 mg; Acetylcysteine in a dose of 200 mg; Boswellia serrata at a dose of 500 mg
  • BHT at a dose of 300 mg
  • Acetylcysteine in a dose of 200 mg
  • Boswellia serrata at a dose of 500 mg in a dosage formulation suitable for oral administration (orally (po)).
  • BHT at a dose of 300 mg
  • Acetylcysteine in a dose of 200 mg
  • Boswellia serrata at a dose of 500 mg in a dosage formulation suitable for oral (po) administration twice or three times a day for 10 days.
  • BHT at a dose of 300 mg
  • Acetylcysteine in a dose of 200 mg
  • Boswellia serrata at a dose of 500 mg in a galenic formulation suitable for oral administration (orally (po) twice a day for 10 days, advantageously in individuals infected or not with SARS-Cov-2 or in pa - tients during the Covid-19 infection, even more advantageously in patients with digestive disorders (diarrhea, nausea) during the Covid-19 infection,
  • BHT at a dose of 500 mg
  • Glutathione (GSH) at a dose of 200 mg
  • Acetylcysteine in a dose of 300 mg.
  • BHT at a dose of 500 mg
  • Glutathione (GSH) at a dose of 200 mg
  • Acetylcysteine at a dose of 300 mg, two or three times a day for 10 days.
  • BHT at a dose of 500 mg
  • Glutathione (GSH) at a dose of 200 mg
  • Acetylcysteine at a dose of 300 mg, two or three times a day for 10 days in a galenic formulation suitable for oral, intravenous, and / or inhalation administration
  • BHT at a dose of 500 mg
  • Glutathione (GSH) at a dose of 200 mg
  • Acetylcysteine at a dose of 300 mg, two or three times daily for 10 days in a dosage formulation suitable for oral, intravenous, and / or inhalation administration, in patients suffering from severe acute respiratory syndrome during of Covid-19 infection.
  • BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg.
  • BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg, in a galenic formulation suitable for intravenous, oral and / or for inhalation administration.
  • BHT at a dose of 500 mg
  • Glutathione at a dose of 100 mg
  • SOD Superoxide Dismutase
  • CAT Catalase
  • BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg, in a dosage formulation suitable for intravenous, oral and / or for inhalation administration, three times a day for 10 days to a month, preferably in patients during the Covid-19 infection, advantageously in patients suffering from severe acute respiratory syndrome during Covid-19 infection.
  • BHT alone or in combination according to the invention for its use according to the invention characterized by use 1 to 3 times per day.
  • BHT alone or in combination according to the invention characterized by use according to the invention for at least 5 days to at least 10 days.
  • BHT alone or in combination according to the invention characterized by a use according to the invention for at least less 5 days to at least 14 days.
  • a composition according to the invention can be a food composition, a pharmaceutical or veterinary composition.
  • the invention also relates to a:
  • composition according to the invention characterized in that it is administered to individuals infected or not by the SARS-CoV-2 coronavirus, advantageously exhibiting no symptoms, more advantageously still orally.
  • composition according to the invention characterized in that it is used in patients infected with the S.4RS-CoV-2 corona virus and exhibiting no symptoms, or at least one symptom among cough, dyspnea, fatigue, sore throat , gastrointestinal disturbances, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
  • Composition according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for administration by the intravenous route and / or by inhalation.
  • composition according to the invention for its use against Covid-19 in a method of treatment according to the invention.
  • Composition comprising BS according to the invention for its use in a method of treating Covid-19 according to the invention characterized in that they are administered only orally.
  • compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered enterally: oral (po), sublingual (sl), by inhalation (in), intrarectal (ir ), or by parenteral, intraperitoneal (ip), subcutaneous (sc), intramuscular (im), intravenous (iv) route.
  • the pharmaceutical compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered enterally: oral (po), sublingual (si), by inhalation (in), intrarectal ( ir), or intravenously (iv), more preferably, the pharmaceutical compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered orally (po) and / or intrarectal (ir) for infections of the “low” GI tract by S ⁇ RS-COV-2; sublingually (si), inhalation (in) for infections of the “upper” GI tract by intravenous (iv) SARS-COV-2, and orally (po) intrarectal (ir) and sublingual (si), by inhalation (in) for all stages of Covid-19, early stage (sore throat, rhinorrhea, nausea, diarrhea), headache, advanced stage (respiratory insufficiency), in patients at risk of developing a severe form (people elderly ( ⁇
  • BHT alone or in combination with NAC and BS can be administered orally in people at risk of contracting SARS-Cov-2 (prevention), in asymptomatic people (SARS-Cov- 2 positive without symptoms, or having at least one sign of infection with SARS-Cov-2, early, advanced, severe uninhibited.
  • BHT alone or in combination either with NAC and GSH; either with GSH, SOD, CAT and ATP can be administered orally (pi, si, intranasal (in) and / or intravenously iv in people susceptible to contracting SARS-Cov-2 (prevention), in asymptomatic people (SARS-Cov-2 positive without symptoms, or with at least one sign of infection with SARS-Cov-2, early, advanced, severe not intubated.
  • the active doses of BHT can be 300 mg 3x / d or 500 mg 3x / d alone or in combination with the NAC 200 mg or 300 mg the BS is at the dose of 500 mg and at least 40% acid (s ) boswellic (s) GSH 100 or 200 mg SOD is at a dose of 200 mg
  • CAT is at a dose of 100 mg
  • ATP is at a dose of 100 mg according to one embodiment, the doses are expressed in mg / kg or in 0.1 ⁇ mg / kg mg / kg means mg / kg by weight.
  • Non-limiting examples of doses, dosages and suppliers of active principle (s) (for the oral or sublingual route in particular) of the various compounds of the invention are described below:
  • BHT is administered at a dose of 300 mg _ ⁇ 150 mg (or 500 mg) 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ⁇ 250 mg 3 times per day, in an individual weighing 61 to 90 kg, for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with MAC at a dose of 200 mg.
  • BHT is administered at a dose of 300 mg _ ⁇ 150 mg (or 500 mg) 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ⁇ 250 mg 3 times per day, in an individual weighing 61 to 90 kg, for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with NAC at a dose of 300 mg.
  • the BHT is administered at a dose of 300 mg _ ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ⁇ 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 100 mg.
  • the BHT is administered at a dose of 300 mg 150 mg, 3 times per day, to an individual weighing between 40 to 60 kg, or 500 mg . ⁇ 250mg 3 times a day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 200 mg.
  • BHT is administered at a dose of 300 mg 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 300 mg.
  • GSH reduced-active glutation: 100 mg (EMS Duhec) or 200 mg (150 mg Energetica Natura Belgium with 50 NAC, to be adjusted)
  • BHT is administered at a dose of 300 mg ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 and 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 100 mg.
  • the BHT is administered at a dose of 300 mg _ + 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ⁇ 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 200 mg.
  • the daily dosage of SOI may vary from 0.01 to 1000 mg in adults per day.
  • the compositions contain 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 25.0; 50.0; 100; 250.0; 500.0 mg of SOD; preferably from 3 mg to approximately 300 mg of SOD / d or more advantageously from 100 to 200 rng / d or from 10 to 20 mg / d
  • SOD 200 mg Used in combination with BHT as a drug that can boost immunity. Pure SOD (EASY NUTRITION / LABO SP) or with BHT 300 or 500mg; 2 tablets of SOD 100 mg per dose -for stimulation of immunity, in particular for the treatment of Covid-19.
  • the daily dosage of SOD may vary from 0.01 to 1000 mg in adults per day.
  • the compositions contain 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 25.0; 50.0; 100; 250.0; 500.0 mg of SOD; preferably from 3 mg to about 300 rng of SOD / d
  • An effective amount of SOD is provided at a dosage level ranging from 0.002 mg / kg to about 2 mg / kg of body weight per day, in particular from about 0.1 mg / kg to 1 mg / kg of body weight per day. our; preferably 200mg 3x / d or 200mg 5x / d.
  • the BHT is administered at a dose of 300 mg _ ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with SOD at a dose of 200 mg.
  • An effective amount of CAT is provided at a dosage level ranging from 0.01 mg / kg to about 1 g / kg of body weight per day, in particular about 0.1 mg / kg to 500 mg / kg of body weight per day ; preferably 100mg 3x / d or 100mg 5x / d; 250 mg 2x / d or 3x / d.
  • Catalase Newpharma is a good source of usable catalase, x / d means times per day
  • the BHT is administered at a dose of 300 mg ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg. ⁇ 250 mg 3 times per day, in an individual weighing between 6! to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with CAT at a dose of 100 mg.
  • the BHT is administered at a dose of 300 mg _ ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 30 mg.
  • the BHT is administered at a dose of 300 mg _ ⁇ 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ⁇ 250 mg 3 times per day, in an individual weighing between 61 and 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 100 mg.
  • the BHT is administered at a dose of 300 mg _ + 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 400 mg.
  • the dose of ATP according to the invention can vary from 1 mg to 1000 mg, preferably from 10 to 100 mg, for example 400 mg.
  • ATEPADENE 30 mg / bottle is a metering source of ATP for its use according to the invention.
  • BS the dose of BS according to the invention can vary from 5 mg to 5000 mg, preferably from 10 to 500 mg, eg 350 mg.
  • Galenic form for oral administration CASPEROME (R).
  • the dose of Nattokinase according to the invention can vary from 1 mg to 500 mg, preferably from 10 to 100 mg (2000 FU), for example 100 mg or 50 mg.
  • QUERCETINE the dose of quercetin according to the invention can vary from 1 mg to 1000 mg, preferably from 10 to 100 mg (2, for example 100 mg or 200 mg, and more advantageously 200 mg 3 times a day.
  • the present invention also relates to a kit product comprising: BHT in a formulation, and at least any one of the active ingredients selected from, G.4TR in a separate formulation,
  • Quercetin in a separate formulation or a combination of three, four, five, six, seven or all of these compounds.
  • the present invention also relates to a kit product comprising: BHT in one formulation, ATP in a separate formulation,
  • GSH in a separate formulation, or a combination of two, three, four, five or six of these compounds.
  • Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, subcutaneous, transdermal, topical, intraperitoneal implants. , intramuscular, intravenous, intrathecal, intranasal and rectal administration forms.
  • the invention relates, according to one aspect, to a composition according to the invention, comprising BHT and at least one other composition comprising a compound selected from CAT, GSH, SOD, ATP, BS and a combination of these compounds. , for simultaneous, separate or sequential use to prevent and / or treat infection with the SARS-CoV coronavirus, in humans or animals.
  • Such a combination product could be used in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus, in the context of simultaneous, separate or sequential use.
  • the at least two active agents included in the combination product can be administered simultaneously, separately or sequentially. It is understood that all the combinations of two, three, four, five or six active compounds mentioned above can each be in the form of a combination product, in a kit, that is to say that the two, three, four or five active compounds can be administered simultaneously, separately or sequentially, to prevent and / or treat infection with the SARS-CoV-2 coronavirus.
  • the invention also relates to a therapeutic method for the prevention and / or treatment of an infection by the coronavirus SARS-CoV-2 in humans, in which, in addition to BHT, an effective amount is administered to a patient.
  • a method of preventing and / or treating a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome comprising the provision of BHT or of a composition according to the invention.
  • a method of preventing and / or treating a disease linked to infection with a coronavirus capable of causing severe acute respiratory syndrome comprising the provision of BHT or of a composition according to the invention that (s) ) comprising BS being intended for oral use only.
  • a method of preventing and / or treating a disease associated with coronavirus infection capable of causing severe acute respiratory syndrome comprising administration by mouth, iv or by inhalation, or by a combination of the routes of administration in individuals with or without symptoms, of BHT or of a composition according to the invention.
  • Method for the prevention and / or treatment of a disease linked to the infection by a coronavirus capable of causing a severe acute respiratory syndrome comprising oral administration in all individuals with or without symptoms, of BHT or of a composition according to the invention.
  • Method of preventing and / or treating a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome comprising administration of BHT or of a composition according to the invention, in an individual, in particular an individual exhibiting at least one of the symptoms selected from cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, advantageously oral administration and intravenously in individuals presenting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, or administration by the oral route and by inhalation in individuals exhibiting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, respiratory syndrome severe acute, or oral, intravenous and inhalation administration in individuals exhibiting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat
  • compositions according to the invention could be modified; any other compositions according to the invention could be.
  • individual is meant a living being, preferably a human being.
  • a comavirus preferably a betacoronavirus, more preferably a virus capable of inducing an acute respiratory syndrome, even more preferably a SARS-Cov, or MERS-Cov , and even more pref- er a SARS-Cov-2) regardless of the degree of the disease - the stage of the disease, the presence or absence of symptoms.
  • a comavirus preferably a betacoronavirus, more preferably a virus capable of inducing an acute respiratory syndrome, even more preferably a SARS-Cov, or MERS-Cov , and even more pref- er a SARS-Cov-2
  • the upper gastrointestinal tract mucosa being the nasal mucosa, the throat, and / or the pulmonary mucosa being especially those with nausea, those with at least one symptom among fever, body aches, fatigue, all dryness, intestinal disturbances (vomiting, nausea, diarrhea) those with diarrhea; elderly patients (over 40 years old, 50 years old, 60 years old, 70 years old, 75 years old).
  • compositions according to the invention can be of pharmaceutical type, intended to be administered to a human being, or of veterinary type, intended to be administered to non-human animals.
  • compositions according to the invention are in particular intended for mammals, such as the pangolin or the bat, or even the golden hamster.
  • Method for the prevention and / or treatment of a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome comprising oral administration in individuals exhibiting symptoms such as gastrointestinal disorders , intestinal pain, diarrhea.
  • the invention also relates in one aspect to products: 1) BHT, NAC, BS
  • a preparation (dose) formulated for the oral route can be:
  • Boswellia serrata (with at least 40% of boswellic acids relative to the total weight): 500 mg
  • the dosage of this composition by way of example can be one dose two to three times a day.
  • Formulations suitable for inhalation and / or intravenous use form part of the invention.
  • Boswellia serrata (with at least 40% of boswellic acids relative to the total weight): 5q0 rng
  • the dosage of this composition as an example can be a dose two to three times per day.
  • the dosage of this exemplary composition can be one dose two to three times per day.
  • a preparation (dose) formulated for the oral or iv or inhaled route can be:
  • Dosage 3 times a day in 250 ml of physiological solution.
  • a preparation (dose) formulated for the oral or iv or inhaled route can be
  • Dosage 3 times a day in 250 ml of physiological solution.
  • the compounds were tested in vitro, at a concentration conventionally used in the literature, in the context of an infection of VERO-E6 cells by the strain of SARS-CoV-2 Italy, Genbank accession No. MT066156.
  • VERO-E6 cells are derived from monkey kidney epithelial cells, and are susceptible to infection with SARS-CoV-2.
  • the infection parameters were determined beforehand in order to obtain the best conditions for observing a possible antiviral effect.
  • the VERO-E6 cells were infected at an MOI (Multiplicity of infection) of 0.5 for a period of 24 hours at 37 ° C. under 5% C02, in the presence or absence (diluent) of compounds tested.
  • MOI Multiplicity of infection
  • the infectious titers (log10 DITC50 / ml or DITC50 / ml) were determined in the culture supernatants of infected cells.
  • the infectious titers are indicated TCID50 / mL (50% Tissue Culture InfectivenDose) in FiglA (log10 TCID50 / mL) and Fig IB (TCID50 / mL). They were obtained by the technique of infection by limiting dilution and calculated by the method of Reed and Muench.
  • a cytotoxicity test and a coronaviras quantification test are carried out after 24 h of incubation.
  • the cytotoxicity of the various compounds is determined for each test in a plate of uninfected cells by a viability test (MTS test, Promega).
  • MTS test transforms a substrate (MTS tetrazolium) into a product (Formazan), soluble in the medium and whose absorbance measured at 490 nm proportionally reflects the number of living cells.
  • the ratio of the absorbance in each well to the average absorbance of the wells of the control cells (not treated with the compounds) is calculated and indicated on the diagrams as an index of cell viability (relative cell viability).
  • the effect on viral production in vitro is measured by determining the infectious titers (TCID50 / mL) carried out on VERQ-E6 cells, the titers being calculated according to the technique of Reed and Muench.
  • the ratio of the infectious titer in each condition was expressed as a function of the infectious titer measured in the control condition (without treatment).
  • infectious titers measured under the experimental conditions in the presence of the compounds tested are greatly reduced compared to the control condition, where the cells have been infected but not treated.
  • BHT (10 ⁇ M), NAC (12.5 ⁇ M) and BS (15 ⁇ M) allow a reduction of 78.8%, 23.4% and 27.8% respectively in infectious titers compared to the control (cf. . Figure 1).
  • NAC reduces 80 to 93% of infectious titers.
  • the results show an activity of BHT on target cells (expressing the SARS-Cov-19 receptor and very reduced on cells not expressing the SARS-Cov-2 receptor in a detectable manner (flow cytometry). .
  • SARS-Cov-19 is infectious on rem (Figure 1), A549 lung ( Figure 3) and HT29 intestine ( Figure 5) cells.
  • the efficacy of the compositions used is dose dependent (not shown).
  • the SARS-Cov-2 virus causes interstitial alveolar pneumonia and in most severe forms acute respiratory failure (ARI), which is initially hypoxic (mismatch between tissue oxygen needs and intakes, and Hypocapnia (abnormally low levels of of carbon (carbon dioxide) in the blood, due to an increase in gas exchange between air and blood in the lungs (pulmonary ventilation).
  • ARI acute respiratory failure
  • MOFS multiple organ collapse syndrome
  • Glutathione 2-amino-5- ⁇ [2 - [(carboxymethyl) amino] - 1- (mercaptomethy ⁇ ) -2-oxoethyl] amino ⁇ -5-oxopentanoic acid
  • N-acetylcysteine or acetylcysteine (C5H9N03S or R) -N-acetyl-L-cysteine) (NAC) is a non-amino acid essential, which stimulates the production of glutathione, an antioxidant
  • SOD Superoxide Dismutase
  • This enzyme is involved in the oxidative explosion and is also an essential component of the free radical elimination mechanism.
  • Catalase is a haem oxidoreductase (EC No 1.11.1.6)
  • compositions and formulations iv, po, in, sublingual amount per formulation BHT 300 mg
  • intravenous (iv) dose three times a day for ten days consisting of: BHT: 500 mg; Glutathione (GSH): 200 mg ; Acetylcysteine 300 mg or
  • BHT 500 mg
  • Glutathione 100 mg
  • SOD Superoxide Dismutase
  • CAT Catalase
  • Clinical classification Patients were grouped into four categories: 1) asymptomatic, 2) with infection of the lower gastrointestinal tract, 3) upper respiratory tract infection (URTI) in cases of rhinitis, pharyngitis or isolated low-grade fever and myalgia, and 4) lower respiratory tract infections (LRTI) for symptoms of pneumonia or bronchitis DESIGN
  • URTI upper respiratory tract infection
  • LRTI lower respiratory tract infections
  • Double blind Double (Participant, caregiver) Description: The intervention-QNS and the isocaloric-NQS are served in opaque glasses of the same shape and color, the caregivers (nurses, dietitians) will not know the members of each group nor the nature or composition of TONS, objective: supportive treatment
  • CRP Measurement of the partial pressure of oxygen (Pa02) / (Fi02) (fraction of oxygenated F inspired, Fi02) ratio
  • Measure of organ failure 6 variables, each representing an organ system (one for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems), and rated from 0 (normal) to 4 (high degree malfunction / failure). Thus, the maximum score can vary from 0 to 24.
  • kidney disease not more than 200 mg of BHT in total / day pregnant women
  • the sublingual and / or oral route is particularly interesting, even if the formulations are not easy to prepare probably in connection with the properties of BHT.
  • the virus is incubated for 20 to 30 minutes in the presence of products 1 and 2.
  • the mix is then used to infect a culture of VeroE6 TMPRSS2.
  • the inhibition of viral replication is defined by real time RTPCR quantifying the number of copies of the viral genome with or without the compound tested. 0% inhibition corresponding to viral re-application without inhibitor, 100% corresponding to uninfected cells.
  • Products 1 and 2 exhibit moderate antiviral activity in the 10- 50 ⁇ M range. antiviaral activity is detectable from ImM
  • Another model of infection in vivo is used: the golden hamster infected with SARS-COV2 as described in Driouich, JS ,, Cochin, M., Lingas, G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun 12, 1735 (2021). https://doi.org/10.1038/s41467-021-21992-w.
  • BHT alone administered intranasally makes it possible to reduce the number of individuals developing an acute respiratory syndrome by 50% and allows the animals to maintain their weight
  • This test is intended for the initial screening of potentially antiviral compounds.
  • the antiviral activity of the compound is evaluated on the basis of the ability of the compound to prevent the virus from causing viral CPE in the culture of mammalian cells. Eight dilutions of the test compound will be tested and the effective antiviral concentration will be determined by regression analysis.
  • the toxicity of the test compound is determined over the time interval.
  • the CPE is determined by microscopic observation of cell culture monolayers as well as by absorption of neutral red dye.
  • the miniature pig shares many physiological similarities with humans, offers several breeding and handling advantages (over non-human primates), making it an optimal species for preclinical experimentation.
  • This project offers several examples drawn from current research in the hope of convincing our proponent that the porcine animal model has gained considerable importance in biomedical research in recent years.
  • the examples cited are drawn from the following areas of investigation: the physiology of the immune response to Corona Family Member viruses, where pigs are used to study immune abnormalities and / or efficacy against viral attacks following treatment with our new compound.
  • the current project is intended to observe and study the effect of our treatment solution against the PEDV virus, therefore for this study 15 pygmy pigs will be used for both the group study and the control.
  • Each pigmy pig will be inoculated with the virus and will then be evaluated after treatment daily and for a period of 2 weeks.
  • Each pygmy pig will be sacrificed and a histopathological examination will be carried out to confirm the tissue and molecular state of each animal.
  • Pigs receiving the drug or dummy treatment will be randomized using a random number generator.
  • the staff who administer the drug or sham treatment will be different from those who assess the effects.
  • Mice and subsequent blood and tissue samples will be labeled so that personnel assessing the effects of treatment and analyzing the results do not know who received the drug or dummy treatment.
  • the streptozotocin-induced hypercholesterolemic diabetic pig model has been used successfully to induce coronary atherosclerosis and shares many features of the pathophysiology of hyperlipidemic vasculopathy in humans. There are various modifications to this pattern involving different regimens of streptozotocin and changes in diet, but vascular lesions can include atheromatous plaques in large vessels as well as hypertrophic changes in the walls of smaller vessels. [1], Compared to total P450 for dogs, monkeys and humans noted some differences, of course, with higher flavin monooxygenase (FMQ) dependent oxygenation activities in minipig hepatic microsomes and CYP activity. -2A lower.
  • FMQ flavin monooxygenase
  • group 1 oral administration, BHT, Ace, Bowellia serrata
  • 2 oral administration BHT, Ace, SOD, NAT, Glu
  • 3 IV administration BHT, Ace, SOD, NAT, Glu
  • the animals will be divided into 3 groups each with a control group and a study group.
  • the animals will be sacrificed after administration of ketamine / xylazme, the internal organs, heart, liver, spleen, lungs and kidney tissue of the pigs will be photographed and weighed. .
  • the cytokine / interleukin profile and. Viral load will also be measured in each histological sample to determine the content of blood cells from different groups of both study and control groups.
  • results will therefore be evaluated by measuring the weight between the two groups of animals at the time of the last treatment, the number of blood cells and cytokines and interleukins will also be evaluated between the 2 groups thus WBC, LY, MO, MPV, MCH and PLT content plus TNF- ⁇ , IFN- ⁇ , IL-6, IL-2 IL-1 ⁇ , IL-10-D-dimers and. viral load will be, evaluated and collected.
  • CLINICAL PROTOCOL ASSUMPTION Patients Patients hospitalized with confirmed COVID-19 were included in this study if they met two main criteria: i) age> 12 years; ii) The carriage of SARS-CoV-2 documented by PCR nasopharyngeal swab on admission regardless of their clinical condition.
  • the patients were grouped into three categories: asymptomatic upper respiratory infection
  • the COVID-19 syndrome follows, at the pathophysiological level, two essential determinants which, with an integrated and reciprocal amplification mechanism, consist of: * systemic replication and propagation of the virus -> multiorgan / multisystem tissue invasion with cytolysis / apoptosis massive uncontrolled expression and amplification of the host's immune-inflammatory response (SIRS - MQDS - MOFS) ⁇ malignant panendothelitis with systemic microvascular occlusion COVID-19 ⁇ clinical classification COVID-19 syndrome can be classified as clinical level, in the following clinical tons: • Mild (80%) ⁇ discovery of fever, cough, sore throat, asthenia and absence of acute respiratory failure (the normal minimum value of Pa02 detected with analysis of blood gases in ambient air is assumed ⁇ 80 mmHg).
  • Part A provides.
  • the solution was prepared in advance according to the dose to be administered, and stored at 4 ° C in the dark.
  • Recording procedure the number, date, user and purpose of each test sample are recorded.
  • HEMAVET 950 animal blood analyzer Model HEMAVET 950FS.
  • BD Accuri C6 flow cytometer Brand BD company.
  • ICAP-Q Inductively Coupled Plasma Mass Spectrometer
  • KCG crossbred miniature pigs will be used at an average age of 5-7 weeks and 10 kg body weight.
  • BHT 250 mg Acetylcysteine: 150 mg Superoxide Dismutase (SOD): 150 mg Nattokinase: 50 mg Gututation: 100 mg.
  • SOD Superoxide Dismutase
  • the animals will be fed in an SPF quality animal facility at the Nam-Khoa laboratories in HCM City Vietnam.
  • the KCG crossbred miniature pigs had free access to food and water throughout the experiment and were housed in 12:12 light / dark conditions in a temperature-controlled environment ( 23 ⁇ 3 oC) and humidity controlled at 40-70%.
  • the experimental procedures were carried out in accordance with BYT-MOH and NIH of the Socialist Republic of Vietnam and were approved by the Ethics Committee of Experimental Animals of SYT-HCM City Vietnam.
  • mice Observe the general condition, body weight and organ index of nude mice
  • the general status of the nude mouse includes activity, mental state, skin color, diet, water intake and urine production.
  • Body weight (BW) was weighed every 3 days.
  • the hearts, liver, spleen, lungs, kidneys and tumors were separated and weighed precisely after the nude mice had been sacrificed, and the heart, liver, spleen, lungs, kidneys and tumors were calculated.
  • tissue weight (mg) / body weight (g) tissue weight / body weight.
  • WBC white blood cells
  • RBC red blood cells
  • HGB hemoglobin
  • HCT d hematocrit
  • MCV medium corpuscular volume.
  • MCH mean corpuscular hemoglobin
  • MHC mean corpuscular hemoglobin concentration
  • PPT lymphocytes
  • LY monocyte
  • NEUT neutrophil granulocyte
  • P-LCR greatest platelet cell ratio
  • the blood cells of the mice will be assessed with a blood count system. As mentioned above in all the groups before and after the experiment period, identify and compare the same parameters between the study and control groups.
  • Serum cytokines will be assessed by flow cytometric analysis. A comparison will be made between the study and control groups IL-1a, IL-Ib, IL-10, IL-6, TNFy, IFN ⁇ serum
  • Mortality at 1 month is defined as the ratio of patients who will live after 1 month from the start of the study compared to those recorded at baseline.
  • Interleukin-6 Interleukin-6, IL-1 ⁇ , IL-2, IL-3, IL-17-IL 10, D-Dimer [Period: baseline, during treatment (cycles 1 and 2 every 12 hours) up to 1 month]
  • IL-6 levels will be assessed using the commercial ELISA method. Lymphocyte count [Period: baseline, during treatment (cycles 1 and 2 every 12 hours) up to 1 month]
  • CRP C-reactive protein
  • Ratio Pa02 partial pressure of oxygen
  • Fi02 fraction of inspired oxygen, Fi02
  • P / F ratio P / F ratio
  • CTCAE Common Terminology Criteria for Adverse Events
  • Radiological response [Timeframe: at baseline (optional), after seven days and if clinically indicated (up to 1 month)]
  • the anti-COVID-19 nutraceutical therapeutic formulation has been modulated into three therapeutic support protocols, aimed respectively at helping in the treatment of clinical forms:
  • Nutraceutical support protocol 1 for mild form ⁇ rational clinical form and mechanism of action of the components Nutraceutical support protocol 1 aims to help in the treatment of the mild clinical form of COVID-19: * Mild clinical tonne (80%) ⁇ discovery of fever, cough, sore throat, asthenia and absence of acute respiratory failure (the normal minimum value of Pa02 detected with analysis of blood gases in ambient air is assumed to be ⁇ 80 mmHg).
  • Nutraceutical support protocol 2 (moderate form) ⁇ rational clinical form and mechanism of action of the components Nutraceutical support protocol 2 aims to help in the treatment of the moderate clinical form of COVID-19: • Mo- derated (15%) ⁇ detection of pneumonia with acute respiratory failure (80 ⁇ Pa02 in ambient air> 60 mmHg).
  • Study design Patient estimate: 75 patients: * 25 without acute respiratory failure ⁇ protocol 1 * 2.5 with moderate acute respiratory failure ⁇ protocol 2 ⁇ 25 with severe respiratory failure and / or shock ⁇ protocol 3
  • SOD Superoxide Dismutase
  • Protocol 3 ⁇ for SNG Composition of 1 capsule ° BHT 250 mg ⁇ Acetylcysteine: 50 mg * Superoxide Dismutase (SOD): 100 mg * Nattokinase: 50 mg ° Glutathione: 50 mg.
  • SOD Superoxide Dismutase
  • Route of administration Dosage of SNG 2 tabs every 8 hours Duration 14 days Status NOT available ⁇ to be prepared (7 weeks).
  • P / F ratio Pa02 (partial pressure of oxygen) / Fi () 2 (fraction of inspired oxygen, Fi02) ratio [Time Frame: baseline values, during treatment (cycles 1 and 2 every 12 hours) up to 'at one month] determined by EGA (values from 300 to 100 mmHg)
  • CCAE Common Terminology Criteria for Adverse Events
  • Radiological evaluation [Timeframe: start (optional), after 7 days and if clinically indicated at 1 month, by chest CT or chest x-ray.

Abstract

The invention relates to 2,6-di-tert-butyl-4-methylphenol (BHT) alone or in combination with one or more other antioxidants and/or an anti-inflammatory for the prevention or treatment of COVID-19, an infection caused by the SARS-CoV-2 virus.

Description

COMPOSITION POUR LA PRÉVENTION OU LE TRAITEMENT DU COVID-19 COMPOSITION FOR THE PREVENTION OR TREATMENT OF COVID-19
DOMAINE TECHNIQUE TECHNICAL AREA
La présente invention porte de manière générale sur une nouvelle composition pour le traitement des infec- tions par un coronavirus et plus particulièrement la Covid-19, l'infection par le SARS-CoV-2. The present invention relates generally to a novel composition for the treatment of infections by a coronavirus and more particularly Covid-19, infection by SARS-CoV-2.
CONTEXTE DE L'INVENTION BACKGROUND OF THE INVENTION
Les coronavirus font partie de l'ordre des Nidovirales, de la famille des Coronaviridae et de la sous-famille des Coronavirinae qui regroupe 4 genres : alphacoronavirus, betacoronavirus, gammacoronavirus et deltaco- ronavirus. Les coronavirus infectent une grande diversité d'hôtes, incluant de nombreuses espèces d'oiseaux et de mammifères, dont l'Homme. Les alphacoronavirus et betacoronavirus circulent parmi les mammifères, les gammacoronavirus et les deltacoronavirus infectent les oiseaux et les mammifères. Au sein des betacoro- navirus, on distingue 4 lignages : le lignage A auquel appartiennent les coronavirus humains HKU1 et OC43, le lignage B auquel appartient le SARS-CoV (pour Severe Acute Respiratory Syndrome Coronavirus), le li- gnage C auquel appartient le MERS-CoV (Middle East Respiratory Syndrome Coronavirus) et le lignage D auquel appartiennent les coronavirus de chauve-souris HKU4 et HKU5, proches du MERS-CoV. Coronaviruses are part of the Nidovirales order, the Coronaviridae family and the Coronavirinae subfamily which includes 4 genera: alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus. Coronaviruses infect a wide variety of hosts, including many species of birds and mammals, including humans. Alphacoronaviruses and betacoronaviruses circulate among mammals, gammacoronaviruses and deltacoronaviruses infect birds and mammals. Within the betacoroviruses, there are 4 lineages: lineage A to which the human coronaviruses HKU1 and OC43 belong, lineage B to which SARS-CoV (stands for Severe Acute Respiratory Syndrome Coronavirus) belongs, lineage C to which the human coronavirus belongs. MERS-CoV (Middle East Respiratory Syndrome Coronavirus) and the D lineage to which the bat coronaviruses HKU4 and HKU5 belong, close to MERS-CoV.
Le SARS-CoV, SARS viras ou virus SRAS, a été isolé en 2003, en association avec un syndrome respiratoi- re aigu sévère (T.G.KSIAZEK et al., The New England Journal of Medicine, 2003, 348, 1319-1330 ; C. DROSTEN et al., The New England Journal of Medicine, 2003, 348, 1967-1976 ; EP 1 694 829 B! ; Peins et al., Lancet, 2003, 361, 1319-). L'épidémie s'est propagée dans différents pays (Vietnam, Hong-Kong, Sin- gapour, Thaïlande et Canada) à partir d'un foyer initial apparu en Chine dans le dernier trimestre de 2002. La sévérité de cete maladie est telle que son taux de mortalité était d'environ 3 à 6 %, L'agent causatif de cette maladie a été identifié et caractérisé : Des séquences génomiques de ce coronavirus ont ainsi été obte- nues, notamment celles de l'isolat Urbani (Genbank n° d'accès AY274119.3 et A. MARRA et al., Science, May l, 2003, 300, 1399-1404) et de l'isoiat de Toronto (Tor2, Genbank n° d'accès AY 278741 et A. ROTA ét al. Science, 2003, 300, 1394-1399). SARS-CoV, SARS viras or SARS virus, was isolated in 2003, in association with severe acute respiratory syndrome (TGKSIAZEK et al., The New England Journal of Medicine, 2003, 348, 1319-1330; C DROSTEN et al., The New England Journal of Medicine, 2003, 348, 1967-1976; EP 1,694,829 B!; Peins et al., Lancet, 2003, 361, 1319-). The epidemic has spread to various countries (Vietnam, Hong-Kong, Singapore, Thailand and Canada) from an initial outbreak which appeared in China in the last quarter of 2002. The severity of this disease is such that its mortality rate was around 3 to 6%. The causative agent of this disease has been identified and characterized: Genomic sequences of this coronavirus have thus been obtained, in particular those of the Urbani isolate (Genbank no. access AY274119.3 and A. MARRA et al., Science, May l, 2003, 300, 1399-1404) and the isoiat of Toronto (Tor2, Genbank accession no AY 278741 and A. ROTA et al. Science, 2003, 300, 1394-1399).
Le coronavirus 2 du syndrome respiratoire aigu sévère, (SARS-CoV-2), émergeant en 2019 en Chine, appar- tient, comme le viras du SRAS, à l'espèce SARSr-CoV ( Severe acute respiratory syndrom-relaied Coronavi- rus}, dans le sous-genre Sarbecovirus, dans le genre Betacoronavirus et la famille Coronaviridae™ . The proximal origin of SARS-CoV-2 . Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerging in 2019 in China, belongs, like the SARS virus, to the SARSr-CoV species (Severe acute respiratory syndrom-relaied Coronavirus }, in the subgenus Sarbecovirus, in the genus Betacoronavirus and the family Coronaviridae ™. The proximal origin of SARS-CoV-2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020 .
Ces virus, SARS-Cov ou SARS-Cov-2 sont des virus enveloppés à ARN monocaténaire, de polarité positive. Ils ont une morphologie typique des coronavirus avec notamment le halo de protubérances protéiques ("Spi- ke"ou spicule) qui leur a donné leur nom ("virus à couronne") (Fields, B. N, In Rnipe, D. M, & In Howley, P. M. (2013). Fields virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins). La taille du génome du SARS-Cov-2 est d'approximativement 30 kilobases. The proximal origin of SARS-CoV-2 . Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020. En général, chaque coronaviras n'affecte qu'une seule espèce. Toutefois, ces viras peuvent traverser la bar- rière d'espèce. Cela pourrait bien être le cas du SARS-CoV-2, qui proviendrait d'un coronaviras de chauve- souris ou de pangolin. These viruses, SARS-Cov or SARS-Cov-2, are enveloped single-stranded RNA viruses of positive polarity. They have a morphology typical of coronaviruses with in particular the halo of protein protuberances ("Spike" or spicule) which gave them their name ("crown virus") (Fields, B. N, In Rnipe, D. M, & In Howley, PM (2013). Fields virology. Philadelphia: Wolters Kluwer Health / Lippincott Williams & Wilkins). The size of the SARS-Cov-2 genome is approximately 30 kilobases. The proximal origin of SARS-CoV-2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, March 17, 2020. In general, each coronaviras affects only one species. However, these viruses can cross the species barrier. This may well be the case with SARS-CoV-2, which is believed to be from a bat or pangolin coronaviras.
Comme le SARS-CoV, le SARS-CoV-2 se lie au récepteur de l'enzyme de conversion de l'angiotensine 2 (ACE2) (Zhang, H., Penninger, J.M., Li, Y. et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS- CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46, 586-590 (2020). https://doi.om/10.1007/s00134-020-05985-9) ; LACE2 est une enzyme de conversion des récepteurs cellulaires de l'angiotensine II. Elle est présente sur les « cellules épithéliales alvéolaires AT2 » situées dans les alvéoles pulmonaires, mais aussi dans l'œsophage, dans les cellules épithéliales supérieures et stratifiées, dans les entérocytes absorbants de l'iléon et du côlon- et dans le pancréas. Like SARS-CoV, SARS-CoV-2 binds to the angiotensin converting enzyme 2 (ACE2) receptor (Zhang, H., Penninger, JM, Li, Y. et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS- CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46, 586-590 (2020). https://doi.om/10.1007/s00134-020-05985-9 ); LACE2 is an angiotensin II cell receptor converting enzyme. It is present on the “AT2 alveolar epithelial cells” located in the pulmonary alveoli, but also in the esophagus, in the upper and stratified epithelial cells, in the absorbing enterocytes of the ileum and the colon and in the pancreas.
Les maladies ou symptomes (Covid-19) que provoquent ces coronaviras de type SARS-Co-2 peuvent aller de l'absence de symptôme, à un rhume accompagné de fièvre, courbatures, mal de gorge, rhinorrhée (atteinte du tractus grastrointestinal « haut »), ou encore provoquer des symptômes plus graves telles que le syndrome respiratoire aigu sévère observé chez des patients infectés par le SRAS- Cov-1, (épidémie en 2003), le MERS-CoV, épidémie en 2012), ou encore souffrant de Covid-19 comme observé en 2020. Les signes avant coureur de ces aggravations sont des nausées, vomissement, diarrée (atteinte du tractus gastrointestinal « bas »). The diseases or symptoms (Covid-19) caused by these SARS-Co-2-type coronaviras can range from the absence of symptoms, to a cold accompanied by fever, body aches, sore throat, rhinorrhea (damage to the gastrointestinal tract "upper "), Or even cause more serious symptoms such as severe acute respiratory syndrome observed in patients infected with SARS-Cov-1, (epidemic in 2003), MERS-CoV, epidemic in 2012), or even suffering from Covid-19 as observed in 2020. The warning signs of these aggravations are nausea, vomiting, diarrhea (damage to the “lower” gastrointestinal tract).
Il n'existe sur le marché aucun vaccin contre le viras SARS-CoV-2. Quelques candidats sont actuellement évalués en essai clinique de phase I aux US et en Chine (https://clinical- trials.gov/ct2/show/NCT0428346 l?term=vaccine&cond=covid-19&draw=2, http://www.chictr.org.cn/show- projen. aspx?proj =51154) . There is no vaccine on the market against the SARS-CoV-2 virus. A few candidates are currently being evaluated in phase I clinical trials in the US and China (https: // clinical- trials.gov/ct2/show/NCT0428346 l? Term = vaccine & cond = covid-19 & draw = 2, http: // www. chictr.org.cn/show- projen. aspx? proj = 51154).
Les symptômes d'une infection respiratoire aiguë (fatigue, fièvre, douleurs musculaires, toux, difficultés res- piratoires... ) sont observés chez 20 à 30% des patients. Des atteintes des reins et de l'intestin ont aussi été observées chez certains patients 10% environ et les patients avec des maladies chroniques préexistantes ainsi que les personnes âgées sont plus susceptibles de développer des formes sévères pouvant aller jusqu'au dé- cès. Ce virus tue environ 1% à 10 % des personnes infectées sans distinction d'age ou d'origine ethnique. Contre la Covid-19, un traitements basé sur une combinaison d'un antibiotique associé à un anti-inflamma- toire, ou associé à de l'hydroxychloroquine (Gautret et al. (2020) Hydroxy chloroquine and azithromy- cin as a treatment of COVID-19: résulte of an open label non randomized clinical trial. International Jour- nal of Antimicrobial Agents - in Press 17 Mardi 2020 - DOI : 10.1016/j. ijantimicag.2020.105949 ) ou enco- re des compléments alimentaires comprenant des acides gras et des vitamines ont été proposés ou sont en cours d'études. (https://clinicaItrials.gov/ct2/show/NCT04323228?tenn=covid-19&draw=4&rank=24) no- tamment pour atténuer le choc cytokinine (storm) observé chez les patients à des stades graves de la maladie Toutefois, il semblerait que les anti inflammatoires non stéroïdiens ou même les corticoïdes accentuent la maladie. Symptoms of an acute respiratory infection (fatigue, fever, muscle pain, cough, breathing difficulties, etc.) are observed in 20 to 30% of patients. Kidney and intestinal damage have also been observed in some patients about 10% and patients with pre-existing chronic diseases as well as the elderly are more likely to develop severe forms which can lead to death. This virus kills about 1% to 10% of infected people regardless of age or ethnicity. Against Covid-19, a treatment based on a combination of an antibiotic associated with an anti-inflammatory drug, or associated with hydroxychloroquine (Gautret et al. (2020) Hydroxy chloroquine and azithromycin as a treatment of COVID-19: result of an open label non randomized clinical trial. International Journal of Antimicrobial Agents - in Press 17 Tuesday 2020 - DOI: 10.1016 / j. Ijantimicag.2020.105949) or even dietary supplements comprising fatty acids and vitamins have been proposed or are under study. (https://clinicaItrials.gov/ct2/show/NCT04323228?tenn=covid-19&draw=4&rank=24) especially to attenuate the cytokinin shock (storm) observed in patients at severe stages of the disease. it seems that non-steroidal anti-inflammatory drugs or even corticosteroids accentuate the disease.
A l'heure actuelle, il n'existe donc pas, ou très peu, de molécules reconnues et/ou approuvées par les autorités de santé pour luter contre les coronavirus de type SARS-Cov, en particulier pour prévenir ou traiter la Co- vid-19, et plus particulièrement prévenir les signes sévères de la maladie. At present, there is therefore no, or very few, molecules recognized and / or approved by the authorities. to fight against coronaviruses of the SARS-Cov type, in particular to prevent or treat Co-vid-19, and more particularly to prevent severe signs of the disease.
Dans ces conditions, il existe un besoin pour de nouvelles solutions prophylactiques et/ou thérapeutiques à l'encontre d'infections par les coronavirus, en particulier la Covid-19, Under these conditions, there is a need for new prophylactic and / or therapeutic solutions against infections by coronaviruses, in particular Covid-19,
Le composé 2,6-di-tert-butyl-4-méthylphénol, a des propriétés antivirales connues mais son efficacité sur les coronavirus, notamment les coronavirus SARS-Cov-2, n'a jamais été suggérée et encore moins démontrée. The compound 2,6-di-tert-butyl-4-methylphenol, has known antiviral properties but its efficacy on coronaviruses, in particular the SARS-Cov-2 coronaviruses, has never been suggested and even less demonstrated.
RESUME DE L'INVENTION De façon surprenante, il a maintenant été démontré que le 2,6-di-tert-butyl-4-méthyl-phénol (BHT) seul ou en combinaison avec un autre antioxidant, et/ou un anti-inflammatoire a une activité antivirale contre le SARS-CoV-2, et permet le traitement et/ou la prévention de l'infection par ce coronavirus.
Figure imgf000004_0001
L'invention porte sur le 2,6-di-tert-butyl-4-méthyl-phénol pour la prévention et/ou le traitement d'une infec- tion par un coronavirus SARS-CoV-2. SUMMARY OF THE INVENTION Surprisingly, it has now been shown that 2,6-di-tert-butyl-4-methyl-phenol (BHT) alone or in combination with another antioxidant, and / or an anti-inflammatory has antiviral activity against SARS-CoV-2, and allows the treatment and / or prevention of infection with this coronavirus.
Figure imgf000004_0001
The invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus SARS-CoV-2.
L'invention porte sur le 2,6-di-tert-butyl-4-méthyl-phénol pour la prévention et/ou le traitement d'une infec- tion par un coronavirus comme le SARS-CoV-2, par activité virucide ou décontaminante. L'invention porte aussi sur : The invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2, by virucidal activity or. decontaminating. The invention also relates to:
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné à un autre antioxi- dant, et/ou un anti-inflammatoire, avantageusement à laN-acétylcystéine (NAC) et/ou à la Boswellia Serrata (BS). - BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS ).
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné à un autre antioxi- dant, et/ou un anti-inflammatoire, avantageusement à la NATTOKINASE. - BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with NATTOKINASE.
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné à un autre antioxi- dant, et/ou un anti -inflammatoire, avantageusement à la N-acétylcystéine (NAC) et/ou à la Bosweîlia Serrata (BS), avantageusement dans une formulation galénique destinée à l' administration orale. - BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Bosweîlia Serrata ( BS), advantageously in a pharmaceutical formulation intended for oral administration.
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné à un autre antioxi- dant, et/ou un anti-inflammatoire, avantageusement à la N-acétylcystéine (NAC) et/ou à la Bosweîlia Serrata- BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Bosweîlia Serrata
(BS), et/ou la Nattokinase avantageusement dans une formulation galénique destinée à l'administration orale.(BS), and / or Nattokinase advantageously in a galenic formulation intended for oral administration.
Selon certains modes de réalisation l'invention porte sur la nattokinase pour la prévention et/on le traitement d'une infection par un coronavirus comme le SARS-CoV-2, sur une composition comprenant la nattokinase pour la prévention et/ou le traitement d'une infection par un coronavirus comme le SARS-CoV-2. According to some embodiments, the invention relates to nattokinase for the prevention and / on the treatment infection with a coronavirus such as SARS-CoV-2, on a composition comprising nattokinase for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2.
L'invention porte sur le 2,6-di-tert-butyl-4-méthyl-phénol pour la prévention et/ou le traitement d'une infec- tion par un coronavirus comme le SARS-CoV-2. The invention relates to 2,6-di-tert-butyl-4-methyl-phenol for the prevention and / or treatment of infection with a coronavirus such as SARS-CoV-2.
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné à un autre antioxi- dant sélectionné parmi Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), et une combinaison de ces composés. - BHT for its use according to the invention, characterized in that BHT is combined with another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), and a combination of these compounds.
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné en outre à de l'Adénosine TriPhosphate (ATF). - BHT for its use according to the invention, characterized in that the BHT is also combined with Adenosine TriPhosphate (ATF).
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est utilisé à une dose de 0,01 mg à 1g, de 0.1 mg à 10 mg, de 1 rng à 100 mg, de 100 rng à 900 mg, de 300 rng à 500 mg, avantageusement à une dose de 0,1 mg/kg à ig/kg, de 1 mg/kg à 0.1g/kg, de 10 mg/kg à 800 mg/kg, de 100mg/kg à 900tng/kg ; de 300mg/kg à 500 mg/kg en poids. Le BHT à une concentration > IμM pour son utilisation dans la prophylaxie ou le traitement de la CO-- BHT for its use according to the invention characterized in that BHT is used at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 rng to 100 mg, from 100 rng to 900 mg, from 300 mg to 500 mg, advantageously at a dose of 0.1 mg / kg to ig / kg, from 1 mg / kg to 0.1 g / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 900tng / kg; from 300 mg / kg to 500 mg / kg by weight. BHT at a concentration> IμM for its use in the prophylaxis or treatment of CO-
VID19. VID19.
- Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré au moins par voie orale, et par voie intraveineuse, sublinguale, rectale, par inhalation, selon les symptômes, pour mettre en contact le BHT avec le SARS-Cov-2. - BHT for its use according to the invention characterized in that the BHT is administered at least orally, and intravenously, sublingually, rectally, by inhalation, depending on the symptoms, to bring the BHT into contact with the SARS- Cov-2.
Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré 1 à 3 fois par jour, avantageusement de 1 à 3 fois par jour pendant au moins 5 jours à au moins 14 jours. BHT for its use according to the invention, characterized in that BHT is administered 1 to 3 times per day, advantageously from 1 to 3 times per day for at least 5 days to at least 14 days.
Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré à des individus présentant ou non des symptômes de la Covid-19. BHT for its use according to the invention, characterized in that BHT is administered to individuals with or without symptoms of Covid-19.
Le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré à un individu in- fecté par le SARS-Cov-2 présentant au moins un symptôme choisi parmi toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, anosmie, agueusie, perte d'appétit, avantageusement dans une formulation galénique appropriée à une administration par voie orale. BHT for its use according to the invention, characterized in that BHT is administered to an individual infected with SARS-Cov-2 exhibiting at least one symptom chosen from cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances. intestinal, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
Le BHT pour son utilisation selon l'invention caractérisé par une utilisation chez un individu infecté par le SARS-Cov-2 présentant des symptomes choisi parmi toux et syndrome respiratoire aigu sévère, avantageuse- ment dans une fonnulation galénique appropriée à une administration par voie intraveineuse et/ou par inhala- tion. BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms chosen from cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration. and / or by inhalation.
L'invention porte sur le 2,6-di-tert-butyl-4-méthyl-phénol (BHT) seul ou en combinaison avec au moins un autre complément alimentaire pour son utilisation dans la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2 (Covid-19). Selon un aspect un complément alimentaire peut être par exemple, SOD ± Zn, Cu et ou Mg, CAT, GSH ATP, N AC, BS. The invention relates to 2,6-di-tert-butyl-4-methyl-phenol (BHT) alone or in combination with at least one other dietary supplement for its use in the prevention and / or treatment of infection. by a SARS-CoV-2 coronavirus (Covid-19). According to one aspect, a food supplement can be, for example, SOD ± Zn, Cu and or Mg, CAT, GSH ATP, N AC, BS.
Selon un aspect un complément alimentaire peut être par exemple, SOD ± Zn, Cu et ou Mg, CAT, GSH ATP, NAC, BS, NATTOKINASE. According to one aspect, a food supplement can be, for example, SOD ± Zn, Cu and or Mg, CAT, GSH ATP, NAC, BS, NATTOKINASE.
L'invention porte sur le BHT pour son utilisation en tant que médicament pour la prévention ou le traitement des infections par les bétacoronavirus, en particulier un SARS-CoV-2. The invention relates to BHT for its use as a medicament for the prevention or treatment of infections with betacoronaviruses, in particular SARS-CoV-2.
On entend par médicament un composé ou une composition ayant un effet antiviral direct ou indirecte. L'invention porte aussi sur le BHT combiné à un autre antioxidant, et/ou un anti-inflammatoire, sur une com- position comprenant le BHT combiné à un autre antioxidant, et/ou un anti-inflammatoire, à des formulations galéniques de ces compositions, appropriées pour une administration par voie orale, sublinguale, intrarectaie, intraveineuse ou par inhalation. The term “drug” is understood to mean a compound or a composition having a direct or indirect antiviral effect. The invention also relates to BHT combined with another antioxidant, and / or an anti-inflammatory, to a composition comprising BHT combined with another antioxidant, and / or an anti-inflammatory, to dosage formulations of these. compositions suitable for oral, sublingual, intrarectal, intravenous or inhalation administration.
L'invention porte sur le BHT caractérisé en ce qu'il est combiné à la N-acétylcystéine (NAC) et/ou à la Bos- wellia Serrata (BS), avantageusement dans une formulation galénique destinée à l'administration orale. The invention relates to BHT characterized in that it is combined with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS), advantageously in a galenic formulation intended for oral administration.
De façon surprenante, les inventeurs ont aussi identifié qu'un composé de fonnule (I) (I : 2,6-di-tert-hutyl-4- R-phénol) ou
Figure imgf000006_0001
dans laquelle R est CH3 (BHT), 0-CH3 (BG1), CH2-OH (BG2), COOH (BG3), ou CHO (BG4) seul, ou en combinaison selon l'invention était très efficace pour prévenir ou traiter les symptomes de la Covid-19. Avantageusement un composé de formule (I) dans laquelle R est CH3 ou 2,6-di-tert-butyl-4-méthyl-phénol (BHT) est très efficace pour prévenir ou traiter les symptomes observés au cours de la Covid-19. Surprisingly, the inventors have also identified that a compound of formula (I) (I: 2,6-di-tert-hutyl-4-R-phenol) or
Figure imgf000006_0001
wherein R is CH3 (BHT), 0-CH3 (BG1), CH2-OH (BG2), COOH (BG3), or CHO (BG4) alone, or in combination according to the invention was very effective in preventing or treating symptoms of Covid-19. Advantageously, a compound of formula (I) in which R is CH3 or 2,6-di-tert-butyl-4-methyl-phenol (BHT) is very effective for preventing or treating the symptoms observed during Covid-19.
Les compositions selon l'invention sont administrées, de préférence par voie orale, chez des patients ne pré- sentant aucun symptôme, ou présentant au moins 1 symptôme parmi (fièvre, fatigue, céphalée, rhinorrhée, toux sèche, courbatures, gène respitatoire, insuffisance respiratoire ; diarrhée, nausée, vomissement, étourdis- sement) ou au moins au moins 2 symptomes dont insuffisance respiratoire et au moins un autre symptôme parmi (fièvre, fatigue, céphalée, rhinorrhée, toux sèche, courbatures, gène respitatoire, insuffisance respira- toire ; diarrhée, nausée, vomissement, étourdissement). The compositions according to the invention are administered, preferably by the oral route, to patients presenting no symptoms, or presenting at least 1 symptom among (fever, fatigue, headache, rhinorrhea, dry cough, stiffness, respiratory discomfort, insufficiency. respiratory; diarrhea, nausea, vomiting, dizziness) or at least 2 symptoms including respiratory failure and at least one of (fever, fatigue, headache, rhinorrhea, dry cough, body aches, respiratory discomfort, respiratory failure) ; diarrhea, nausea, vomiting, dizziness).
Le BHT, ou les compositions selon l'invention peuvent être administrées par l'une quelconque parmi toutes les voies d'administration selon l'invention, ou une combinaison de voies d'administration, à tous les pa- tients ou personnes susceptibles d'être infectées par le virus SARS-Cov2 ou infectées par le SARS-Cov-2, BHT, or the compositions according to the invention can be administered by any one of all the routes of administration according to the invention, or a combination of routes of administration, to all the patients or persons susceptible to. be infected with the SARS-Cov2 virus or infected with SARS-Cov-2,
Les compositions selon l'invention peuvent être administrées : de préférence par voie orale, The compositions according to the invention can be administered: preferably orally,
-par voie orale, peros et/ou sublinguale chez tous les patients ou individus susceptibles d'être contaminé par le SARS-Cov-2 -orally, peros and / or sublingually in all patients or individuals likely to be contaminated by the SARS-Cov-2
- par voie intrarectale et/ou orale (peros, sublinguale), de préférence orale et intrarectale chez des patients présentant des signes d'infection de l'intestin (nausée, diarhée, présence de virus dans le nez, dans les fécès),- by intrarectal and / or oral (peros, sublingual), preferably oral and intrarectal route in patients presenting signs of infection of the intestine (nausea, diarrhea, presence of virus in the nose, in the faeces),
- par inhalation pour les patients présentant des signes d'infection des voies respiratoires (présence de virus dans le nez, exsudât, crachat), - by inhalation for patients with signs of respiratory tract infection (presence of virus in the nose, exudate, sputum),
-par voie intraveineuse chez tous les patients, en particulier chez des patients intubés, ou si la composition est plus efficace par cette voie, selon le symptôme. - intravenously in all patients, in particular in intubated patients, or if the composition is more effective by this route, depending on the symptom.
L'invention porte aussi, selon un aspect, sur le BHT pour prévenir et/ou traiter la Covid-19 caractérisé en ce qu'il est combiné à un autre antioxidant, en particulier à un composé sélectionné parmi Catalase (CAT), Su- peroxide dismutase (SOD), gluthation (GSH), et une combinaison de ces composés, avantageusement à un autre antioxidant sélectionné parmi Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adéno- sine triphosphate (ATP) et une combinaison de ces composés, ou encore à un autre antioxidant sélectionné parmi N acétylcystéïne (NAC), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adénosine triphosphate (ATP) et une combinaison de ces composés. The invention also relates, according to one aspect, to BHT for preventing and / or treating Covid-19, characterized in that it is combined with another antioxidant, in particular with a compound selected from Catalase (CAT), Su- peroxide dismutase (SOD), gluthation (GSH), and a combination of these compounds, advantageously to another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds, or also to another antioxidant selected from N acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds.
L'invention porte aussi, selon un aspect, sur le BHT caractérisé en ce qu'il est combiné à un autre antioxi- dant, en particulier à un composé sélectionné parmi Catalase (CAT), Superoxide dismutase (SOD), glutha- tion (GSH), et une combinaison de ces composés, avantageusement à un autre antioxidant sélectionné parmi Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adénosine triphosphate (ATP) et une com- binaison de ces composés, ou encore à un autre antioxidant sélectionné parmi N acétylcystéïne (NAC), Cata- lase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adénosine triphosphate (ATP) et une combinai- son de ces composés. The invention also relates, according to one aspect, to BHT characterized in that it is combined with another antioxidant, in particular with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), glutha- tion ( GSH), and a combination of these compounds, advantageously with another antioxidant selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds, or alternatively to another antioxidant selected from N acetylcysteine (NAC), Catalyst (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP) and a combination of these compounds.
Selon un aspect, le BHT combiné à un composé sélectionné parmi Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), BS et une combinaison de ces composés, avantageusement à un composé sélec- tionné parmi Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adénosine triphosphate (ATP) , BS et une combinaison de ces composés, ou encore à un autre antioxidant sélectionné parmi N acétyicystéï- ne (NAC), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adénosine triphosphate (ATP), BS et une combinaison de ces composés. According to one aspect, BHT combined with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), BS and a combination of these compounds, advantageously with a compound selected from Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), adenosine triphosphate (ATP), BS and a combination of these compounds, or to another antioxidant selected from N acetyicysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD) , gluthation (GSH), adenosine triphosphate (ATP), BS and a combination of these compounds.
Ces compositions selon l'invention peuvent être utilisées pour la prévention ou le traitement d'une infection par un virus enveloppé, un parasite ayant une bicouche lipidique (enveloppé). These compositions according to the invention can be used for the prevention or treatment of an infection by an enveloped virus, a parasite having a lipid bilayer (enveloped).
La présente invention porte aussi sur le BHT seul ou en combinaison avec un anti-inflammatoire par exem- ple la Boswellia Serrata pour prévenir ou traiter la Covid-19. The present invention also relates to BHT alone or in combination with an anti-inflammatory, for example Boswellia Serrata, to prevent or treat Covid-19.
La présente invention porte sur la NATTOKINA SE pour prévenir ou traiter les symptômes et problèmes de coagulation (formation de caillots) liés à une infection virale, de préférence liés à la covid-19. The present invention relates to NATTOKINA SE for preventing or treating the symptoms and coagulation problems (formation of clots) linked to a viral infection, preferably linked to covid-19.
L'invention porte également, selon un aspect, sur le BHT pour pré venir et/ou traiter la Covid-19 caractérisé en ce qu'il est combiné à un autre antioxidant sélectionné parmi l'un des composés suivants : NAC, CAT, SOD, ATP, GSH et une combinaison des ces composés associé(s) et à un anti-inflammatoire, avantageuse- ment, le BS. L'invention porte sur le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est combiné en outre à de l'Adénosine TriPhosphate (ATP). L'invention porte sur le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est utilisé à une dose (x) de 0,1 mg à 10g, de 1 mg à 1g, de 10 mg 800 mg, de l00mg à 90Qmg, de 300mg à 500 mg.The invention also relates, according to one aspect, to BHT for preventing and / or treating Covid-19, characterized in that it is combined with another antioxidant selected from one of the following compounds: NAC, CAT, SOD , ATP, GSH and a combination of these associated compound (s) and an anti-inflammatory, advantageously, BS. The invention relates to BHT for its use according to the invention characterized in that the BHT is further combined with Adenosine TriPhosphate (ATP). The invention relates to BHT for its use according to the invention characterized in that the BHT is used at a dose (x) of 0.1 mg to 10g, from 1 mg to 1g, from 10 mg 800 mg, from 100 mg at 90Qmg, from 300mg to 500 mg.
La dose (x) peut être par kg en poids corporel. L'invention porte sur le BHT pour son utilisation selon l'in- vention caractérisée par une utilisation d'une dose 1 à 3 fois par jour. L'invention porte sur le BHT pour son utilisation selon l'invention caractérisée par une utilisation pendant au moins 5 jours à au moins 28 jours, pendant au moins 5 jours à au moins 14 jours, pendant au moins 5 jours à au moins 10 jours. The dose (x) can be per kg body weight. The invention relates to BHT for its use according to the invention characterized by the use of a dose of 1 to 3 times per day. The invention relates to BHT for its use according to the invention characterized by use for at least 5 days to at least 28 days, for at least 5 days to at least 14 days, for at least 5 days to at least 10 days .
L'invention porte sur le BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est adminis- tré à des individus présentant ou non des symptomes de la Covid-19. The invention relates to BHT for its use according to the invention characterized in that BHT is administered to individuals with or without symptoms of Covid-19.
L'invention porte sur le BHT pour son utilisation selon l'invention caractérisée par une utilisation chez un in- dividu infecté par le SARS-Cov-2 présentant ou non au moins un symptôme parmi toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, anosmie, agueusie, perte d'appétit, avantageusement dans une formulation galénique appropriée à une administration par voie orale. on entend par un individu infecté par le SARS-Cov-2, un individu chez qui des séquences virales spécifique du SARS-Cov-2 sont détectables, au moins par PCR dans un échantillon prélevé soit au niveau du nez, ou dans un prélèvement de sang, ou dans un prélèvement de fécès. The invention relates to BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 who may or may not have at least one symptom of cough, dyspnea, fatigue, sore throat, disorders. gastrointestinal, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration. by an individual infected with SARS-Cov-2 is meant an individual in whom specific viral sequences of SARS-Cov-2 are detectable, at least by PCR in a sample taken either from the nose, or from a sample of blood, or in a faeces sample.
L'invention porte sur le BHT pour son utilisation selon l'invention caractérisée par une utilisation chez un in- dividu infecté par le SARS-Cov-2 présentant des symptômes tels que toux et syndrome respiratoire aigu sé- vère, avantageusement dans une formulation galénique appropriée à une administration par voie intraveineu- se et/ou par inhalation. The invention relates to BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a pharmaceutical formulation. suitable for intravenous and / or inhalation administration.
Le BHT, les compositions selon l'invention sont administrées par voie orale à tous les patients et personnes susceptibles d'être infectées le virus. Les compositions selon l'invention sont administrées : BHT, the compositions according to the invention are administered orally to all patients and persons likely to be infected with the virus. The compositions according to the invention are administered:
- par voie intrarectale et/ou orale (iutragastrique, sublinguale), de préférence orale et intrarectale chez des pa- tients présentant des signes d'infection de l'intestin (nausée, diarhée, présence de virus dans le nez, dans les fécès), - intrarectal and / or oral (iutragastric, sublingual), preferably oral and intrarectal in patients showing signs of infection of the intestine (nausea, diarrhea, presence of virus in the nose, in the faeces) ,
- par inhalation pour les patients présentant des signes d'infection des voies respiratoires (présence de virus dans le nez, exsudât, crachat) , BREVE DESCRIPTION DES FIGURES - by inhalation for patients with signs of respiratory tract infection (presence of virus in the nose, exudate, sputum), BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Mesure des titres infectieux de SARS-CoV-2 à 24 heures post -infection, sur des cellules traitées par du diluant (contrôle), le BHT seul ou une combinaison BHT et (NAC ou BS ou les deux NAC et BS), rappor- tés au titre infectieux des cellules témoins infectées et non traitées. Les titres infectieux ont été obtenus par technique d'infection par dilution limite et calcul par la méthode de Reed et Muench. Figure 1. Measurement of the infectious titers of SARS-CoV-2 at 24 hours post-infection, on cells treated with diluent (control), BHT alone or a combination of BHT and (NAC or BS or both NAC and BS) , reported to the infectious titer of infected and untreated control cells. The infectious titers were obtained by infection technique by limiting dilution and calculation by the method of Reed and Muench.
A) Les résultats sont exprimés en log10 TCID/mL (50% Tissue Culture Infective Dose) B) Les résultats sont exprimés en TCID/mL A) The results are expressed in log10 TCID / mL (50% Tissue Culture Infective Dose) B) The results are expressed in TCID / mL
Figure 2. Mesure des IC50 (concentration nécessaire pour obtenir 50% de production virale normalisée) des composés testés (A- Control B-BHT, C-BHT- NAC, D-BHT- BS) sur des cellules VeroE6 infectées par le co- ronavirus SARS-COV-2. Les titres infectieux ont été obtenus par technique d'infection par dilution limite et calcul par la méthode de Reed et Muench. Figure 2. Measurement of the IC50 (concentration necessary to obtain 50% of normalized viral production) of the compounds tested (A- Control B-BHT, C-BHT- NAC, D-BHT- BS) on VeroE6 cells infected with co- ronavirus SARS-COV-2. The infectious titers were obtained by infection technique by limiting dilution and calculation by the method of Reed and Muench.
Figure 3A. Mesure d'efficacité antivirale des composés testés (A- BHT, B- BHT-NAC, C-BHT-BS D-BHT- NAC-BS) et Figure 3B. (A- Diluant, B-NAC, C-BS ; D-NAC-BS) sur des cellules humaines épithéliales res- piratoires A549 infectées par le coronavirus SARS-COV-2 : Les titres infectieux ont été obtenus par techni- que d'infection par dilution limite et calcul par la méthode de Reed et Muench. La production virale normali- sée est mesurée en parallèle de la viabilité des cellules, en fonction de la concentration de composés utilisés. Figure 4A. Mesure d'efficacité antivirale des composés testés (A- BHT, B- BHT-CAT, C-BHT-GSH, D-BHT- SOD) et Figure 4B A- diluant, B- CAT, C-GSH, D-SOD, E- ATP) sur des cellules humaines épithéliales res- piratoires A549 infectées par le coronavirus SARS-COV-2 : Les titres infectieux ont été obtenus par techni- que d'infection par dilution limite et calcul par la méthode de Reed et Muench. La production virale normali- sée est mesurée en parallèle de la viabilité des cellules, en fonction de la concentration de composés utilisés. Figure 5A. Mesure d'efficacité antivitale des composés testés (A- BHT, B- BHT-NAC, C-BHT-BS) et Figure 5B. (A- diluant, B-NAC, C-BS) sur des cellules humaines épithéliales intestinales exprimant l'enzyme de conversion de l'angiotensine 2 ( ACE2 ) et la protéase TMPRSS2, infectées par le coronavirus SARS-COV-2 : Les titres infectieux ont été obtenus par technique d'infection par dilution limite et calcul par la méthode de Reed et Muench. La production virale normalisée est mesurée en parallèle de la viabilité des cellules, en fonction de la concentration de composés utilisés. Figure 3A. Measure of antiviral efficacy of the compounds tested (A-BHT, B- BHT-NAC, C-BHT-BS D-BHT-NAC-BS) and FIG. 3B. (A- Diluent, B-NAC, C-BS; D-NAC-BS) on human respiratory epithelial cells A549 infected with the SARS-COV-2 coronavirus: The infectious titers were obtained by technique of infection by limiting dilution and calculation by the method of Reed and Muench. Normalized viral production is measured alongside cell viability, depending on the concentration of compounds used. Figure 4A. Measure of antiviral efficacy of the compounds tested (A- BHT, B- BHT-CAT, C-BHT-GSH, D-BHT- SOD) and Figure 4B A- diluent, B- CAT, C-GSH, D-SOD, E-ATP) on human respiratory epithelial cells A549 infected with the SARS-COV-2 coronavirus: The infectious titers were obtained by infection technique by limit dilution and calculation by the method of Reed and Muench. Normalized viral production is measured alongside cell viability, depending on the concentration of compounds used. Figure 5A. Measure of antivital efficacy of the compounds tested (A-BHT, B- BHT-NAC, C-BHT-BS) and FIG. 5B. (A- diluent, B-NAC, C-BS) on human intestinal epithelial cells expressing angiotensin-converting enzyme 2 (ACE2) and protease TMPRSS2, infected with the SARS-COV-2 coronavirus: The titers infectious were obtained by the technique of infection by limiting dilution and calculation by the method of Reed and Muench. Normalized viral production is measured alongside cell viability, depending on the concentration of compounds used.
Figure 4A. Mesure d'efficacité antivirale des composés testés (A- BHT, B- BHT-CAT, C-BHT-GSH, D-BHT- SOD, E-BHT-CAT-SOD-GSH-ATP (all)) et Figure 4B A- diluant, B- CAT, C-GSH, D-SOD, E- ATP ; F- ail) sur des cellules humaines épithéliales intestinales exprimant l'enzyme de conversion de l'angiotensine 2 ( ACE2 ) et la protéase TMPRSS2, infectées par le coronavirus SARS-COV-2 : Les titres infectieux ont été ob- tenus par technique d'infection par dilution limite et calcul par la méthode de Reed et Muench. La production virale normalisée est mesurée en parallèle de la viabilité des cellules, en fonction de la concentration de com- posés utilisés. Figure 4A. Measure of antiviral efficacy of the compounds tested (A- BHT, B- BHT-CAT, C-BHT-GSH, D-BHT- SOD, E-BHT-CAT-SOD-GSH-ATP (all)) and Figure 4B A - diluent, B-CAT, C-GSH, D-SOD, E- ATP; F- ail) on human intestinal epithelial cells expressing angiotensin converting enzyme 2 (ACE2) and protease TMPRSS2, infected with the SARS-COV-2 coronavirus: Infectious titers were obtained by technique of infection by limiting dilution and calculation by the method of Reed and Muench. The normalized viral production is measured in parallel with the viability of the cells, as a function of the concentration of compounds used.
Figure 6 : Activité anti-virale du BHT sur cellules cibles sans décontamination : la quantité d'ARN mesurée à 48h comprend l'inoculum. Produit 1 et produit 2 comprennent du BHT, vs contrôle positif Remdesivir testé en parallèle. Figure 6: Anti-viral activity of BHT on target cells without decontamination: the quantity of RNA measured at 48 hours comprises the inoculum. Product 1 and Product 2 include BHT, vs Remdesivir positive control tested in parallel.
DESCRIPTION DETAILLEE DE l'INVENTION DETAILED DESCRIPTION OF THE INVENTION
La présente invention porte sur le BHT, pour son utilisation dans la prévention et/ou le traitement d'une infec- lion par le coronavirus SARS-CoV-2 (Covid-19). The present invention relates to BHT, for its use in the prevention and / or treatment of an infection with the coronavirus SARS-CoV-2 (Covid-19).
La présente invention porte sur une composition comprenant le BHT et un excipient ou un diluant pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2 (Covid-19). La présente invention porte sur une composition pharmaceutique comprenant le BHT et un excipient pharma- ceutique approprié pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavi- rus SARS-CoV-2 (Covid-19). The present invention relates to a composition comprising BHT and an excipient or diluent for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19). The present invention relates to a pharmaceutical composition comprising BHT and a pharmaceutical excipient suitable for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19).
Selon un aspect, la présente invention porte sur une composition alimentaire comprenant le BHT et un exci- pient approprié pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2 (Covid-19). In one aspect, the present invention relates to a food composition comprising BHT and an excipient suitable for its use in the prevention and / or treatment of infection with the coronavirus SARS-CoV-2 (Covid-19).
L'invention porte sur le BHT ou une composition comprenant le BHT, pour son utilisation en tant qu'antivi- ral pour la prévention ou le traitement des infections par les betacoronavirus, en particulier un SARS-CoV-2, The invention relates to BHT or a composition comprising BHT, for its use as an antiviral for the prevention or treatment of infections by betacoronaviruses, in particular SARS-CoV-2,
VIRUS- ISOLATS VIRAUX VIRUSES - VIRAL ISOLATES
Le BHT est très efficace en particulier pour prévenir et/ou traiter la COVID-19 mais aussi pour la prévention et/ou le traitement des infections à Coronavirus, plus précisémment à betacoronavirus, comme le SARS-Cov, MERS-Cov, SARS-Cov-2. BHT is very effective in particular for preventing and / or treating COVID-19 but also for the prevention and / or treatment of Coronavirus infections, more specifically betacoronavirus, such as SARS-Cov, MERS-Cov, SARS-Cov -2.
Selon un aspect, la présente invention porte sur le BHT, pour son utilisation pour la prévention et/ou le trai- tement des infections à Coronavirus, plus précisémment à betacoronavirus, comme le SARS-Cov, MERS- Cov, SARS-Cov-2, According to one aspect, the present invention relates to BHT, for its use for the prevention and / or treatment of infections with Coronavirus, more precisely with betacoronavirus, such as SARS-Cov, MERS-Cov, SARS-Cov-2 ,
Le BHT seul ou en combinaison avec au moins un autre composé pour son utilisation dans la prévention et/ou le traitement d'une infection par un bétacoronavirus, de préférence, susceptible de provoquer un syndro- me aigu sévère, un SARS-Cov, MERS-Cov, SARS-Cov-2, ou n'importe quel isolât de ces virus est un aspect de la présente invention. BHT alone or in combination with at least one other compound for its use in the prevention and / or treatment of infection with a beta-coronavirus, preferably capable of causing severe acute syndrome, SARS-Cov, MERS -Cov, SARS-Cov-2, or any isolate of these viruses is an aspect of the present invention.
Le BHT, seul ou en combinaison avec au moins un autre composé, pour son utilisation dans la prévention etiou le traitement d'une infection par un bétacoronavirus, de préférence, susceptible de provoquer un syndro- me aigu sévère, et présentant au moins 70 % d'identité, au moins 80% d'identité, au moins 90% d'identité, au moins 96 % d'identité, et jusqu'à 100% d'identité de séquence avec la sequence d'un SARS-Cov, ou MERS-Cov, ou SARS-Cov-2, ou de n'importe quel isolât de ces virus, est un aspect de la présente invention, de préférence SARS-Cov-2 ou n'importe quel isolat de SARS-Cov-2. BHT, alone or in combination with at least one other compound, for its use in the prevention and / or the treatment of an infection by a betacoronavirus, preferably, capable of causing a severe acute syndrome, and exhibiting at least 70% identity, at least 80% identity, at least 90% identity, at least 96% identity, and up to 100% sequence identity with the sequence of a SARS-Cov, or MERS-Cov, or SARS-Cov-2, or any isolate of these viruses, is an aspect of the present invention, preferably SARS-Cov-2 or any isolate of SARS-Cov-2.
Le BHT, seul ou en combinaison avec au moins un autre composé, pour son utilisation dans la prévention et/ou le traitement d'une infection par le SARS-Cov-2, ou de n'importe quel isolât de ce virus dont la liste décrite et arrêtée la veille du jour du dépôt de la présente demande : https://www.ncbi.nlm.nih.gov/gen - bank/sars-cov-2-seqs/ BHT, alone or in combination with at least one other compound, for its use in the prevention and / or treatment of infection with SARS-Cov-2, or any isolate of this virus listed described and closed the day before the day of filing of this request: https://www.ncbi.nlm.nih.gov/gen - bank / sars-cov-2-seqs /
On entend par un coronavirus SARS-CoV-2 un isolat de ce viras, comme ceux identifiés et séquencés en Ita- lie (MT066156, ou encore MT008022, MT008023, ou tout autre beta coronavirus émergent de type SARS, responsable de la pandémie en 2020. Mais n'importe quel isolat de SARS-Cov-2 pouvant potentiellement in- duire la Covid-19 (maladie) est désigné par SARS-Cov-2 dans cette étude. By a SARS-CoV-2 coronavirus is meant an isolate of this virus, such as those identified and sequenced in Italy (MT066156, or MT008022, MT008023, or any other emerging beta coronavirus of the SARS type, responsible for the pandemic in 2020. But any SARS-Cov-2 isolate that can potentially induce Covid-19 (disease) is referred to as SARS-Cov-2 in this study.
L'infection par le SARS-Cov-2 peut notamment être établie en effectuant au moins une détection et/ou une ti- tration virale à partir de prélèvements respiratoires, ou des fécès ou en dosant les anticorps spécifiques du SARS-CoV-2 circulants dans le sang. La détection chez les individus infectés de ce virus spécifique est réali- sée par des méthodes de diagnostic classiques, notamment de biologie moléculaire (PCR), bien connues de l'Homme du métier. SARS-Cov-2 infection can in particular be established by performing at least one detection and / or viral titration from respiratory samples, or faeces or by assaying specific antibodies to circulating SARS-CoV-2. in the blood. Detection of this specific virus in infected individuals is carried out by conventional diagnostic methods, in particular molecular biology (PCR), well known to those skilled in the art.
Par « infection par le coronavirus SARS-CoV-2 » on désigne le fait qu'un organisme, par exemple un humain présente des cellules ayant été infectées par un coronavirus SARS-CoV-2, ou des séquences virales du SARS-CoV-2 détectables par réaction en chaîne par polymérase (PCR). By “infection with the SARS-CoV-2 coronavirus” is meant the fact that an organism, for example a human, has cells which have been infected with a SARS-CoV-2 coronavirus, or viral sequences of SARS-CoV-2 detectable by polymerase chain reaction (PCR).
SIGNES CLINIQUES - STADES COVID-19 CLINICAL SIGNS - COVID-19 STAGES
Les signes cliniques ou symptômes de la Covid-19 (la maladie observée chez des patients infectés par le SARS-Cov-2) peuvent être, en fonction de leur fréquence : The clinical signs or symptoms of Covid-19 (the disease observed in patients infected with SARS-Cov-2) may be, depending on their frequency:
Aucun : asymptomatique Stade primaire (précoce) None: asymptomatic Primary (early) stage
• la fièvre (sauf chez l'enfant) chez 83 % à 98 % des patients, • fever (except in children) in 83% to 98% of patients,
• la toux, le plus souvent sèche, chez 59 % à 82 % des patients, • cough, most often dry, in 59% to 82% of patients,
• la dyspnée (gêne respiratoire) chez 31 % à 55 % des patients ; • dyspnea (difficulty breathing) in 31% to 55% of patients;
Stade intermédiaire signes secondaires (modéré) Intermediate stage secondary signs (moderate)
• la fatigue chez 44 % à 69 % des patients, • fatigue in 44% to 69% of patients,
• les douleurs musculaires (courbatures) chez 11 % à 44 % des patients, • muscle pain (stiffness) in 11% to 44% of patients,
• des maux de gorge chez 5 % à 17 % des patients, • sore throat in 5% to 17% of patients,
• des crachats chez 26 % à 28 % des patients, • sputum in 26% to 28% of patients,
• une anosmie (perte totale de l'odorat) dans 10 % à 15 % des cas89 ; l'anosmie est une manifestation fré- quente dans les infections virales, une agueusie (perte du goût) a été rapportée par tes patients de la Covid-19, • anosmia (total loss of smell) in 10% to 15% of cases 89 ; anosmia is a frequent manifestation in viral infections, ageusia (loss of taste) has been reported by your Covid-19 patients,
• une perte d'appétit chez 40 % des patients ; • loss of appetite in 40% of patients;
- stade avancé (avec syndrome respiratoire) - advanced stage (with respiratory syndrome)
• céphalée chez 6 % à 8 % des patients, • headache in 6% to 8% of patients,
• vertiges chez 9 % des patients, • dizziness in 9% of patients,
• crachats sanglants chez 5 % des patients, • bloody sputum in 5% of patients,
• douleurs de poitrine chez 2 % à 5 % des patients, • chest pain in 2% to 5% of patients,
• écoulement nasal chez 4 % à 5 % des patients, • nasal discharge in 4% to 5% of patients,
• troubles gastro-intestinaux (douleur, nausée ou diarrhée) chez 1 % à 10 % des patients (stade intermé- diaire également) • gastrointestinal disturbances (pain, nausea or diarrhea) in 1% to 10% of patients (also intermediate stage)
• difficultés respiratoires • breathing difficulties
• détresse respiratoire https://www.medixiv.Org/content/10.1101/2020.02.06.20020974vl.full.pdf • respiratory distress https://www.medixiv.Org/content/10.1101/2020.02.06.20020974vl.full.pdf
A un stade avancé, les patients souffrent d'insuffisance respiratoire aigue. Ces patients doivent être intubés, voire placés en coma artificiel et intubé. At an advanced stage, patients suffer from acute respiratory failure. These patients must be intubated, or even placed in an artificial coma and intubated.
Il peut ne pas y avoir de fièvre et elle n'est pas toujours le premier signe de la maladie (elle peut apparaître après la toux). La diarrhée ou les douleurs abdominales apparaissent un ou deux jours avant les troubles res- piratoires notamment chez les personnes âgées. There may not be a fever and it is not always the first sign of the illness (it can appear after a cough). Diarrhea or abdominal pain appear one or two days before the respiratory problems, especially in the elderly.
Les critères de gravité (forme sévère de la Covid-19) sont : The severity criteria (severe form of Covid-19) are:
- le syndrome respiratoire severe aigu ou détresse respiratoire aiguë qui correspond par exemple, à une fréquence respiratoire supérieure à 30 par minute, une saturation en oxygène au repos inférieure à 93 % (SaO2), un rapport pression en oxygène sur concentration en oxygène inférieur à 300 mm de mercure (PaO2/FiO2). - severe acute respiratory syndrome or acute respiratory distress which corresponds for example to a respiratory rate greater than 30 per minute, an oxygen saturation at rest of less than 93% (SaO 2 ), a lower oxygen pressure to oxygen concentration ratio at 300 mm of mercury (PaO 2 / FiO 2 ).
- choc cytokinique - cytokine shock
La détresse respiratoire aiguë est observée dans 30 % des cas, une myocardite dans 10 % des cas et une sur- infection bactérienne : dans 10 % des cas une libération importante de cytokine responsable d'une lymphohis- tiocytose hémophagocytaire secondaire (choc cytokinique) pouvant entraîner la mort, est observée. Acute respiratory distress is observed in 30% of cases, myocarditis in 10% of cases and bacterial over-infection: in 10% of cases a significant release of cytokine responsible for secondary hemophagocytic lymphohistiocytosis (cytokine shock) can result in death, is observed.
Le terme « traitement » désigne le fait de combattre l'infection par le coronavirus SARS-CoV-2 dans un orga- nisme. Grâce à l'administration d'au moins une composition selon l'invention, le titre infectieux dans l'orga- nisme peut diminuer par rapport à celui prélevé précédemment chez le même patient, et de préférence le vi- rus ne sera plus détectable dans l'organisme. Le terme « traitement » désigne aussi le fait d'atténuer au moins un des symptômes associés à l'infection virale (syndrome respiratoire aigue, fièvre, céphalée, diarhée, vomis- sement, défaillance rénale, toux, etc...). Les compositions selon l'invention sont également destinées à une utilisation dans la prévention d'une infection par le SARS-CoV-2. The term "treatment" refers to combating infection with the SARS-CoV-2 coronavirus in an organism. Thanks to the administration of at least one composition according to the invention, the infectious titre in the organism can decrease compared to that taken previously from the same patient, and preferably the virus will no longer be detectable in the organism. the body. The term “treatment” also designates the act of reducing at least one of the symptoms associated with the viral infection (acute respiratory syndrome, fever, headache, diarrhea, vomiting, renal failure, cough, etc.). The compositions according to the invention are also intended for use in the prevention of infection by SARS-CoV-2.
Au sens de l'invention, le terme « prévention » désigne le fait d'empêcher, ou du moins de dim inuer la proba- bilité d'apparition, d'une infection dans un organisme humain ou animal par le SARS-CoV-2. For the purposes of the invention, the term “prevention” denotes the fact of preventing, or at least reducing the probability of bility of onset of infection in a human or animal organism by SARS-CoV-2.
Les compositions selon l'invention peuvent être de type alimentaire, pharmaceutique, destinées à être admi- nistrées à un être humain. Selon l'invention, le terme « véhicule pharmaceutique approprié » désigne des véhicules ou des excipients, c'est à dire des composés ne présentant pas d'action propre sur l'infection ici considérée. Ces véhicules ou ex- cipients sont pharmaceutiquement acceptables, ce qui signifie qu'ils peuvent être administrés à un individu sans génération d'effets délétères significatifs. L'invention porte selon un aspect sur un composé de formule 2,6-di-tert-butyl-4-R-phénol ou
Figure imgf000013_0001
dans laquelle R est CH3 ou
Figure imgf000013_0002
pour la prévention et/ou le traitement des infections à bétaCoronavirus, en particulier de la Covid-19. The compositions according to the invention may be of the food or pharmaceutical type intended to be administered to a human being. According to the invention, the term “suitable pharmaceutical vehicle” denotes vehicles or excipients, ie compounds not exhibiting any specific action on the infection considered here. These vehicles or excipients are pharmaceutically acceptable, which means that they can be administered to an individual without generating significant deleterious effects. The invention relates in one aspect to a compound of formula 2,6-di-tert-butyl-4-R-phenol or
Figure imgf000013_0001
where R is CH3 or
Figure imgf000013_0002
for the prevention and / or treatment of betaCoronavirus infections, in particular Covid-19.
Les composés de formule (I) dans laquelle R est CH3 (BHT), R est OCH3 (BG1), R est CH20H (BG2), R est COOH (BG3), sont particulièrement intéressants pour la prévention ou traitement de symptomes liés à l'infection par les bétacoronavirus, en particulier les coronavirus associés au syndrome respiratoire aigu sé- vère (SRAS), et plus particulièrement les symptômes lier au SARS-CoV2 ou Covid-19. Un composé de formule I, de préférence R est COOH, CHO, CH2-OH, CO-CH3 pour son utilisation dans la prévention et/ou le traitement d'une infection par le SARS-Cov, MERS-Cov, SARS-Cov-2 est un aspect de la présente invention. Un composé de formule I, de préférence dans laquelle R est CH3, pour son utilisation dans la prévention et/ou le traitement d'une infection par le SARS-CoV-2, est un aspect de la présente invention. The compounds of formula (I) in which R is CH3 (BHT), R is OCH3 (BG1), R is CH20H (BG2), R is COOH (BG3), are particularly useful for the prevention or treatment of symptoms related to the infection with betacoronaviruses, in particular the coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or Covid-19. A compound of formula I, preferably R is COOH, CHO, CH2-OH, CO-CH3 for its use in the prevention and / or treatment of infection by SARS-Cov, MERS-Cov, SARS-Cov- 2 is one aspect of the present invention. A compound of formula I, preferably wherein R is CH3, for use in the prevention and / or treatment of infection with SARS-CoV-2, is one aspect of the present invention.
Les composés de la formule (I), sont décrits et fabriqués dans EP0557404B1, incorporé en entier par référen- ce dans la présente demande. The compounds of formula (I) are described and manufactured in EP0557404B1, incorporated in full by reference in the present application.
Une composition comprenant un composé de formule (I) peut être utilisée pour la prévention ou le traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particulièrement les symptomes liés au SARS-Cov-2 , pour la prévention ou traitement de la Covid-19. A composition comprising a compound of formula (I) can be used for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly symptoms linked to SARS-Cov- 2, for the prevention or treatment of Covid-19.
Selon un mode de réalisation particulier, le BG1 est combiné à un composé sélectionné parmi N-acétyl cystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particulièrement les symp- tômes lier au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG1 is combined with a compound selected from N-acetyl cysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
Selon un mode de réalisation particulier, le BG2 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particulièrement les symp- tômes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG2 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid- 19.
Selon un mode de réalisation particulier, le BG3 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particulièrement les symp- tômes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG3 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid- 19.
Selon un mode de réalisation particulier, le BG4 est combiné à un composé sélectionné parmi N-acétyl cystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particulièrement les symp- tômes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG4 is combined with a compound selected from N-acetyl cysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
Selon un mode de réalisation particulier, le BG1 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particuliè- rement les symptomes lier au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. Selon un mode de réalisation particulier, le BG2 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particuliè- rement les symptomes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG1 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19. According to a particular embodiment, BG2 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
Selon un mode de réalisation particulier, le BG3 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particuliè- rement les symptomes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG3 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
Selon un mode de réalisation particulier, le BG4 est combiné à un composé sélectionné parmi N-acétylcystéi- ne, Catalase, Superoxide dismutase (SOD), adénosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE et une combinaison des ces composés, pour la prévention ou traitement de symptomes liés à l'infection par les coronavirus associés au syndrome respiratoire aigu sévère (SRAS), et plus particuliè- rement les symptomes liés au SARS-CoV2 ou pour la prévention ou traitement de la Covid-19. According to a particular embodiment, BG4 is combined with a compound selected from N-acetylcysteine, Catalase, Superoxide dismutase (SOD), adenosine triphosphate (ATP), gluthation (GSH), Boswellia ser- rata, NATTOKINASE and a combination of these compounds, for the prevention or treatment of symptoms linked to infection by coronaviruses associated with severe acute respiratory syndrome (SARS), and more particularly the symptoms linked to SARS-CoV2 or for the prevention or treatment of Covid -19.
BUT L' hydroxy toluène butylé, BHT ou 2,6-di-tert-butyl-4-méthylphénol est une molécule obtenue par synthèse. 11 résulte de la réaction entre le p-crésoî et l'isobutylène. Ce dérivé phénolique renferme un hydrogène labile qui peut être cédé à tout corps gras oxydable. Le BHT est considéré comme un anti-oxydant aussi efficace que la vitamine E. Breveté initialement en 1947 pour des applications dans l'industrie du caoutchouc, la classification de cet ad- ditif est dans la catégorie des ingrédients « généralement reconnus comme sûrs » (GRAS). PURPOSE Butylated hydroxy toluene, BHT or 2,6-di-tert-butyl-4-methylphenol is a molecule obtained by synthesis. It results from the reaction between p-cresol and isobutylene. This phenolic derivative contains a labile hydrogen which can be transferred to any oxidizable fatty substance. BHT is considered as an anti-oxidant as effective as vitamin E. Initially patented in 1947 for applications in the rubber industry, the classification of this additive is in the category of ingredients "generally recognized as safe" ( FAT).
Le Cosmetic Ingrédient Review (CIR) vient de conclure, une nouvelle fois, à son caractère sûr d'emploi (https://www.cir-safety.org/sites/defauit/files/BHT.pdf). Depuis sa mise sur le marché, le BHT a fait l'objet de très nombreuse études (environ 15 000 publication). Un effet protecteur du BHT utilisé par voie orale vis-à-vis de la carcinogenèse a même été évoqué (Barsha Dassarma, Dilip K. Nandi, Somnath Gangopadhyay, Saptadip Samanta, Hepatoprotective effeet of food pre- servatives (butyiated hydroxyanisole, butylated hydroxytoluene) on carbon tetrachloride-mduced hepatotoxi- city m rat, Toxicology Reports, 5, 2018, Pages 31-37). Ses propriétés antivirales sont exploitées, en plus de l'effet antioxydant classiquement reconnu (Merino O, Aguagüina WE, Esponda P, Risopatrón J, Isachenko E, Isachenko V, Sanchez R., Protective effeet of bu- tylated hydroxytoluene on sperm fonction in human spermatozoa cryopreserved by vitrification techni- que, Andrologia,, 2015, 47, 2, Pages 186-193). The Cosmetic Ingredient Review (CIR) has once again concluded that it is safe to use (https://www.cir-safety.org/sites/defauit/files/BHT.pdf). Since its introduction on the market, BHT has been the subject of numerous studies (approximately 15,000 publications). A protective effect of BHT used orally against carcinogenesis has even been mentioned (Barsha Dassarma, Dilip K. Nandi, Somnath Gangopadhyay, Saptadip Samanta, Hepatoprotective effect of food preservatives (butyiated hydroxyanisole, butylated hydroxytoluene) on carbon tetrachloride-mduced hepatotoxi- city m rat, Toxicology Reports, 5, 2018, Pages 31-37). Its antiviral properties are exploited, in addition to the classically recognized antioxidant effect (Merino O, Aguagüina WE, Esponda P, Risopatrón J, Isachenko E, Isachenko V, Sanchez R., Protective effect of butylated hydroxytoluene on sperm function in human spermatozoa cryopreserved by vitrification techni- que, Andrologia ,, 2015, 47, 2, Pages 186-193).
Le BHT est aussi connu comme antiviral agissant sur des virus comme le virus de l'herpès ou le virus de la polio (US4350707A). Le document US7696330B2 suggère le BHT comme excipient possible dans une com- position destinée à traiter un SARS-Cov, mais le BHT n'a jamais été décrit comme un principe actif encore moins un principe actif anti -viral anti-SARS-Cov, ou anti-SARS-Cov-2. BHT is also known as an antiviral agent acting on viruses such as the herpes virus or the polio virus (US4350707A). Document US7696330B2 suggests BHT as a possible excipient in a composition intended to treat SARS-Cov, but BHT has never been described as an active principle, much less an anti-virus anti-SARS-Cov active principle, or anti-SARS-Cov-2.
Son utilisation comme anti-viral pour traiter une infection par un bétacoronavirus tel que le SARS-Cov-2, SARS-Cov, ou même MERS-Cov n'a jamais été même suggérée. Its use as an anti-viral to treat a beta-coronavirus infection such as SARS-Cov-2, SARS-Cov, or even MERS-Cov has never even been suggested.
Les inventeurs ont identifié l'activité antivirale du BHT sur le SARS-Cov-2, en particulier lorsque le BHT est utilisé avec un autre composé. Les premiers résultats suggèrent que le BHT seul diminue nettement les symptômes induits par ce virus. The inventors have identified the antiviral activity of BHT on SARS-Cov-2, in particular when BHT is used with another compound. The first results suggest that BHT alone markedly decreases the symptoms induced by this virus.
Le BHT réduit la charge virale infectieuse. BHT reduces the infectious viral load.
L'intérêt du BHT est qu'il est très actif contre le SARS-Cov2 et un complément alimentaire, son utilisation pour prévenir ou traiter la Covid-19 est particulièrement intéressante. The interest of BHT is that it is very active against SARS-Cov2 and a food supplement, its use to prevent or treat Covid-19 is particularly interesting.
Selon un aspect, la présente invention concerne une composition pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2 (Covid-19), caractérisée en ce qu'elle com- prend, dans un véhicule pharmaceutique approprié, un composé de formule 2,6-di-tert-butyl-4-méthylphénol (BHT), Selon un aspect, la présente invention concerne une composition pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2 (Covid-19), caractérisée en ce qu'elle com- prend, dans un véhicule pharmaceutique approprié, un composé BG1 ou BG2 ou BG3 ou BG4. According to one aspect, the present invention relates to a composition for its use in the prevention and / or treatment of an infection by the coronavirus SARS-CoV-2 (Covid-19), characterized in that it comprises, in a suitable pharmaceutical carrier, a compound of formula 2,6-di-tert-butyl-4-methylphenol (BHT), According to one aspect, the present invention relates to a composition for its use in the prevention and / or treatment of a infection with the coronavirus SARS-CoV-2 (Covid-19), characterized in that it comprises, in an appropriate pharmaceutical vehicle, a compound BG1 or BG2 or BG3 or BG4.
DOSES DOSES
La posologie quotidienne du BHT (ou de BG1 à BG4) pourra varier de 0,01 à 1 000 mg/kg chez l'adulte par jour. Typiquement, les compositions contiennent 0,01 ; 0,05 ; 0,1 ; 0,5 : 1,0 ; 2,5 ; 5,0 ; 10,0 : 15,0 : 25,0 ; 50,0 ; 100 ; 250,0. ; 500,0 ; 700,0 ; 800,0 ; 900,0 ; 1000,0 ; 1500,0 ; 2000,0 ; 3000,0 ; 4000,0 ou 5000,0 mg/kg de BHT selon l'invention. The daily dosage of BHT (or BG1 to BG4) may vary from 0.01 to 1000 mg / kg in adults per day. Typically, the compositions contain 0.01; 0.05; 0.1; 0.5: 1.0; 2.5; 5.0; 10.0: 15.0: 25.0; 50.0; 100; 250.0. ; 500.0; 700.0; 800.0; 900.0; 1000.0; 1500.0; 2000.0; 3000.0; 4000.0 or 5000.0 mg / kg of BHT according to the invention.
Selon un aspect la dose maximale adminsitrée par voie orale de BHT est lg/kg en poids. http://www.scc-que- bec .org/wp-content/uploads/2017/08/BHT-Marilou-N adeau-2016.pdf. According to one aspect, the maximum oral dose of BHT is 1 g / kg by weight. http: //www.scc-que- bec .org / wp-content / uploads / 2017/08 / BHT-Marilou-N adeau-2016.pdf.
Une composition selon l'invention contient d'environ 0,01 mg à environ 5 000 mg de BHT, selon l'invention, de préférence de 1 mg à environ 1000 mg de BHT, plus prérentiellement 300 mg ou 500 mg de BHT. A composition according to the invention contains from about 0.01 mg to about 5000 mg of BHT, according to the invention, preferably from 1 mg to about 1000 mg of BHT, more preferably 300 mg or 500 mg of BHT.
Une quantité efficace du BHT, seul ou dans une composition selon l'invention est fournie à un niveau poso- logique allant de 0,0002 mg / kg à environ 2 g / kg de poids corporel par jour, en particulier d'environ 0,001 mg / kg à 900 mg /kg de poids corporel par jour ; de 75 à 400 mg/kg de poids corporel par jour, ou 0.3 mg/kg de poids corporel par jour. An effective amount of BHT, alone or in a composition according to the invention is provided at a dosage level ranging from 0.0002 mg / kg to about 2 g / kg of body weight per day, in particular about 0.001. mg / kg to 900 mg / kg body weight per day; 75 to 400 mg / kg body weight per day, or 0.3 mg / kg body weight per day.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg (ou 500 mg) 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500mg 3 fois par jour_± 200mg, chez un individu pesant entre 61 à 90 kg, ± 100 mg 3 fois par jour, ou pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours. According to one embodiment, BHT is administered at a dose of 300 mg (or 500 mg) 3 times a day, in an individual weighing between 40 to 60 kg, or 500 mg 3 times a day_ ± 200 mg, in an individual weighing between 61 at 90 kg, ± 100 mg 3 times a day, or for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days.
La durée du traitement, les doses, les voies d'injection (po, in, sl, iv) seront évalués en fonction de l'évolu- tion des symptomes de la Covid-19. The duration of treatment, the doses, the injection routes (po, in, sl, iv) will be evaluated according to the evolution of the symptoms of Covid-19.
Ces doses correspondent à une activité anti-SARS-Cov-2 du BHT utilisé en tant que médicament. These doses correspond to an anti-SARS-Cov-2 activity of BHT used as a drug.
Un médicament est toute substance ou composition présentée comme possédant des propriétés curatives ou préventives à l'égard des maladies humaines ou animales A drug is any substance or composition presented as having curative or preventive properties with regard to human or animal diseases.
Dans un mode de réalisation particulier, le BHT ou le BHT dans une composition comprenant le BHT selon l'invention peut être utilisé à une concentration comprise entre 0,01 μM et 200 μM, ou à une concentration de 0,01 ; 0,05 ; 0,1 ; 0,5 ; 1,0 ; 2,5 ; 5,0 ; 10,0 ; 15,0 ; 20,0 μM. In a particular embodiment, the BHT or the BHT in a composition comprising the BHT according to the invention can be used at a concentration of between 0.01 μM and 200 μM, or at a concentration of 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 20.0 μM.
Dans un mode de réalisation particulier, le BHT ou le BHT dans une composition comprenant le BHT selon l'invention peut être utilisé à une concentration comprise entre 0,01 mM et 200 mM, ou à une concentration de 0,01 ; 0,05 ; 0,1 ; 0,5 ; 1,0 : 2,5 ; 5,0 ; 10,0 ; 15,0 ; 20,0 mM. In a particular embodiment, the BHT or the BHT in a composition comprising the BHT according to the invention can be used at a concentration of between 0.01 mM and 200 mM, or at a concentration of 0.01; 0.05; 0.1; 0.5; 1.0: 2.5; 5.0; 10.0; 15.0; 20.0 mM.
L'invention porte sur de nouvelles compositions comprenant le BHT et un autre antioxidant. New compositions are provided comprising BHT and another antioxidant.
L'invention porte aussi sur de nouvelles compositions comprenant le BHT, un autre antioxidant, et un anti-in- flammatoire. The invention also relates to novel compositions comprising BHT, another antioxidant, and an anti-inflammatory.
Parmi les anti oxydants selon l'invention combinés au BHT, la quercétine est particulièrement préférée.Among the antioxidants according to the invention combined with BHT, quercetin is particularly preferred.
La présente invention porte sur la quercétine pour le traitement ou la prévention de la Covid-19. The present invention relates to quercetin for the treatment or prevention of Covid-19.
La présente invention porte sur la quercétine pour le traitement ou la prévention de la Covid-19, utilisée à la dose de 200 mg trois fois par jour. The present invention relates to quercetin for the treatment or prevention of Covid-19, used at a dose of 200 mg three times a day.
La présente invention porte sur la quercétine et le BHT pour le traitement ou la prévention de la Covid-1 ; L a quercétine à la dose de 200 mg trois fois par jour en combinaison avec le BHT à la dose de 250 mg 1 à 3 fois par jour, The present invention relates to quercetin and BHT for the treatment or prevention of Covid-1; Quercetin at a dose of 200 mg three times a day in combination with BHT at a dose of 250 mg 1 to 3 times a day,
La présente invention porte aussi sur le glutathion pour la prévention ou le traitement de la Covid-19,The present invention also relates to glutathione for the prevention or treatment of Covid-19,
La présente invention porte aussi sur la N acétylcytéine associée au glutathion pour la prévention ou le traite- ment de la Covid-19. The present invention also relates to N acetylcyteine associated with glutathione for the prevention or treatment of Covid-19.
La présente invention porte aussi sur la Boswellia Serrata (avec au moins 40% d'acides boswelliques par rap- port au poids total) pour la prévention ou le traitement de la Covid-19, The present invention also relates to Boswellia Serrata (with at least 40% of boswellic acids relative to the total weight) for the prevention or treatment of Covid-19,
La présente invention porte sur la CASPEROME (R) pour la pré vention ou le traitement de la Covid-19 La présente invention porte aussi sur la N acétylcytéine et la Boswellia serrata (avec au moins 40% d'acides boswelliques par rapport au poids total) pour la prévention ou le traitement de la Covid-19, La présente invention porte aussi sur la SOD pour la prévention ou le traitement de la Covid-19, SOD en combinaison avec Zn, Cu, Mg, The present invention relates to CASPEROME (R) for the prevention or treatment of Covid-19 The present invention also relates to N acetylcytein and Boswellia serrata (with at least 40% of boswellic acids relative to the total weight ) for the prevention or treatment of Covid-19, The present invention also relates to SOD for the prevention or treatment of Covid-19, SOD in combination with Zn, Cu, Mg,
La présente invention porte aussi sur la CAT pour la prévention ou le traitement de la Covid-19, The present invention also relates to CAT for the prevention or treatment of Covid-19,
La présente invention porte aussi sur la GSH, en particulier le sublinthion (300mg) pour la prévention ou le traitement de la Covid-19, The present invention also relates to GSH, in particular sublinthion (300mg) for the prevention or treatment of Covid-19,
La présente invention porte aussi sur l'ATP pour la prévention ou le traitement de la Covid-19, The present invention also relates to ATP for the prevention or treatment of Covid-19,
La présente invention porte aussi sur la SOD+ CAT+ GSH + ATP pour la prévention ou le traitement de la Covid-19. The present invention also relates to SOD + CAT + GSH + ATP for the prevention or treatment of Covid-19.
La présente invention porte aussi sur la mattokinase pour la prévention ou le traitement de la Covid-19, The present invention also relates to mattokinase for the prevention or treatment of Covid-19,
COMPOSITIONS COMPOSITIONS
2,6-di-tert-butyl-4-méthyl-phénol (BHT) pour la prévention et/ou le traitement d'une infection par un corona- virus SARS-CoV-2, 2,6-di-tert-butyl-4-methyl-phenol (BHT) for the prevention and / or treatment of infection by a SARS-CoV-2 corona virus,
Une composition ou un kit comprenant la quercétine et le BHT A composition or kit comprising quercetin and BHT
BHT pour son utilisation selon l'invention, caractérisé en ce que le BHT est combiné à un autre antioxidant, et/ou un anti-inflammatoire, avantageusement à la N-acétylcystéine (NAC) et/ou à la Boswellia Serrata (BS), et /ou la nattokinase, avantageusement dans une formulation galénique destinée à l' administration orale. BHT for its use according to the invention, characterized in that the BHT is combined with another antioxidant, and / or an anti-inflammatory, advantageously with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS), and / or nattokinase, advantageously in a galenic formulation intended for oral administration.
2,6-di-tert-butyl-4-méthyl-phénol (BHT) en combinaison avec l'un quelconque des principes actifs sélection- nés parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et. une combinaison de ces principes actifs. 2,6-di-tert-butyl-4-methyl-phenol (BHT) in combination with any of the active ingredients selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT ), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and. a combination of these active ingredients.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV- 2 An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus
Un principe actif sélectionné parmi Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active ingredient selected from Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active ingredient selected from N-acetylcysteine (NAC), Nattokinase, Catalase (CAT), Superoxide dis- mutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or the treatment of an infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Catalase (CAT), Su- peroxide dismutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2.An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Super- oxide dismutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces princi- pes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active principle selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Super- oxide dismutase (SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active principles, for prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT),, gluthation (GSH), Adénosine triphosphate (ATP), et une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), Adénosine triphosphate (ATP), et une combinaison de ces principes ac- tifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-Co V-2, An active principle selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), Adenosine triphosphate (ATP), and a combination of these active principles, for prevention and / or the treatment of an infection with a SARS-Co V-2 coronavirus,
Un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), et une combinaison de ces principes actifs, pour la pré vention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active ingredient selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), and a combination of these active ingredients, for prevention and / or treatment of an infection with a SARS-CoV-2 coronavirus.
Un principe actif sélectionné parmi 2,6-di-tert-butyl-4-méthyl-phénol (BHT), N-acétylcystéine (NAC), Bos- wellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adénosi- ne triphosphate (ATP), une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. An active principle selected from 2,6-di-tert-butyl-4-methyl-phenol (BHT), N-acetylcysteine (NAC), Bos- wellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD) ), gluthation (GSH), Adenosine triphosphate (ATP), a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV-2 coronavirus.
2,6-di-tert-butyl-4-méthyl-phénol (BHT), et/ou un principe actif sélectionné parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adé- nosine triphosphate (ATP), et une combinaison de ces principes actifs. 2,6-di-tert-butyl-4-methyl-phenol (BHT), and / or an active principle selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase ( SOD), gluthation (GSH), Adenosine triphosphate (ATP), and a combination of these active ingredients.
Principe actif pour son utilisation selon la revendication 1, dans une formulation galénique destinée à une voie d'administration sélectionnée parmi administration orale, intranasale, sublinguale, intraveineuse, intra- rectale, mtraoculaire, en inhalation, ou une combinaison de ces voies d'administration. Active principle for its use according to claim 1, in a galenic formulation intended for a route of administration selected from oral, intranasal, sublingual, intravenous, intra-rectal, mtraocular, inhalation, or a combination of these administration routes. .
Composition comprenant un principe actif selon la revendication 1 ou kit comprenant un mois deux principe actif selon la revendication 1 ou 2 et un excipient acceptable. Composition comprising an active principle according to claim 1 or a kit comprising one month two active principle according to claim 1 or 2 and an acceptable excipient.
Composition ou kit selon la revendication 3 comprenant le BHT Composition or kit according to claim 3 comprising BHT
Composition ou kit selon la revendication 4 caractérisé en ce que le BHT est à une dose de 0,01 mg à 1g, de 0.1 mg à 10 mg, de 1 mg à 100 mg, de 100 mg à 900 mg, de 300 mg à 500 mg, avantageusement administré à une dose de 0,1 mg/kg à Ig/kg, de 1 mg/kg à 0.1 g/kg, de 10 mg/kg à 800 mg/kg, de 100mg/kg à 90Qmg/kg ; de 300mg/kg à 500 mg/kg en poids ; ou encore avantageusement administré à une dose de 0,1 mg/individu à Ig/individu de 1 mg/individu à 0.1g/individu, de 10 mg/individu à 800 mg/individu, de 100mg/mdividu à 900mg/mdividu : de 300mg/indivi- du à 500 mg/individu ; ou encore plus avantageusement administré par jour à une dose de 0,1 mg/individu à 1 g/individu de 1 mg/in- dividu à O.lg/individu, de 10 mg/individu à 800 mg/individu, de 100mg/individu à 900mg/individu ; de 300mg/individu à 500 mg/individu ; ou encore plus avantageusement administré par jour à une dose de 0,1 mg/individu à 1 g/individu de 1 mg/in- dividu à O.lg/individu, de 10 mg/individu à 800 mg/individu, de 100mg/individu à 900mg/individu ; de 300mg/individu à 500 mg/individu pendant au moins 5 jours. Composition or kit according to Claim 4, characterized in that the BHT is at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 100 mg to 900 mg, from 300 mg to 500 mg, advantageously administered at a dose of 0.1 mg / kg to Ig / kg, from 1 mg / kg to 0.1 g / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 90 mg / kg ; from 300 mg / kg to 500 mg / kg by weight; or again advantageously administered at a dose of 0.1 mg / individual to Ig / individual from 1 mg / individual to 0.1 g / individual, from 10 mg / individual to 800 mg / individual, from 100 mg / individual to 900 mg / individual: from 300 mg / individual to 500 mg / individual; or even more advantageously administered per day at a dose of 0.1 mg / individual to 1 g / individual of 1 mg / in dividu at O.lg / individual, from 10 mg / individual to 800 mg / individual, from 100 mg / individual to 900 mg / individual; from 300 mg / individual to 500 mg / individual; or even more advantageously administered per day at a dose of 0.1 mg / individual to 1 g / individual from 1 mg / individual to 0.1 g / individual, from 10 mg / individual to 800 mg / individual, from 100 mg / individual at 900 mg / individual; from 300mg / individual to 500 mg / individual for at least 5 days.
Ces doses pouvant être administrées pendant au moins 7, 8, 9, 10, il, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 jour, la durée de temps pouvat être doublée ou triplée, voire quadruplée ou multipliée par 5, 6, 7, 8, 9, 10, 11, 12. These doses can be administered for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 days, the length of time can be doubled or tripled, even quadrupled or multiplied by 5, 6, 7, 8, 9, 10, 11, 12.
Composition ou kit selon l'invention caractérisé en ce que la BS est administrée à un individu à la dose de 250 mg, l'Acéthylcystéine à la dose de 100 mg, le BHT est à une dose de 150 mg, en combinaison avec de l'huile végétale, la composition ou le kit étant adminsitré deux fois par jour pendant 30 jours, Composition or kit according to the invention characterized in that BS is administered to an individual at a dose of 250 mg, Acethylcysteine at a dose of 100 mg, BHT is at a dose of 150 mg, in combination with 'vegetable oil, the composition or the kit being adminsitré twice a day for 30 days,
7. Composition ou kit selon l'invention caractérisé en ce que la SOD est administrée par voie orale à un indi- vidu à la dose de 100 mg, l'Acéthylcystéine à la dose de 50 mg, le BHT est à une dose de 250 mg, en combi- naison avec de l'huile végétale, la Nattokinase est administrée à la dose de 50 mg, le gluthation est adminis- tré à la dose de 50mg, la composition ou le kit étant adminsitré toutes les 12 heures pendant 21 jours. 7. Composition or kit according to the invention characterized in that SOD is administered orally to an individual at a dose of 100 mg, Acethylcysteine at a dose of 50 mg, BHT is at a dose of 250. mg, in combination with vegetable oil, Nattokinase is administered at a dose of 50 mg, gluthation is administered at a dose of 50 mg, the composition or the kit being administered every 12 hours for 21 days .
Composition ou kit selon l'invention caractérisé en ce que la SOD est administrée par voie orale à un indivi- du à la dose de 100 mg, TAcéthylcystéine à la dose de 50 mg, le BHT est à une dose de 250 mg, en combi- naison avec de l'huile végétale, la Nattokinase est administrée à la dose de 50 mg, le gluthation est adminis- tré à la dose de 50mg, la composition ou le kit étant adminsitré toutes les 8 heures pendant 14 jours. Composition or kit according to the invention characterized in that the SOD is administered orally to an individual at a dose of 100 mg, TAcethylcysteine at a dose of 50 mg, BHT is at a dose of 250 mg, in combination - Nation with vegetable oil, Nattokinase is administered at a dose of 50 mg, gluthation is administered at a dose of 50 mg, the composition or the kit being administered every 8 hours for 14 days.
Composition ou kit pour son utilisation selon l'un quelconque des modes de réalisatios précédants caractérisé en ce que le BHT est combiné en outre à de TAdénosine Triphosphate (ATP). Composition or kit for its use according to any one of the preceding embodiments, characterized in that the BHT is further combined with TAdenosine Triphosphate (ATP).
BHT pour son utilisation selon l'une queîconconque des modes de réalisations précédants caractérisé en ce que le BHT est combiné à la Nattokinase et /ou de TAdénosine TriPhosphate (ATP). BHT for its use according to one of the preceding embodiments, characterized in that the BHT is combined with Nattokinase and / or TAdenosine TriPhosphate (ATP).
BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est utilisé à une dose de 0,01 mg à lg, de 0.1 mg à 10 mg, de 1 mg à 100 mg, de 100 mg à 900 mg, de 300 mg à 500 mg, avantageusement à une dose de 0,1 mg/kg à Ig/kg, de 1 mg/kg à 0. Ig/kg, de 10 mg/kg à 800 mg/kg, de 100mg/kg à 900mg/kg ; de 300mg/kg à 500 mg/kg en poids. BHT for its use according to the invention characterized in that the BHT is used at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 100 mg to 900 mg, from 300 mg to 500 mg, advantageously at a dose of 0.1 mg / kg to Ig / kg, from 1 mg / kg to 0. Ig / kg, from 10 mg / kg to 800 mg / kg, from 100 mg / kg to 900 mg / kg; from 300 mg / kg to 500 mg / kg by weight.
BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré au moins par voie ora- le, et par voie intraveineuse, sublinguale, rectale, par inhalation, pour metre en contact le BHT avec le SARS-Cov-2 dès le début du contact. BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré 1 à 3 fois par jour, avantageusement de 1 à 3 fois par jour pendant au moins 5 jours à au moins 14 jours. BHT for its use according to the invention, characterized in that the BHT is administered at least by the oral route, and by the intravenous, sublingual, rectal route, by inhalation, to bring the BHT into contact with the SARS-Cov-2 from the start of contact. BHT for its use according to the invention, characterized in that the BHT is administered 1 to 3 times per day, advantageously from 1 to 3 times per day for at least 5 days to at least 14 days.
BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré à des individus pré- sentant ou non des symptômes de la Covid-19. BHT for its use according to the invention, characterized in that the BHT is administered to individuals who may or may not have symptoms of Covid-19.
BHT pour son utilisation selon l'invention caractérisé en ce que le BHT est administré à un individu infecté par le SARS-Cov-2 présentant au moins un symptôme choisi parmi toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, anosmie, agueusie, perte d'appétit, avanta- geusement dans une formulation galénique appropriée à une administration par voie orale. BHT for its use according to the invention, characterized in that the BHT is administered to an individual infected with SARS-Cov-2 exhibiting at least one symptom chosen from cough, dyspnea, fatigue, sore throat, gastrointestinal disorders, pain intestinal, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
BHT pour son utilisation selon l'invention caractérisé par une utilisation chez un individu infecté par le SARS-Cov-2 présentant des symptomes sélectionnés parmi toux et syndrome respiratoire aigu sévère, avan- tageusement dans une formulation galénique appropriée à une administration par voie intraveineuse et/ou par inhalation. BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms selected from cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration and / or by inhalation.
Selon un aspect , la présente invention porte sur une composition comprenant le BHT et un (autre) anti-oxy- dant et un véhicule pharmaceutiquement acceptable. In one aspect, the present invention relates to a composition comprising BHT and an (other) anti-oxidant and a pharmaceutically acceptable carrier.
Les antioxydants sont des molécules qui possèdent la propriété d'empêcher les réactions en chaîne néfastes provoquées par les radicaux libres. Le BHT est considéré comme un antioxydant, comme la SOD, CAT, G SH et la NA C, Antioxidants are molecules that have the property of preventing harmful chain reactions caused by free radicals. BHT is considered an antioxidant, like SOD, CAT, G SH and NA C,
On parle de stress oxydant lorsque les cellules font face à un afflux de radicaux libres ou d'espèces réactives de l'oxygène. Ces composés, s'ils ne sont pas neutralisés par des antioxydants, peuvent contribuer à oxyder et donc à dégrader les composants cellulaires. We talk about oxidative stress when cells face an influx of free radicals or reactive oxygen species. These compounds, if they are not neutralized by antioxidants, can help oxidize and therefore degrade cellular components.
On entend par anti-oxydant les molécules antioxydantes, Antioxidant is understood to mean antioxidant molecules,
- les vitamines A, E, C, les caroténoïdes et les polyphénols. - vitamins A, E, C, carotenoids and polyphenols.
- les enzymes de détoxification, - detoxification enzymes,
* le glutathion, (G SH) * glutathione, (G SH)
* la super oxyde dismutase (SOD - que l'on trouve de manière naturelle dans la spiruline) en complément avec le cuivre, le zinc et le magnésium, * super oxide dismutase (SOD - found naturally in spirulina) in addition to copper, zinc and magnesium,
* mais aussi la catalase (CAT) (enzyme qui protège l'organisme des effets néfastes du péroxyde d'hydrogè- ne), la thioredoxine (protéine d'oxydoréduction qui agit comme un antioxydant, indispensable aux mam- mifères). * but also catalase (CAT) (enzyme which protects the organism from the harmful effects of hydrogen peroxide), thioredoxin (redox protein which acts as an antioxidant, essential for mammals).
* la NAC est aussi considérée comme antioxydant, elle active la production de GSH par les cellules. • La Nattokinase (EC 3.4.21,62) qui a une activité fibrynolytique, (enzyme dérivée d'un aliment japonais appelé nattô. Le nattô est produit par fermentation en ajoutant la bactérie Bacillus natto, qui produit égale- ment l'enzyme, au soja bouilli). * NAC is also considered as an antioxidant, it activates the production of GSH by cells. • Nattokinase (EC 3.4.21,62) which has fibrynolytic activity, (enzyme derived from a Japanese food called nattô. Nattô is produced by fermentation by adding the bacterium Bacillus natto, which also produces the enzyme, with boiled soy).
• La quercétine ou le quercétol de formule 3,3',4',5,7-pentahydroxy-2-phénylchromén-4-one ou 2-(3,4-dihy- droxyphényl)-3,5,7-trihydroxy-4H-chromén-4-one, est un composé organique de la famille des flavonoï- des, plus précisément du sous-groupe des flavonols. C'est un métabolite secondaire présent dans certaines plantes • Quercetin or quercetol of formula 3,3 ', 4', 5,7-pentahydroxy-2-phenylchromén-4-one or 2- (3,4-dihy-droxyphenyl) -3,5,7-trihydroxy- 4H-chromen-4-one, is an organic compound of the flavonoid family, more precisely of the flavonol subgroup. It is a secondary metabolite present in some plants
Les antioxydants selon l'invention sont : Hydroxytoluène butylé, ou 2,6-di-Ar/-butyl-4-méthylphénol - ( B HT ) (antiviral, anti-oxydant), le Glutathion (GSH): acide 2-amino-5-{ [2-[(carboxyméthyl)amiûo]- 1 -(mercaptométhyl)-2-oxoéthyl]ami- no } -5 -oxopentanoïque . The antioxidants according to the invention are: Butylated hydroxytoluene, or 2,6-di-Ar / -butyl-4-methylphenol - (B HT) (antiviral, antioxidant), Glutathione (GSH): 2-amino acid- 5- {[2 - [(carboxymethyl) amino] - 1 - (mercaptomethyl) -2-oxoethyl] amino} -5 -oxopentanoic acid.
Selon l'invention le GSH utilisé dans la prévention ou le traitement de la Covid-19 est le glutathion réduit, la N-acétylcystéine ou acétylcystéine (C5H9NO3S ou R)- N-acétyl-L-cystéine) (MAC) qui est un acide animé non essentiel, et stimule la production de glutathion. According to the invention, the GSH used in the prevention or treatment of Covid-19 is reduced glutathione, N-acetylcysteine or acetylcysteine (C 5 H 9 NO 3 S or R) - N-acetyl-L-cysteine) ( MAC) which is a lively nonessential acid, and stimulates the production of glutathione.
La Superoxyde Dismutase (SOD). On entend par SOI) des métailoprotéines de classification EC 1.15.1.1 à Cu Zn Fe ou Mn. N° CAS : 9054-89-1. Superoxide Dismutase (SOD). The term SOI) is understood to mean metailoproteins of classification EC 1.15.1.1 with Cu Zn Fe or Mn. CAS No: 9054-89-1.
Cette enzyme intervient dans l'explosion oxydative et est également une composante essentielle du mécams me d'élimination des radicaux libres. La Cataiase (CAT) est une oxydoreductase à hème de classification N° EC 1.11.1.6. This enzyme is involved in the oxidative explosion and is also an essential component of the free radical elimination mechanisms. Cataiase (CAT) is a heme oxidoreductase with classification EC No. 1.11.1.6.
L' Adénosine triphosphate (ATF) est un nucléotide de formule : [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4- dihydroxyoxolan-2-y!]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate l'ATP potentialise les effets des anti -oxydants. Adenosine triphosphate (ATF) is a nucleotide of the formula: [[(2R, 3S, 4R, 5R) -5- (6-aminopurin-9-yl) -3,4- dihydroxyoxolan-2-y!] Methoxy- hydroxyphosphoryl] phosphono hydrogen phosphate ATP potentiates the effects of anti-oxidants.
Les antioxidants selon l'invention combinés au BHT peuvent être avantageusement GSH, CAT, SOD, ou GSH, CAT SOD et N AC ; The antioxidants according to the invention combined with BHT can advantageously be GSH, CAT, SOD, or GSH, CAT SOD and N AC;
Les compositions selon l'invention comprenant de la SOD sont optionellement compiémentées en Cuivre Zinc, Magnésium, avantageusement en Zinc. The compositions according to the invention comprising SOD are optionally supplemented with Copper, Zinc, Magnesium, advantageously with Zinc.
Ces antioxydants peuvent être combinés à de l'ATP ce qui augmente encore plus leur activité dans une situ- ation de stress oxydant. Le stress oxydant peut avoir diverses origines : exogènes (pollution atmosphérique, nanoparticules, etc.) ou endogènes (métabolisme énergétique). Souvent négligée, cette dernière catégorie n'en est pas moins signifi- cative. En effet, pour pouvoir fonctionner efficacement, les cellules ont besoin d'ATP, produit par les mito- chondries. Or cette production d'ATP génère des espèces réactives de l'oxygène. Plus les cellules sont sollici- tées, plus elles fabriquent de l'ATP et génèrent du stress oxydant. Apporter de l'ATP sans générer de stress oxydant en présence de BHT et de SOD, CAT, GSH améliore encore les performances antivirales de la com- position selon l'invention sur le SARS-Cov-2. These antioxidants can be combined with ATP which further increases their activity under oxidative stress. Oxidative stress can have various origins: exogenous (atmospheric pollution, nanoparticles, etc.) or endogenous (energy metabolism). Often neglected, this last category is nonetheless significant. In order to be able to function effectively, cells need ATP, produced by the mitochondria. However, this production of ATP generates reactive oxygen species. The more cells are called upon, the more they manufacture ATP and generate oxidative stress. Providing ATP without generating oxidative stress in the presence of BHT and SOD, CAT, GSH further improves the antiviral performance of the composition according to the invention on SARS-Cov-2.
Les antioxidants selon l'invention sont avantageusement GSH, CAT, SOD ou GSH, CAT SOD et NAC asso- ciés ou non à de l'ATP. The antioxidants according to the invention are advantageously GSH, CAT, SOD or GSH, CAT SOD and NAC, whether or not associated with ATP.
En outre, le BHT en présence de glutination (GSH) et de NAC est particulièrement intéressant car le GSH dissocie les molécules de graisses. In addition, BHT in the presence of glutination (GSH) and NAC is particularly interesting because GSH dissociates fat molecules.
Le BHT peut aussi être combiné selon l'invention à un anti-inflammatoire, de préférence à la Boswellia Ser- rata (BS). BHT can also be combined according to the invention with an anti-inflammatory, preferably with Boswellia Serratata (BS).
BS BS
Boswellia Serrata (BS) est une plante dont est issu et produit l'encens. Il est également connu sous le nom d'oli-banum indien, de salai guggul et de sallaki en sanskrit. Bien que les anti-inflammatoires soient décon- seillés vivement dans le cas de la Covid-19, le BS de manière surprenante agit, probablement sur le niveau d'IL-6 qui est généré chez les patients et l'initiateur de la tempête cytokinique. https:/7dumas.ccsd.cnrs.fr/dumas-01845371/document Boswellia Serrata (BS) is a plant from which incense originates and produces. It is also known as Indian oli-banum, salai guggul, and sallaki in Sanskrit. Although anti-inflammatory drugs are strongly discouraged in the case of Covid-19, BS surprisingly acts, probably on the level of IL-6 that is generated in patients and the initiator of the cytokine storm. . https: /7dumas.ccsd.cnrs.fr/dumas-01845371/document
Selon certain mode de réalisation le BHT en combinaison avec BS est à prescrire par voie orale pour un pa- tient Covid-19 souffrant de nausée, diarhée. According to a certain embodiment, BHT in combination with BS is to be prescribed orally for a Covid-19 patient suffering from nausea or diarrhea.
La Boswellia Fort titré à 65% d'acides bosweiliques (ONATERA) est particulièrement intéressante, la Boswellia serrata est bien connue et décrite par exemple dans le document WO2011114350 ou encore dans Gupta I, Gupta V, et al. Effects of Boswellia serrata gum resin in patients with bronchial asth- ma: results of a double-blind, placebo-controlled, 6-week clinical study./itir J Med Res 1998 Nov 17;3( 11):511-4, incorporés par référence. Boswellia Fort titrated at 65% bosweilic acids (ONATERA) is particularly interesting, Boswellia serrata is well known and described for example in document WO2011114350 or also in Gupta I, Gupta V, et al. Effects of Boswellia serrata gum resin in patients with bronchial asth- ma: results of a double-blind, placebo-controlled, 6-week clinical study./itir J Med Res 1998 Nov 17; 3 (11): 511-4, incorporated by reference.
La BS décrite dans WO2011114350_est particulièrement appropriée pour les formulations selon l'invention, en particulier les formulations appropriées pour la voie d'adminsitration iv, si, par inhalation. The BS described in WO2011114350_is particularly suitable for the formulations according to the invention, in particular the formulations suitable for the route of administration iv, si, by inhalation.
La BS selon l'invention comprend au moins The BS according to the invention comprises at least
- l'acide b-boswellique (bBA) : - b-boswellic acid (bBA):
- l'acide a-boswellique (aBA), - a-boswellic acid (aBA),
- l'acide 11-céto-β-boswellique (KBA), - 11-keto-β-boswellic acid (KBA),
- l'acide 3-0-acétyl-11-céto -boswellique (AKBA), - 3-0-acetyl-11-keto -boswellic acid (AKBA),
- l'acide 3-0-acétyl -β-boswellique (AbBA) - 3-0-acetyl -β-boswellic acid (AbBA)
- l'acide 3-0-acétyl -a-boswellique (AaBA). - 3-0-acetyl -a-boswellic acid (AaBA).
En particulier le produit Casperome (R) est particulièrement intéressant pour l'invention. In particular, the product Casperome (R) is particularly advantageous for the invention.
Le BHT est combiné à un composé choisi parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adénosine TriPhosphate (ATP), ou avec deux de ces composés, ou trois de ces composés, ou quatre de ces composés ou cinq de ces composés. BHT is combined with a compound selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Catalase (CAT), Superoxide dismutase (SOD), gluthation (GSH), Adenosine TriPhosphate (ATP), or with two of these compounds , or three of these compounds, or four of these compounds or five of these compounds.
Selon un aspect de l'invention, le BHT est combiné à la N-acétylcystéine (NAC) et/ou à la Boswellia Serrata (BS). Le BHT est combiné à la Boswellia Serrata (BS) pour une formulation galénique orale. According to one aspect of the invention, BHT is combined with N-acetylcysteine (NAC) and / or with Boswellia Serrata (BS). BHT is combined with Boswellia Serrata (BS) for an oral dosage formulation.
Selon un aspect de l'invention, le BHT est combiné à la Boswellia Serrata (B) telle que préparée et décrite dans le document, WO2011114350A3, avantageusement, pour une formulation galénique intraveineuse. Selon un aspect de l'invention, le BHT pour son utilisation selon l'invention est caractérisé en ce qu'il est combiné à la N-acétylcystéine et au GSH. According to one aspect of the invention, BHT is combined with Boswellia Serrata (B) as prepared and described in document, WO2011114350A3, advantageously, for an intravenous dosage formulation. According to one aspect of the invention, BHT for its use according to the invention is characterized in that it is combined with N-acetylcysteine and with GSH.
Selon un aspect de l'invention, le BHT pour son utilisation selon l'invention est caractérisé en ce qu'il est combiné à la N-acétylcystéine et au BS. According to one aspect of the invention, BHT for its use according to the invention is characterized in that it is combined with N-acetylcysteine and with BS.
Les compositions selon l'invention comprennent l'une quelconque des combinaisons suivantes : The compositions according to the invention comprise any one of the following combinations:
BHT, NAC : BHT, GSH ; BHT, SOD ; BHT, CAT ; BHT, AIT ; BHT, BS ; BHT, NAC: BHT, GSH; BHT, SOD; BHT, CAT; BHT, AIT; BHT, BS;
BHT, NAC, GSH ; BHT, NAC, SOD ; BHT, NAC, CAT ; BHT, NAC, ATP ; BHT, NAC, BS ; BHT, NAC, GSH; BHT, NAC, SOD; BHT, NAC, CAT; BHT, NAC, ATP; BHT, NAC, BS;
BHT, GSH, SOD ; BHT, GSH, CAT ; BHT, GSH, ATP ; BHT, GSH, BS ; BHT, GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS;
BHT, SOD, CAT ; BHT, SOD, ATP ; BHT, SOD, BS ; BHT, SOD, CAT; BHT, SOD, ATP; BHT, SOD, BS;
BHT, CAT, ATP ; BHT, CAT, BS ; BHT, CAT, ATP; BHT, CAT, BS;
BHT, ATP, BS ; BHT, ATP, BS;
BHT, NAC, GSH ,SOD ; BHT, NAC, GSH, CAT ; BHT, NAC, GSH, ATP ; BHT, NAC, GSH, BS ; BHT, NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT, NAC, GSH, BS;
BHT, NAC, GSH, SOD, CAT ; BHT, NAC, GSH, SOD, ATP ; BHT, NAC, GSH, SOD, BS ; BHT, NAC, GSH, SOD, CAT, ATP ; BHT, NAC, GSH, SOD, CAT, BS ; BHT, NAC, GSH, SOD, CAT, ATP, BS, et un véhicule. BHT, NAC, GSH, SOD, CAT; BHT, NAC, GSH, SOD, ATP; BHT, NAC, GSH, SOD, BS; BHT, NAC, GSH, SOD, CAT, ATP; BHT, NAC, GSH, SOD, CAT, BS; BHT, NAC, GSH, SOD, CAT, ATP, BS, and a vehicle.
Les compositions selon l'invention comprennent Time quelconque des combinaisons suivantes : The compositions according to the invention comprise Time any of the following combinations:
BHT, NAC ; BHT, GSH ; BHT, SOD ; BHT, CAT ; BHT, ATP ; BHT, BS ; BHT N. VI TÜ ; BHT, NAC; BHT, GSH; BHT, SOD; BHT, CAT; BHT, ATP; BHT, BS; BHT N. VI TÜ;
BHT, NAC, NATTO, GSH ; BHT, NAC, SOD, NATTO ; BHT, NAC, CAT , NATTO; BHT, NAC, ATP, NATTO ; BHT, NAC, BS, NATTO ; BHT, NAC, NATTO, GSH; BHT, NAC, SOD, NATTO; BHT, NAC, CAT, NATTO; BHT, NAC, ATP, NATTO; BHT, NAC, BS, NATTO;
BHT, GSH, SOD, NATTO; BHT, GSH, CAT , NATTO; BHT, GSH, ATP , NATTO; BHT, GSH, BS , NAT- TO; BHT, GSH, SOD, NATTO; BHT, GSH, CAT, NATTO; BHT, GSH, ATP, NATTO; BHT, GSH, BS, NAT-TO;
BHT, SOD, CAT , NATTO; BHT, SOD, ATP , NATTO; BHT, SOD, BS, NATTO ; BHT, SOD, CAT, NATTO; BHT, SOD, ATP, NATTO; BHT, SOD, BS, NATTO;
BHT, CAT, ATP , NATTO; BHT, CAT, BS, NATTO ; BHT, CAT, ATP, NATTO; BHT, CAT, BS, NATTO;
BHT, ATP, BS, NATTO ; BHT, ATP, BS, NATTO;
BHT, NAC, GSH ,SQD, NATTO; BHT, NAC, GSH, CAT, NATTO; BHT, NAC, GSH, ATP, NATTO; BHT, NAC, GSH, BS, NATTO ; BHT, NAC, GSH, SQD, NATTO; BHT, NAC, GSH, CAT, NATTO; BHT, NAC, GSH, ATP, NATTO; BHT, NAC, GSH, BS, NATTO;
BHT, NAC, GSH, SOD, CAT, NATTO ; BHT, NAC, GSH, SOD, ATP , NATTO; BHT, NAC, GSH, SOD, BS, NATTO ; BHT, NAC, GSH, SOD, CAT, ATP, NATTO ; BHT, NAC, GSH, SOD, CAT, BS, NATTO ; BHT, NAC, GSH, SOD, CAT ATP, BS, NATTO et un véhicule. selon un aspect l'invention porte sur le BHT ou l'une quelconque des molécules nommées BG1, BG2, BG3 ou BG4 combiné à la nattokinase (NATTO) pour la prévention ou le traitement de la Covid-19. BHT, NAC, GSH, SOD, CAT, NATTO; BHT, NAC, GSH, SOD, ATP, NATTO; BHT, NAC, GSH, SOD, BS, NATTO; BHT, NAC, GSH, SOD, CAT, ATP, NATTO; BHT, NAC, GSH, SOD, CAT, BS, NATTO; BHT, NAC, GSH, SOD, CAT ATP, BS, NATTO and a vehicle. according to one aspect, the invention relates to BHT or any of the molecules named BG1, BG2, BG3 or BG4 combined with nattokinase (NATTO) for the prevention or treatment of Covid-19.
La Nattokinase est un puissant agent fibrinolytique, La Nattokinase est une enzyme qui contribue à l'activa- tion de la décomposition des caillots. La nattokinase est une enzyme produite par la fermentation du natto, un condiment japonais traditionnel. Le natto vient de haricots de soja bouillis que Ton ensemence avec un certain type de bactérie probiotique (Bacilius subtilis) poux assurer la fermentation. Même si la substance a fait l'objet de nombreuses études en Asie, ce n'est que récemment que des études ont été réalisées en Améri- que du Nord sur cete puissante enzyme et sur sa capacité de dissoudre les caillots sanguins. Nattokinase is a potent fibrinolytic agent, Nattokinase is an enzyme which helps to activate the breakdown of clots. Nattokinase is an enzyme produced by the fermentation of natto, a traditional Japanese condiment. Natto comes from boiled soy beans which are seeded with a certain type of probiotic bacteria (Bacilius subtilis) lice to ensure fermentation. Although the substance has been the subject of numerous studies in Asia, it is only recently that studies have been carried out in America. than the North on this powerful enzyme and its ability to dissolve blood clots.
Selon l'invention la NATTOKINASE est utilisée pour la prévention ou le traitement de la COVID-19, de pré- férence à la dose de 50 mg par individu par prise ou 50 mg/kg/jour ou 50 mg/kg/prise. According to the invention, NATTOKINASE is used for the prevention or treatment of COVID-19, preferably at a dose of 50 mg per individual per dose or 50 mg / kg / day or 50 mg / kg / dose.
Selon un mode de réalisation la NATTOKINASE est utilisée pour la prévention ou le traitement de la CO- VID-19, de préférence à la dose de 100 mg par individu par prise ou 100 mg/kg/jour ou 100 mg/kg/prise. According to one embodiment, NATTOKINASE is used for the prevention or treatment of CO-VID-19, preferably at a dose of 100 mg per individual per intake or 100 mg / kg / day or 100 mg / kg / intake.
COMPOSITION PHARMACEUTIQUES PHARMACEUTICAL COMPOSITION
L'invention porte sur une composition de préférence pharmaceutique comprenant au moins un principes actif sélectionnés selon l'invention parmi, BHT, BG1, BG2, BG3, BG4, SOD, CAT, GSH, ATP, BS, NATTO, une combinaison de ces principes actifs et un excipient, pharmaceutiquemennt acceptable s'il est destiné à la composition pharmaceutique . The invention relates to a preferably pharmaceutical composition comprising at least one active principle selected according to the invention from, BHT, BG1, BG2, BG3, BG4, SOD, CAT, GSH, ATP, BS, NATTO, a combination of these principles active ingredients and an excipient which is pharmaceutically acceptable if it is intended for the pharmaceutical composition.
L'invention porte sur une composition pharmaceutique comprenant dans un véhicule pharmaceutique appro- prié le BHT selon l'une quelconque des combinaisons comprenant le BHT selon l'invention. The invention relates to a pharmaceutical composition comprising in a suitable pharmaceutical vehicle the BHT according to any of the combinations comprising the BHT according to the invention.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, un composé de formule 2,6-di-Îert-butyl-4-méthyl-phénol et la N-acétylcystéine (NAC) et, soit, la Boswellia Serrata (BS), soit le GSH. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-ert-butyl-4-methyl-phenol and N-acetylcysteine (NAC) and either Boswellia Serrata (BS) or the GSH.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, un composé de fonnule 2,6-di-tert-butyl-4-méthyl-phénol et la Nattokinase. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-tert-butyl-4-methyl-phenol and Nattokinase.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, un composé de formule 2,6-di-tert-butyl-4-méthyl-phénol et la Nattokinase et la N-acétylcystéine (NAC). A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2,6-di-tert-butyl-4-methyl-phenol and Nattokinase and N-acetylcysteine (NAC).
L'invention porte sur une composition pharmaceutique comprenant dans un véhicule pharmaceutique appro- prié la Natokinase et la N-acétylcystéine (NAC) et, soit, la Boswellia Serrata (BS), soit le GSH. Disclosed is a pharmaceutical composition comprising in a suitable pharmaceutical carrier Natokinase and N-acetylcysteine (NAC) and either Boswellia Serrata (BS) or GSH.
L'invention porte sur une composition pharmaceutique comprenant dans un véhicule pharmaceutique appro- prié la Nattokinase et la Boswellia Serrata (BS). Disclosed is a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and Boswellia Serrata (BS).
L'invention porte sur une composition pharmaceutique comprenant dans un véhicule pharmaceutique appro- prié la Nattokinase et le GSH. Disclosed is a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and GSH.
L'invention porte sur une composition pharmaceutique comprenant dans un véhicule pharmaceutique appro- prié la Nattokinase et la BS et le GSH. Disclosed is a pharmaceutical composition comprising in a suitable pharmaceutical carrier Nattokinase and BS and GSH.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, un composé de formule 2, 6-di-tert-butyl-4-méthyl -phénol et une combinaison de SOD, CAT, GSH et ATR. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of the formula 2, 6-di-tert-butyl-4-methyl-phenol and a combination of SOD, CAT, GSH and ATR.
Une composition pharmaceutique comprenant, dans un véhicule phamiaceutique approprié, un composé de formule 2,6-di-tert-butyl-4-méthyl-phénol et une combinaison de Nattokinase, SOD, CAT, GSH et ATP.A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, a compound of formula 2,6-di-tert-butyl-4-methyl-phenol and a combination of Nattokinase, SOD, CAT, GSH and ATP.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, la Nattokinase et l'ATP. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and ATP.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, la Nattokinase et la SOD, de préférence SOD2. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and SOD, preferably SOD2.
Une composition pharmaceutique comprenant, dans un véhicule pharmaceutique approprié, la Nattokinase et la CATALASE. A pharmaceutical composition comprising, in a suitable pharmaceutical vehicle, Nattokinase and CATALASE.
Une composition pharmaceutique sous forme de kit comprenant au moins deux des actifs sélectionnés par- mis BHT ou BG1, ou BG2 ou BG2 ou BG4, et la Nattokinase ou l'ATP. A pharmaceutical composition in the form of a kit comprising at least two of the active agents selected from BHT or BG1, or BG2 or BG2 or BG4, and nattokinase or ATP.
Les véhicules qui sont pharmaceutiquement acceptables peuvent être notamment des solutions salines isoto- niques, stériles (phosphate monosodique ou disodique, chlorure de sodium, de potassium, decalcium ou de magnésium ou similaires, ou des mélanges de tels sels), ou des compositions sèches, notamment lyophili- sées, qui, en fonction des cas, d'eau stérilisée ou de sérum physiologique, permettent la constitution de solu- tions injectables. The vehicles which are pharmaceutically acceptable can in particular be isotonic, sterile saline solutions (monosodium or disodium phosphate, sodium, potassium, decalcium or magnesium chloride or the like, or mixtures of such salts), or dry compositions, in particular lyophilized, which, depending on the case, sterilized water or physiological serum, allow the constitution of injectable solutions.
Les formes pharmaceutiques appropriées pour une utilisation injectable (iv) comprennent les solutions ou dispersions aqueuses stériles; des formulations comprenant de l'huile de sésame, de l'huile d'arachide ou une solution aqueuse de propylène glycol; et des poudres stériles pour la préparation extemporanée de solutions ou de dispersions injectables stériles. Dans tous les cas, le véhicule doit être stérile et fluide dans la mesure où il existe une facilité de seringue. Il doit être stable dans les conditions de fabrication et de stockage et doit être préservé de Faction contaminante de micro-organismes, tels que les bactéries et les champignons. Pharmaceutical forms suitable for injectable use (iv) include sterile aqueous solutions or dispersions; formulations comprising sesame oil, peanut oil or an aqueous solution of propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the vehicle should be sterile and fluid as long as there is syringe ease. It must be stable under the conditions of manufacture and storage and must be preserved from the contaminating action of microorganisms, such as bacteria and fungi.
Des solutions comprenant la BHT sous forme de base libre ou de sels pharmacologiquement acceptables peu- vent être préparées dans de l'eau mélangée de manière appropriée à un agent tensioactif, tel que l'hydroxypro- pylcellulose. Les dispersions peuvent également être préparées dans du glycérol, des polyéthylèneglycols li- quides et leurs mélanges et dans des huiles. Dans des conditions normales de stockage et d'utilisation, ces préparations contiennent un conservateur pour empêcher la croissance de micro-organismes. Le BHT (ou composé BH1 à BG4) pour son utilisation selon de la présente invention peut être formulé en une composition sous forme neutre ou sous forme de sel. Les sels pharmaceutiquement acceptables compren- nent les sels formés avec les groupes carboxyle libres peuvent également être dérivés de bases inorganiques telles que, par exemple, les hydroxydes de sodium, de potassium, d'ammonium, de calcium ou ferriques, et de bases organiques telles que l'isopropylamine, la triméthylamine,rhistidme, la procaïne et analogues. Le sup- port peut également être un solvant ou un milieu de dispersion contenant, par exemple, de l'eau, de l'éthanol, du polyol (par exemple, du glycérol, du propylène glycol et du polyéthylène glycol liquide, etc.), leurs mé- langes appropriés et des huiles végétales. Solutions comprising BHT as the free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. BHT (or compound BH1 to BG4) for its use according to the present invention can be formulated in a composition in neutral form or in salt form. Pharmaceutically acceptable salts include salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases such. as isopropylamine, trimethylamine, rhistidme, procaine and the like. The carrier can also be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.) , their appropriate mixtures and vegetable oils.
La fluidité appropriée peut être maintenue, par exemple, en utilisant un revêtement, tel que la lécithine, en maintenant la taille de particule requise dans le cas d'une dispersion et en utilisant des tensioaetifs. La pré- vention de l'action des micro-organismes peut être réalisée par divers agents antibactériens et antifongiques, par exemple les parabens, le chlorobutanol, le phénol, l'acide sorbique, le thimérosal, etc. Dans de nombreux cas, il sera préférable d'inclure des agents isotoniques, par exemple des sucres ou du chlorure de sodium. L'absorption prolongée des compositions injectables peut être obtenue par l'utilisation dans les compositions d'agents retardant l'absorption, par exemple le monostéarated'aluminium et de préférence une gélatine. The proper fluidity can be maintained, for example, by using a coating, such as lecithin, by maintaining the required particle size in the case of dispersion and using surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases it will be preferable to include isotonic agents, for example sugars or sodium chloride. Prolonged absorption of the injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example aluminum monostearate and preferably gelatin.
La composition selon l'invention, permet en agissant sur les membranes virales de disloquer le virus dès qu'il entre en contact avec la composition et donc de réduire nettement « l'inoculum » et donc de diminuer la probabilité de dissémination du viras dans l'organisme et celle de transmission d'hôte à hôte. The composition according to the invention, by acting on the viral membranes, makes it possible to disrupt the virus as soon as it comes into contact with the composition and therefore to significantly reduce the “inoculum” and therefore to reduce the probability of dissemination of the virus in the virus. organism and that of host-to-host transmission.
L'intérêt de la composition selon l'invention est qu'elle ne contient pas de produit nocif pour l'organisme.The advantage of the composition according to the invention is that it does not contain any product harmful to the organism.
Des solutions injectables stériles sont préparées en incorporant les composés actifs dans la quantité requise dans le solvant approprié avec plusieurs des autres ingrédients énumérés ci-dessus, selon les besoins, suivis d'une stérilisation par filtration. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent along with several of the other ingredients listed above, as needed, followed by filtration sterilization.
Les dispersions selon l'invention sont préparées en incorporant les agents stérilisés de la présente invention dans un véhicule stérile qui contient le milieu de dispersion basique et les autres ingrédients requis parmi ceux énumérés ci-dessus. Dans le cas de poudres stériles pour la préparation de solutions injectables stériles, les procédés de préparation typiques sont les techniques de séchage sous vide et de lyophilisation qui don- nent une poudre de BHT ou de BHT en combinaison de la présente invention, plus tout ingrédient ou exci- pient désiré supplémentaire provenant d'une solution filtrée stérile. The dispersions according to the invention are prepared by incorporating the sterilized agents of the present invention in a sterile vehicle which contains the basic dispersion medium and the other required ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, typical preparation methods are vacuum drying and lyophilization techniques which yield a powder of BHT or BHT in combination of the present invention, plus any ingredient. or additional desired excipient from sterile filtered solution.
Pour une administration parentérale dans une solution aqueuse, la solution doit être tamponnée de manière appropriée si nécessaire et le diluant liquide doit d'abord être rendu isotonique avec une quantité suffisante de solution saline ou de glucose. Ces solutions aqueuses particulières conviennent particulièrement à l'admi- nistration intraveineuse, intramusculaire, sous-cutanée et intraperitoneale, A cet égard, les milieux aqueux stériles qui peuvent êtreutilisés seront connus de l'homme du métier. Certaines variations de dosage se pro- duiront nécessairement en fonction de l'état du sujet traité. Dans tous les cas, la personne responsable de l'ad- ministration déterminera la dose appropriée pour chaque sujet, le véhicule approprié, la durée du traitement, la ou les voies d'injection (po, in, si, iv), évalués en fonction de l'évolution des symptomes de la Covid-19. For parenteral administration in an aqueous solution, the solution should be appropriately buffered if necessary and the liquid diluent should first be made isotonic with a sufficient amount of saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, sterile aqueous media which can be used will be known to those skilled in the art. Certain variations in dosage will necessarily occur depending on the condition of the subject being treated. In all cases, the person responsible for administration will determine the appropriate dose for each subject, the appropriate vehicle, the duration of treatment, the route (s) of injection (po, in, si, iv), evaluated in depending on the evolution of the symptoms of Covid-19.
Selon un aspect un suppositoire de la présente invention peut être préparé en mélangeant à l'état fondu un tri- glycéride d'acide gras, une base d'huile constituée d'une combinaison d'un ou plusieurs glycérides d'acide gras en 04-18, et si nécessaire, des poudres insolubles dans les triglycérides d'acides gras, en y ajoutant le BHT seul ou e combinaison selon l'invention, en mélangeant et en remuant uniformément le mélange résul- tant, et en remplissant le mélange dans un récipient, un moule ou similaire, et en refroidissant et en solidi- fiant la garniture. La méthode de mélange n'est pas spécifiquement limitée. In one aspect a suppository of the present invention can be prepared by melt mixing a fatty acid tri-glyceride, an oil base consisting of a combination of one or more fatty acid glycerides at 4 0. -18, and if necessary, powders insoluble in the triglycerides of fatty acids, adding thereto the BHT alone or in the combination according to the invention, mixing and uniformly stirring the resulting mixture, and filling the mixture in a container, mold or the like, and cooling and solidifying the filling. The method of mixing is not specifically limited.
Les méthodes de fabrication de ces formulations sont bien connues de l'homme du métier : https://www.tech- niques-ingenieur.fr/base-documentaire/bxomedical-pharma-thl5/mise-en-forme-des-medicaments- 42611210/formulation-et-fabrication-des-suppositoires-pha2020/ The methods of manufacturing these formulations are well known to those skilled in the art: https: //www.tech-niques-ingenieur.fr/base-documentaire/bxomedical-pharma-thl5/mise-en-forme-des-medicaments - 42611210 / formulation-and-manufacture-of-pha2020-suppositories /
DOSES JOURNALIERES POSOLOGIES DAILY DOSES DOSAGE
Composition pharmaceutique selon l'invention caractérisée en ce que le BHT est utilisé à une dose comprise entre 0,01 g/kg/jour et 0,50 g/kg/jour, de préférence entre 0,10 g/kg 0,25 g/kg/jour. Pharmaceutical composition according to the invention, characterized in that the BHT is used at a dose of between 0.01 g / kg / day and 0.50 g / kg / day, preferably between 0.10 g / kg 0.25 g / kg / day.
Composition pharmaceutique selon l'invention caractérisée en ce que le BHT est utilisé à une dose de 300 mg à 500 mg ou à une dose de 0,25 g/kg de masse corporelle/) our, de préférence à une dose allant de 10 mg à la dose maximale de 0,25 g/kg en poids (corporel) /jour. Pharmaceutical composition according to the invention, characterized in that the BHT is used at a dose of 300 mg to 500 mg or at a dose of 0.25 g / kg of body mass /) our, preferably at a dose ranging from 10 mg at the maximum dose of 0.25 g / kg (body weight) / day.
Composition pharmaceutique selon l'invention caractérisée en ce que le BHT est utilisé à une dose comprise entre 0,01 mg/kg/jour et 0.5 mg/kg/jour de préférence entre 0,1 mg/kg 0,250 mg/kg/jour. Pharmaceutical composition according to the invention, characterized in that the BHT is used at a dose of between 0.01 mg / kg / day and 0.5 mg / kg / day, preferably between 0.1 mg / kg 0.250 mg / kg / day.
Selon un aspect, la composition pharmaceutique selon l'invention est caractérisée en ce que le BHT est utili- sé à la dose de 300 mg ou à la dose de 500 mg ou à une dose de 0,25 mg/kg en poids/jour, de préférence à une dose allant de 10 mg à la dose maximale de 0,25 mg/kg en poids/jour. According to one aspect, the pharmaceutical composition according to the invention is characterized in that the BHT is used at a dose of 300 mg or at a dose of 500 mg or at a dose of 0.25 mg / kg in weight / day. , preferably at a dose ranging from 10 mg to the maximum dose of 0.25 mg / kg in weight / day.
Composition pharmaceutique selon l'invention caractérisée par une administration ! à 12 fois par jour, avan- tageusement de 1 à 5 fois par jour, plus avantageusement de 1 à 3 fois par jour. Pharmaceutical composition according to the invention characterized by an administration! to 12 times per day, preferably 1 to 5 times per day, more preferably 1 to 3 times per day.
Composition pharmaceutique selon l'invention caractérisée en ce qu'elle est administrée au moins 2 jours consécutifs, au moins 3 jours consécutifs, au moins 4 jours consécutifs, au moins 5 jours consécutifs, au moins 6 jours consécutifs, au moins 7 jours consécutifs, au moins 8 jours consécutifs, au moins 9 jours con- sécutifs, au moins 10 jours consécutifs, au moins 15 jours consécutifs, au moins 21 jours consécutifs, au moins 28 jours consécutifs, pendant au moins 1 mois, pendant au moins 2 mois. Pharmaceutical composition according to the invention, characterized in that it is administered at least 2 consecutive days, at least 3 consecutive days, at least 4 consecutive days, at least 5 consecutive days, at least 6 consecutive days, at least 7 consecutive days, at least 8 consecutive days, at least 9 consecutive days, at least 10 consecutive days, at least 15 consecutive days, at least 21 consecutive days, at least 28 consecutive days, for at least 1 month, for at least 2 months.
Composition pharmaceutique selon l'invention caractérisée en ce qu'elle est sous une forme galénique appro- priée à une administration par voie orale. Pharmaceutical composition according to the invention, characterized in that it is in a galenic form suitable for oral administration.
UTILISATION DES COMPOSITIONS USE OF COMPOSITIONS
Les combinaisons selon l'invention sont utilisées pour la prévention et/ou le traitement des infections à Coro- navirus, avantageusement à bétacoronaviras, et plus avantageusement par le SÀRS-Cov, MERS-Cov, la CO- VID-19, et plus avantageusement encore la Covid-19. The combinations according to the invention are used for the prevention and / or treatment of infections with Coronavirus, advantageously with betacoronaviras, and more advantageously by SÀRS-Cov, MERS-Cov, CO-VID-19, and more advantageously again the Covid-19.
Une composition pharmaceutique selon l'invention peut être caractérisée en ce qu'elle est utilisée dans la pré- vention et / ou le traitement d'une infection par un coronavims, avantageusement un betacoronavims, plus avantageusement, le SARS-CoV-2. A pharmaceutical composition according to the invention can be characterized in that it is used in the prevention and / or the treatment of an infection by a coronavirus, advantageously a betacoronavims, more advantageously SARS-CoV-2.
L'invention porte sur de nouvelles compositions caractérisées en ce qu'elles comprennent, dans un véhicule pharmaceutique approprié, un composé de formule 2,6-di-tert-butyl-4-méthylphénol (BHT) et l'un quel- conque des antioxydants ou compléments alimentaires sélectionnés parmi N-acétylcystéine (NAC), Catalase (CAT), Superoxide dismutase (SOD), Glutathion (GSH), adénosine triphosphate (ATP) et Bowellia Serrata (BS)et une combinaison de ces antioxydants ou compléments alimentaire. The invention relates to novel compositions characterized by comprising, in a vehicle suitable pharmaceutical, a compound of the formula 2,6-di-tert-butyl-4-methylphenol (BHT) and any of the antioxidants or dietary supplements selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), Glutathione (GSH), adenosine triphosphate (ATP) and Bowellia Serrata (BS) and a combination of these antioxidants or dietary supplements.
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi N- acétylcystéine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adénosine triphosphate (ATP) et Bo- wellia Serrata (BS), une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19. In another aspect, the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adenosine triphosphate (ATP) and Bo-wellia Serrata (BS). , a combination of these compounds, for the prevention or treatment of Covid-19.
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi N- acétylcystéine (NAC), Superoxide dismutase (SOD), GSH, adénosine triphosphate (ATP) et Bowellia Serrata (BS), une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19. According to another aspect, the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Superoxide dismutase (SOD), GSH, adenosine triphosphate (ATP) and Bowellia Serrata (BS), a combination of these. compounds, for the prevention or treatment of Covid-19.
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi N- acétylcystéine (NAC), Catalase (CAT), GSH, adénosine triphosphate (ATP) et Bowellia Serrata (BS), une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19. According to another aspect, the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), GSH, adenosine triphosphate (ATP) and Bowellia Serrata (BS), a combination of these compounds. , for the prevention or treatment of Covid-19.
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi N- aeétylcystéine (NAC), Catalase (CAT), Superoxide dismutase (SOD), GSH et Bowella Serrata (BS), une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19, According to another aspect, the present invention relates to BHT, combined with a compound selected from N-aeetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), GSH and Bowella Serrata (BS), a combination of these compounds. , for the prevention or treatment of Covid-19,
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi N- acétylcystéine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adénosine triphosphate (ATP) GSH, une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19. According to another aspect, the present invention relates to BHT, combined with a compound selected from N-acetylcysteine (NAC), Catalase (CAT), Superoxide dismutase (SOD), adenosine triphosphate (ATP) GSH, a combination of these compounds, for the prevention or treatment of Covid-19.
Selon un autre aspect, la présente invention porte sur le BHT, combiné à un composé sélectionné parmi Cata- lase (CAT), Superoxide dismutase (SOD), GSH, adénosine triphosphate (ATP) et Bowella Serrata (BS), une combinaison de ces composés, pour la prévention ou le traitement de la Covid-19. According to another aspect, the present invention relates to BHT, combined with a compound selected from Catalyst (CAT), Superoxide dismutase (SOD), GSH, adenosine triphosphate (ATP) and Bowella Serrata (BS), a combination of these. compounds, for the prevention or treatment of Covid-19.
La prévention et/ou le traitement de la Covid-19 comprend T utilisation du Prevention and / or treatment of Covid-19 includes the use of
BHT ; d'une composition comprenant : BHT, NAC : BHT, GSH ; BHT, SOD ; BHT, CAT ; BHT, ATP ; BHT, BS ; BHT, NA C, GSH ; BHT, NAC, SOD ; BHT, NAC, CAT ; BHT, NAC, ATP ; BHT, NAC, BS ; BHT, GSH, SOD ; BHT, GSH, CAT ; BHT, GSH, ATP ; BHT, GSH, BS ; BHT, SOD, CAT ; BHT, SOD, ATP ; BHT, SOD, BS ; BHT, CAT, ATP ; BHT, CAT, ATP ; BHT, CAT, BS ; BHT, ATP, BS ; BHT, NAC, GSH ,SOD ;BHT , NAC, GSH, CAT ; BHT, NAC, GSH, ATP ; BHT NAC, GSH, BS : BHT, NAC, GSH, SOD, CAT ; BHT, NAC, GSH, SOD, ATP ; BHT, NAC, GSH, SOD, BS ; BHT, NAC, GSH, SOD, CAT, ATP ; BHT, NAC, GSH, SOD, CAT, BS ; BHT, NAC, GSH, SOD, CAT, ATP, BS ; ou BHT, NAC ; BHT, GSH ; BHT, SOD ; BHT, CAT ; BHT, ATP ; BUT. BS ; BHT; of a composition comprising: BHT, NAC: BHT, GSH; BHT, SOD; BHT, CAT; BHT, ATP; BHT, BS; BHT, NA C, GSH; BHT, NAC, SOD; BHT, NAC, CAT; BHT, NAC, ATP; BHT, NAC, BS; BHT, GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS; BHT, SOD, CAT; BHT, SOD, ATP; BHT, SOD, BS; BHT, CAT, ATP; BHT, CAT, ATP; BHT, CAT, BS; BHT, ATP, BS; BHT, NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT NAC, GSH, BS: BHT, NAC, GSH, SOD, CAT; BHT, NAC, GSH, SOD, ATP; BHT, NAC, GSH, SOD, BS; BHT, NAC, GSH, SOD, CAT, ATP; BHT, NAC, GSH, SOD, CAT, BS; BHT, NAC, GSH, SOD, CAT, ATP, BS; Where BHT, NAC; BHT, GSH; BHT, SOD; BHT, CAT; BHT, ATP; GOAL. BS;
BHT, NAC, GSH ; BHT, NAC, SOD ; BHT NAC, CAT ; BUT, NAC, ATP ; BHT, NAC, BS ; BHT, NAC, GSH; BHT, NAC, SOD; BHT NAC, CAT; BUT, NAC, ATP; BHT, NAC, BS;
BHT, GSH, SOD ; BHT, GSH, CAT ; BHT, GSH, ATP ; BHT, GSH, BS ; BHT, GSH, SOD; BHT, GSH, CAT; BHT, GSH, ATP; BHT, GSH, BS;
BHT, SOI), CAT ; BHT, SOD, ATP ; BHT, SOD, BS : BHT, SOI), CAT; BHT, SOD, ATP; BHT, SOD, BS:
BHT, CAT, ATP ; BHT, CAT, BS ; BHT, CAT, ATP; BHT, CAT, BS;
BHT, ATP, BS ; BHT, ATP, BS;
BHT, NAC, GSH ,SOD ; BHT, NAC, GSH, CAT ; BHT, NAC, GSH, ATP ; BHT, NAC, GSH, BS ; BHT, NAC, GSH, SOD; BHT, NAC, GSH, CAT; BHT, NAC, GSH, ATP; BHT, NAC, GSH, BS;
BHT, NAC, GSH, SOD, CAT ; BHT, NAC, GSH, SOD, ATP ; BHT, NAC, GSH, SOD, BS ; BHT, NAC, GSH, SOD, CAT, ATP ; BHT, NAC, GSH, SOD, CAT, BS ; BHT, NAC, GSH, SOD, CAT, ATP, BS, en pré- sence de Zn quand la composition comprend la SOD. BHT, NAC, GSH, SOD, CAT; BHT, NAC, GSH, SOD, ATP; BHT, NAC, GSH, SOD, BS; BHT, NAC, GSH, SOD, CAT, ATP; BHT, NAC, GSH, SOD, CAT, BS; BHT, NAC, GSH, SOD, CAT, ATP, BS, in the presence of Zn when the composition comprises SOD.
Selon un aspect préféré de l'invention, ladite composition pour son utilisation telle que citée ci-dessus est ca- ractérisée en ce qu'elle comprend une combinaison d'au moins deux des composés suivants : NAC, BS, GSH. According to a preferred aspect of the invention, said composition for its use as cited above is characterized in that it comprises a combination of at least two of the following compounds: NAC, BS, GSH.
Ladite composition pourra selon d'autres modes de réalisation notamment comprendre toutes les combinai- sons possibles de BHT avec l'un quelconque des composés, NAC, GSH, SOD, CAT, ATP BS, et combinaisons des dits composés. Said composition may, according to other embodiments, in particular comprise all the possible combinations of BHT with any one of the compounds, NAC, GSH, SOD, CAT, ATP BS, and combinations of said compounds.
Selon un premier aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de BHT. According to a first aspect, the pharmaceutical composition for its use according to the invention comprises at least one effective amount of BHT.
Selon un second aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de NAC. According to a second aspect, the pharmaceutical composition for its use according to the invention comprises at least one effective amount of NAC.
Selon un troisième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de BS. According to a third aspect, the pharmaceutical composition for its use according to the invention comprises at least an effective amount of BS.
Selon un quatrième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de GSH. According to a fourth aspect, the pharmaceutical composition for its use according to the invention comprises at least an effective amount of GSH.
Selon un cinquième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de SOD. According to a fifth aspect, the pharmaceutical composition for its use according to the invention comprises at least an effective amount of SOD.
Selon un sixième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de CAT. According to a sixth aspect, the pharmaceutical composition for its use according to the invention comprises at least one effective amount of CAT.
Selon un septième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace d'ATP. According to a seventh aspect, the pharmaceutical composition for its use according to the invention comprises at least one effective amount of ATP.
Selon un septième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de NATTOKINASE. According to a seventh aspect, the pharmaceutical composition for its use according to the invention comprises at least one effective amount of NATTOKINASE.
Selon un septième aspect, la composition pharmaceutique pour son usage selon l'invention comprend au moins une quantité efficace de quercétine. According to a seventh aspect, the pharmaceutical composition for its use according to the invention comprises at least an effective amount of quercetin.
Par « quantité efficace », on entend selon un aspect au sens de l'invention (pour une combinaison) une quan- tité de composé, seule ou avec du BHT à une quantité sous-efficace, par rapport au contrôle (p<0,049), suffi- santé pour inhiber de manière significative (p<0.05 test t ou ki2) la prolifération et/ou la réplication du coro- navirus SARS-Cov-2, et/ou le développement de l'infection virale au sein de l'organisme, et /ou l' apparition de symptômes représentatif d'un stade sévère de la Covid-19. Cette inhibition peut être quantifiée, par exem- ple en mesurant le titre viral comme cela est présenté dans les exemples de la présente demande. By “effective amount” is meant according to one aspect within the meaning of the invention (for a combination) an amount of compound, alone or with BHT in an undereffective amount, relative to the control (p <0.049). , suffi- health to significantly inhibit (p <0.05 t or ki2 test) the proliferation and / or replication of the SARS-Cov-2 coronavirus, and / or the development of viral infection within the organism, and / or the appearance of symptoms representative of a severe stage of Covid-19. This inhibition can be quantified, for example by measuring the viral titer as presented in the examples of the present application.
Selon un aspect, par "quantité thérapeutiquement efficace" de BHT, on entend une quantité suffisante de BHT, pour réduire la fréquence et /ou l'intensité d'un symptôme induit par le SARS-Cov-2 par rapport à la fréquence et /ou l'intensité du symptôme mesurée initialement et sans traitement ou/et encore pouvant rédui- re la charge virale du SARS-Cov-2 mesurée ou évaluée dans un endroit précis de l'organisme (nez, bouche, gorge, exsudât pulmonaire, rectum) ou la virémie (charge virale dans le sang) - mesurée initialement sans traitement avec un rapport bénéfice / risque raisonnable applicable à tout traitement médical. According to one aspect, by "therapeutically effective amount" of BHT is meant a sufficient amount of BHT, to reduce the frequency and / or the intensity of a symptom induced by SARS-Cov-2 with respect to the frequency and / or the intensity of the symptom measured initially and without treatment or / and still being able to reduce the viral load of SARS-Cov-2 measured or evaluated in a specific place of the organism (nose, mouth, throat, pulmonary exudate, rectum ) or viraemia (viral load in the blood) - measured initially without treatment with a reasonable benefit / risk ratio applicable to any medical treatment.
Selon un aspect, "quantité thérapeutiquement efficace" de BHT est la quantité réduisant d'au moins 10% à 20% la fréquence et /ou l'intensité d'un symptôme induit par le SARS-Cov-2 (et/ou) ou la charge virale, plus préférentiellement d'au moins 30%, encore plus préférentiellement d'au moins 50 %. According to one aspect, "therapeutically effective amount" of BHT is the amount reducing by at least 10% to 20% the frequency and / or intensity of a symptom induced by SARS-Cov-2 (and / or) or the viral load, more preferably at least 30%, even more preferably at least 50%.
Le risque apporté au patient dans le cas de l'invention est moindre et représente un avantage par rapport au traitement proposés auparavant puisqu'aucun effet secondaire n'est observé. The risk to the patient in the case of the invention is lower and represents an advantage over the treatment proposed previously since no side effects are observed.
On comprendra cependant que l'utilisation quotidienne de ces composés ou combinaisons selon la présente invention seront décidées par le médecin traitant dans le cadre d'un jugement médical éclairé. It will be understood, however, that the daily use of these compounds or combinations according to the present invention will be decided by the attending physician on the basis of sound medical judgment.
Le niveau de dose thérapeutiquement efficace spécifique à un sujet particulier dépendra de divers facteurs, notamment de la nature et la gravité du symptôme, de la charge virale, de l'activité spécifique du BHT, de la composition spécifique utilisée, de l'âge, du poids corporel, de l'état de santé général, du sexe et du régime alimentaire du sujet; du moment de l'administration, de la voie d'administration de la durée du traitement; des autres médicaments éventuellement utilisés. The level of therapeutically effective dose specific to a particular subject will depend on various factors including the nature and severity of the symptom, viral load, specific activity of BHT, specific composition used, age, the subject's body weight, general health, sex and diet; the time of administration, the route of administration and the duration of treatment; other drugs that may be used.
Par exemple, il est tout à fait classique de commencer des doses de traitement à des niveaux inférieurs à ceux nécessaires pour obtenir l'effet thérapeutique souhaité et d'augmenter progressivement la dose jusqu'à l'obten- tion de l'effet souhaité. Dans le cas présent de telles précautions ne sont pas nécessaires et surtout non souhai- tables car des symptômes classiques et (toux, fièvre 38±C 0,5+C, courbatures, fatigue) peuvent dans 20 à 30% des cas évoluer vers des symptomes plus sévères (syndrome respiratoire aigu). Un traitement d'attaque à une dose d'environ 300mg/kg à 500 mg/kg est donc recommandée. For example, it is quite conventional to start treatment doses at levels lower than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is obtained. In the present case, such precautions are not necessary and above all undesirable because classic symptoms and (cough, fever 38 ± C 0.5 + C, stiffness, fatigue) can in 20 to 30% of cases progress to more severe symptoms (acute respiratory syndrome). An attack treatment at a dose of approximately 300 mg / kg to 500 mg / kg is therefore recommended.
Au sens de ia présente invention, on entend par les termes « activité antivirale » ou « action antivirale », une action sur le virus ou sur ses cellules cibles infectées, notamment faction d'inhiber le cycle de réplication du virus ou sa capacité à infecter et à se répliquer dans des cellules hôtes, cet effet antiviral pouvant être obtenu par la modulation d'un certain nombre de gènes des cellules cibles. For the purposes of the present invention, the terms “antiviral activity” or “antiviral action” are understood to mean an action on the virus or on its infected target cells, in particular the faction of inhibiting the replication cycle of the virus or its ability to infect. and to replicate in host cells, this antiviral effect being obtainable by modulating a number of genes in target cells.
Au sens de la présente invention, on entend par les termes « activité antivirale » ou « action antivirale », une action du BHT ou des compositions selon l'invention sur un symptôme ou plusieurs symptômes chez des in- dividus infectés par le SARS-Cov-2 ; de manière plus générale un symptôme ou plusieurs symptômes chez des individus infectés par un coronavirus potentiellement capable d'induire une détresse respiratoire aigue. Au sens de la présente invention, on entend par les tenues « activité antivirale » ou « action anti virale », une action du BHT ou des compositions selon l'invention sur le pourcentage d'individu infectés par le SARS- Cov-2. Une activité antivirale signifie par exemple une réduction de la charge virale, normalisation de la fiè- vre (retour à une température corporelle normale soit environ 37°C plus ou moins 0,5 °C, normalisation des gaz du sang, retour à un aspect normal des selles, arrêt des nausées, diminution de la toux, diminution de l'IL-6 dans le sang. For the purposes of the present invention, the terms “antiviral activity” or “antiviral action” are understood to mean an action of BHT or of the compositions according to the invention on one symptom or more symptoms in individuals infected with SARS-Cov. -2; more generally, one symptom or several symptoms in individuals infected with a coronavirus potentially capable of inducing acute respiratory distress. For the purposes of the present invention, the expression “antiviral activity” or “anti-viral action” outfits is understood to mean an action of BHT or of the compositions according to the invention on the percentage of individuals infected with SARS-Cov-2. Antiviral activity means, for example, a reduction in viral load, normalization of fever (return to normal body temperature, i.e. around 37 ° C plus or minus 0.5 ° C, normalization of blood gases, return to normal appearance. normal bowel movements, stop nausea, decrease coughing, decrease IL-6 in the blood.
Il est entendu que la composition pour son utilisation selon l'invention comprend du BHT et/ou un autre anti oxydant et qu'elle peut donc également comprendre d'autres composés actifs, en sus du véhicule pharmaceu- tique approprié. It is understood that the composition for its use according to the invention comprises BHT and / or another antioxidant and that it can therefore also comprise other active compounds, in addition to the appropriate pharmaceutical vehicle.
Le BHT et un autre antioxydant, un autre anti-inflammatoire ou leurs mélanges, peuvent être employés en thérapie seuls, ou en combinaison avec au moins un autre agent actif. BHT and another antioxidant, another anti-inflammatory, or mixtures thereof, can be used in therapy alone, or in combination with at least one other active agent.
Il peut s'agir de composés permettant d'améliorer l'activité de ces composés, ou encore d'autres actifs connus pour une activité particulière. They may be compounds making it possible to improve the activity of these compounds, or else other active agents known for a particular activity.
Ces composés actifs supplémentaires pourront être choisis parmi les classes pharmaceutiques d'agents cités dans la demande WO 2015/157223, à savoir parmi les agents antibactériens, les agents antiparasitaires, les inhibiteurs de la neurotransmission, les inhibiteurs du récepteur aux oestrogènes, les inhibiteurs de synthèse et réplication de l'ADN, les inhibiteurs de la maturation des protéines, les inhibiteurs des voies kinase, les in- hibiteurs du cytosquelette, les inhibiteurs du métabolisme des lipides, les agents antiinflammatoires, les inhi- biteurs des canaux ioniques, les inhibiteurs d'apoptose et les inhibiteurs de cathepsine. Ces composés actifs pourront notamment être choisis parmi des agents antibactériens, des inhibiteurs de canaux ioniques, des agents immunosuppresseurs et des agents antiviraux. On peut par exemple citer comme agent antiviral l'acy- clovir, l'hydroxychloroquine . These additional active compounds may be chosen from the pharmaceutical classes of agents cited in application WO 2015/157223, namely from antibacterial agents, antiparasitic agents, neurotransmission inhibitors, estrogen receptor inhibitors, inhibitors of DNA synthesis and replication, protein maturation inhibitors, kinase pathway inhibitors, cytoskeletal inhibitors, lipid metabolism inhibitors, anti-inflammatory agents, ion channel inhibitors, inhibitors for apoptosis and cathepsin inhibitors. These active compounds may in particular be chosen from antibacterial agents, ion channel inhibitors, immunosuppressive agents and antiviral agents. As an antiviral agent, mention may be made, for example, of acyclovir and hydroxychloroquine.
Selon un aspect particulier de l'invention, la composition pharmaceutique pour son utilisation dans la préven- tion et/ou le traitement d'une infection par le coronavirus SARS-CoV-2, comprend, en outre de T ATP. According to a particular aspect of the invention, the pharmaceutical composition for its use in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus, further comprises T ATP.
Selon un autre aspect particulier de l'invention, ia composition pharmaceutique pour son utilisation dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2, comprend, le BHT et outre une combinaison d'au moins deux composés choisis parmi G SH, CAT SOD, NAC, au moins un autre agent antiviral. According to another particular aspect of the invention, the pharmaceutical composition for its use in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus, comprises, BHT and, in addition to a combination of at least two compounds chosen from G SH, CAT SOD, NAC, at least one other antiviral agent.
Il est entendu que cet agent antiviral sera utilisé aux doses nécessaires pour présenter une action antivirale, cette dose étant désignée comme étant « efficace », ce dosage pouvant être facilement déterminé par l'homme du métier. Au sens de l'invention, un agent antiviral désigne un composé agissant sur un viras, en inhibant et/ou ralen- tissant et/ou prévenant l'infection virale associée. It is understood that this antiviral agent will be used in the doses necessary to exhibit an antiviral action, this dose being designated as being “effective”, this dosage being able to be easily determined by a person skilled in the art. For the purposes of the invention, an antiviral agent denotes a compound which acts on a virus, by inhibiting and / or slowing down and / or preventing the associated viral infection.
Les agents antiviraux sont classifiés en différentes catégories en fonction de leur mode d'action. On peut citer notamment : Antiviral agents are classified into different categories based on their mode of action. We can cite in particular:
- les analogues de nucléotides, qui interfèrent ou stoppent la synthèse d'ADN ou d'ARN ; ainsi que les inhibi- teurs des enzymes impliquées dans la synthèse d'ADN ou d'ARN (hélicase, réplicase) ; - nucleotide analogs, which interfere with or stop the synthesis of DNA or RNA; as well as inhibitors of enzymes involved in DNA or RNA synthesis (helicase, replicase);
- les composés qui inhibent les étapes de maturation du virus au cours de son cycle de réplication ; - compounds which inhibit the stages of maturation of the virus during its replication cycle;
- les composés qui interfèrent avec la liaison à la membrane cellulaire, ou à l'entrée des viras dans des cellu- les hôtes (Inhibiteurs de fusion ou d'entrée) ; - compounds which interfere with the binding to the cell membrane, or to the entry of viruses into host cells (fusion or entry inhibitors);
- les agents qui empêchent le viras de s'exprimer au sein de la cellule hôte après son entrée, en bloquant le bourgeonement au sein de la cellule ; - agents which prevent the virus from expressing itself within the host cell after its entry, by blocking the budding within the cell;
Le mésylate de camostat pour une indication thérapeutique du le SARS-CoV-2 :https://www.sciencesetave- nir.fr/sante/coronaviras-deux-moiecules-soiides-candidates-pour-empecher-le-viras-d-infecter-les-ceilu- ies_143002 Camostat mesylate for a therapeutic indication for SARS-CoV-2: https: //www.sciencesetave-nir.fr/sante/coronaviras-deux-moiecules-soiides-candidates-pour-empecher-le-viras-d- infect-les-ceilu- ies_143002
Les agents qui restreignent la propagation des virus vers d'autres cellules. On peut citer en particulier les agents antiviraux bien connus de l'Homme du métier, destinés à lutter contre des virus à ARN, tels que les in- hibiteurs de protéase, les inhibiteurs d'hélicase, et les inhibiteurs d'entrée cellulaire du virus SARS-CoV-2 dans les cellules cibles. Agents that restrict the spread of viruses to other cells. Mention may in particular be made of the antiviral agents well known to those skilled in the art, intended to combat RNA viruses, such as protease inhibitors, helicase inhibitors, and inhibitors of cell entry of the virus. SARS-CoV-2 in target cells.
Selon un aspect particulier de l'invention, la composition pharmaceutique est caractérisée en ce que l'autre agent antiviral est choisi parmi les composés suivants : la ribavirine, un interféron, ou une combinaison des deux. According to a particular aspect of the invention, the pharmaceutical composition is characterized in that the other antiviral agent is chosen from the following compounds: ribavirin, an interferon, or a combination of the two.
Au sens de l'invention, on entend par « un interféron » ou « l'interféron » un composé appartenant à la famil- le des interférons, qui sont des glycoprotéines sécrétées par les cellules du système immunitaire. For the purposes of the invention, the term “an interferon” or “interferon” is understood to mean a compound belonging to the family of interferons, which are glycoproteins secreted by cells of the immune system.
Les interférons sont une famille de petites molécules protéiques d'un poids moléculaire d'environ 15 000 à 21 000 dations. Trois classes majeures d'interférons ont été identifiées : alpha, bêta et gamma. Ces 3 classes principales ne sont pas elles-mêmes homogènes et peuvent regrouper plusieurs espèces moléculaires diffé- rentes d'interféron. Plus de 14 interférons alfa humains génétiquement différents ont été identifiés. Interferons are a family of small protein molecules with a molecular weight of about 15,000 to 21,000 dations. Three major classes of interferons have been identified: alpha, beta and gamma. These 3 main classes are not themselves homogeneous and can group together several different molecular species of interferon. More than 14 genetically different human alfa interferons have been identified.
Il est entendu que dans la composition pharmaceutique ou vétérinaire selon l'invention, l'interféron utilisé se- ra un polypeptide recombinant, synthétisé en laboratoire. It is understood that in the pharmaceutical or veterinary composition according to the invention, the interferon used will be a recombinant polypeptide, synthesized in the laboratory.
En particulier, l'interféron utilisé sera l'interféron aîfa-2b recombinant dont l'efficacité sur la réplication virale in vitro et in vivo a été démontrée. In particular, the interferon used will be recombinant interferon afa-2b, the efficacy of which on viral replication in vitro and in vivo has been demonstrated.
De tels agents antiviraux sont disponibles dans le commerce, et leurs conditions d'utilisation sont décrites dans des ouvrages de référence comme Le Dictionnaire Vidal. Such antiviral agents are commercially available, and their conditions of use are described in reference works such as The Vidal Dictionary.
Selon un aspect particulier de l'invention, la composition pharmaceutique pour son utilisation selon l'inven- tion consistera en une combinaison d'agents actifs telles que citées ci-dessus, et un véhicule pharmaceutique adapté. According to a particular aspect of the invention, the pharmaceutical composition for its use according to the invention will consist of a combination of active agents as mentioned above, and a suitable pharmaceutical vehicle.
On entend par un médicament toute substance ou composition présentée comme possédant des propriétés cu- ratives ou préventives à l'égard des maladies humaines ou animales. Selon un aspect particulier de l'invention, la composition pharmaceutique consistera en l'une des combinai- sons de composés telles que citées ci-dessus, et un véhicule pharmaceutique adapté. A medicament is understood to mean any substance or composition presented as having curative or preventive properties with regard to human or animal diseases. According to a particular aspect of the invention, the pharmaceutical composition will consist of one of the combinations of compounds as mentioned above, and a suitable pharmaceutical vehicle.
L'invention porte également selon un aspect, sur des produits selon l'invention, des dosages des produits se- lon l'invention, des posologies des produits selon l'invention, des voies d'administration des produits selon l'invention avantageuses, pour la prévention et/ou le traitement de la Covid-19. According to one aspect, the invention also relates to the products according to the invention, dosages of the products according to the invention, dosages of the products according to the invention, advantageous routes of administration of the products according to the invention, for the prevention and / or treatment of Covid-19.
Les compositions pharmaceutiques pour l'utilisation selon la présente invention sont adaptées pour une admi- nistration orale (po), sublinguale, par inhalation, sous-cutanée, intramusculaire, intraveineuse (iv), transder- mique, oculaire ou rectale, avantageusement orale, iv et par inhalation. The pharmaceutical compositions for the use according to the present invention are suitable for oral (po), sublingual, inhalation, subcutaneous, intramuscular, intravenous (iv), transdermal, ocular or rectal, advantageously oral, iv and by inhalation.
VOIES D'ADMINISTRATION ROUTES OF ADMINISTRATION
Selon un aspect, les produits ou les compositions selon l'invention sont administrés par au moins une voie d'admmistrtation ou par plusieurs voies d'administration, à tous les patients ou personnes susceptibles d'être infectées le virus SARS-Cov2. According to one aspect, the products or compositions according to the invention are administered by at least one route of administration or by several routes of administration, to all patients or persons liable to be infected with the SARS-Cov2 virus.
Selon un aspect, les produits ou les compositions selon l'invention peuvent être administrés : According to one aspect, the products or the compositions according to the invention can be administered:
- par voie intrarectale et/ou orale (intragastrique, sublinguale), de préférence orale et intrarectale chez des pa- tients présentant des signes d'infection de l'intestin (nausée, diarhée, présence de virus dans le nez, dans les fécès), - intrarectal and / or oral (intragastric, sublingual), preferably oral and intrarectal in patients showing signs of infection of the intestine (nausea, diarrhea, presence of virus in the nose, in the faeces) ,
- par inhalation pour les patients présentant des signes d'infection des voies respiratoires (présence de virus dans le nez, exsudât, ou crachat) - by inhalation for patients with signs of respiratory tract infection (presence of virus in the nose, exudate, or sputum)
- par voie intraveineuse pour les patients souffrant de n'importe quel symptôme relatif à l'infection par le SARS-Cov2 - comme le syndrome respiratoire aigue. - intravenously for patients with any symptoms related to SARS-Cov2 infection - such as acute respiratory syndrome.
Selon une mise en œuvre particulière de l'invention, la composition pour son utilisation selon l'invention est caractérisée en ce qu'elle est sous une forme galénique destinée à une administration par inhalation. L'inhalation désigne l'absorption par les voies respiratoires. C'est en particulier une méthode d'absorption de composés à des fins thérapeutiques, de certaines substances sous forme de gaz, de micro-gouttelettes ou de poudre en suspension. According to a particular implementation of the invention, the composition for its use according to the invention is characterized in that it is in a galenic form intended for administration by inhalation. Inhalation refers to absorption through the respiratory tract. It is in particular a method of absorbing compounds for therapeutic purposes, certain substances in the form of gas, micro-droplets or powder in suspension.
L'administration de compositions pharmaceutiques par inhalation, c'est-à-dire par les voies nasale et/ou buc- cale, ou rectale est bien connue de l'Homme du métier. The administration of pharmaceutical compositions by inhalation, that is to say by the nasal and / or oral, or rectal routes is well known to those skilled in the art.
On distingue deux types d'administration par inhalation : There are two types of administration by inhalation:
• l'administration par insufflation lorsque les compositions sont sous la forme de poudres, et •l'administration par nébulisation lorsque les compositions sont sous la forme d'aérosols (suspen- sions) ou sous la forme de solutions, par exemple de solutions aqueuses, mises sous pression. L'utili- sation d'un nébuliseur ou d'un pulvérisateur sera alors recommandée pour administrer la composition pharmaceutique selon l'invention. • administration by insufflation when the compositions are in the form of powders, and • administration by nebulization when the compositions are in the form of aerosols (suspensions) or in the form of solutions, for example aqueous solutions. , put under pressure. The use of a nebulizer or a sprayer will then be recommended to administer the pharmaceutical composition according to the invention.
La forme galénique considérée ici est donc choisie parmi : une poudre, une suspension aqueuse de gouttelet- tes ou une solution sous pression. Le BHT seul ou en combinaison pour une utilisation contre la Covid-19 selon l'invention, peut être caractéri- sé par : une formulation galénique appropriée à une administration par voie orale (sublinguale, per os); une formulation galénique appropriée à une administration par inhalation, une formulation galénique appropriée à une administration par voie intraveineuse, une fonnulation galénique appropriée à une administration par voie intrarectale, de préférence une administration orale pour tous les individus qu'ils présentent des symptômes ou aucun symptôme, et plus avantageusement une administration orale pour les patients souffrant au moins de désor- dres intestinaux et plus avantageusement encore, une administration intraveineuse ou par inhalation pour les patients souffrant de syndrome respiratoire aigu sévère, et encore plus avantageusement encore, une administration intraveineuse et par inhalation pour les patients souffrant de syndrome respiratoire aigu sévère. The dosage form considered here is therefore chosen from: a powder, an aqueous suspension of droplets or a solution under pressure. BHT alone or in combination for use against Covid-19 according to the invention can be characterized by: a galenic formulation suitable for oral administration (sublingual, per os); a dosage formulation suitable for administration by inhalation, a dosage formulation suitable for intravenous administration, a dosage formulation suitable for intrarectal administration, preferably oral administration to all individuals showing symptoms or no symptoms , and more preferably oral administration for patients suffering from at least one intestinal disorder and still more preferably intravenous or inhalation administration for patients suffering from severe acute respiratory syndrome, and still more preferably intravenous and via administration. inhalation for patients with severe acute respiratory syndrome.
BHT pour son utilisation contre la Covid-19 selon l'invention caractérisé par une utilisation chez un individu infecté ou non par le Covid-19 et ne présentant aucun symptome, avantageusement dans une fonnulation ga- lénique appropriée à une administration par voie orale et rectale. BHT for its use against Covid-19 according to the invention characterized by use in an individual infected or not with Covid-19 and not showing any symptoms, advantageously in a galenic formulation suitable for oral and rectal administration .
BHT pour son utilisation contre la Covid-19 selon l'invention caractérisé par une utilisation chez un individu infecté par le SÀRS-Coe-2 présentant des symptomes tels que toux, dyspnée, fatigue, maux de gorge, trou- bles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, anosmie, agueusie, perte d'appétit, avantageu- sement dans une formulation galénique appropriée à une administration par voie orale. BHT for its use against Covid-19 according to the invention characterized by use in an individual infected with SÀRS-Coe-2 exhibiting symptoms such as cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a dosage formulation suitable for oral administration.
BHT pour son utilisation selon l'invention caractérisé par une utilisation chez un individu infecté par le SARS-Cov-2 présentant des symptomes tels que toux et syndrome respiratoire aigu sévère, avantageusement dans une formulation galénique appropriée à une administration par voie intraveineuse et ou par inhalation. BHT for its use according to the invention characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for intravenous administration and / or by inhalation.
L'invention porte sur les combinaisons de doses et posologies suivantes selon un aspect : The following dosage and dosage combinations are provided in one aspect:
BHT à une dose de 300 mg; Acétylcystéine à une dose de 200 mg; Boswellia serrata à une dose de 500 mgBHT at a dose of 300 mg; Acetylcysteine in a dose of 200 mg; Boswellia serrata at a dose of 500 mg
BHT à une dose de 300 mg; Acétylcystéine à une dose de 200 mg; Boswellia serrata à une dose de 500 mg dans une formulation galénique appropriée pour une administration par voie orale (per os (po)). BHT at a dose of 300 mg; Acetylcysteine in a dose of 200 mg; Boswellia serrata at a dose of 500 mg in a dosage formulation suitable for oral administration (orally (po)).
BHT à une dose de 300 mg; Acétylcystéine à une dose de 200 mg; Boswellia serrata à une dose de 500 mg dans une formulation galénique appropriée pour une administration par voie orale (po) deux fois ou trois par jour pendant 10 jours . BHT at a dose of 300 mg; Acetylcysteine in a dose of 200 mg; Boswellia serrata at a dose of 500 mg in a dosage formulation suitable for oral (po) administration twice or three times a day for 10 days.
BHT à une dose de 300 mg; Acétylcystéine à une dose de 200 mg; Boswellia serrata à une dose de 500 mg dans une formulation galénique appropriée pour une administration par voie orale (per os (po) deux fois par jour pendant 10 jours, avantageusement chez des individus infectés ou non par le SARS-Cov-2 ou chez pa- tients au cours de l'infection Covid-19, encore plus avantageusement chez des patients présentant de troubles digestifs (diarrhée, nausée) au cours de l'infection Covid-19, BHT at a dose of 300 mg; Acetylcysteine in a dose of 200 mg; Boswellia serrata at a dose of 500 mg in a galenic formulation suitable for oral administration (orally (po) twice a day for 10 days, advantageously in individuals infected or not with SARS-Cov-2 or in pa - tients during the Covid-19 infection, even more advantageously in patients with digestive disorders (diarrhea, nausea) during the Covid-19 infection,
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 200 mg; Acetylcysteine à une dose de 300 mg.BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 200 mg; Acetylcysteine in a dose of 300 mg.
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 200 mg; Acetylcysteine à une dose de 300 mg, deux ou troi s foi s par j our pendant 10 j ours . BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 200 mg; Acetylcysteine at a dose of 300 mg, two or three times a day for 10 days.
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 200 mg; Acetylcysteine à une dose de 300 mg, deux ou trois fois par jour pendant 10 jours dans une formulation galénique appropriée pour une administra- tion par voie orale, intraveineuse, et/ou par inhalation, BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 200 mg; Acetylcysteine at a dose of 300 mg, two or three times a day for 10 days in a galenic formulation suitable for oral, intravenous, and / or inhalation administration,
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 200 mg; Acetylcysteine à une dose de 300 mg, deux ou trois fois par jour pendant 10 jours dans une formulation galénique appropriée pour une administra- tion par voie orale, intraveineuse, et/ou par inhalation, chez des patients souffrant de syndrome respiratoire aigu sévère au cours de l' infection Covid-19. BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 200 mg; Acetylcysteine at a dose of 300 mg, two or three times daily for 10 days in a dosage formulation suitable for oral, intravenous, and / or inhalation administration, in patients suffering from severe acute respiratory syndrome during of Covid-19 infection.
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 100 mg; Superoxyde Dismutase (SOD) à une dose de 200 mg; Catalase (CAT) à une dose de 100 mg; ATP à une dose de 100 mg. BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 100 mg; Superoxyde Dismutase (SOD) à une dose de 200 mg; Catalase (CAT) à une dose de 100 mg; ATP à une dose de 100 mg, dans une formulation galénique appropriée pour une administration par voie intraveineuse, orale et/ou pour une administration par inhalation. BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg. BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg, in a galenic formulation suitable for intravenous, oral and / or for inhalation administration.
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 100 mg; Superoxyde Dismutase (SOD) à une dose de 200 mg; Catalase (CAT) à une dose de 100 mg; ATP à une dose de 100 mg, dans une formulation galénique appropriée pour une administration par voie intraveineuse, orale et/ou pour une administration par inhalation, trois fois par jour pendant 10 jours, avantageusement chez des patients au cours de l'infection Covid-19, BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg, in a galenic formulation suitable for intravenous, oral and / or inhalation administration, three times a day for 10 days, advantageously in patients during Covid-infection. 19,
BHT à une dose de 500 mg ; Glutathion (GSH) à une dose de 100 mg; Superoxyde Dismutase (SOD) à une dose de 200 mg; Catalase (CAT) à une dose de 100 mg; ATP à une dose de 100 mg, dans une formulation galénique appropriée pour une administration par voie intraveineuse, orale et/ou pour une administration par inhalation, trois fois par jour pendant 10 jours à un mois, avantageusement chez des patients au cours de l'in- fection Covid-19, avantageusement chez des patients souffrant de syndrome respiratoire aigu sévère aïs cours de l'infection Covid-19. BHT seul ou en combinaison selon l'invention pour son utilisation selon l'invention caractérisé par une utili- sation 1 à 3 fois par jour. BHT at a dose of 500 mg; Glutathione (GSH) at a dose of 100 mg; Superoxide Dismutase (SOD) at a dose of 200 mg; Catalase (CAT) at a dose of 100 mg; ATP at a dose of 100 mg, in a dosage formulation suitable for intravenous, oral and / or for inhalation administration, three times a day for 10 days to a month, preferably in patients during the Covid-19 infection, advantageously in patients suffering from severe acute respiratory syndrome during Covid-19 infection. BHT alone or in combination according to the invention for its use according to the invention characterized by use 1 to 3 times per day.
BHT seul ou en combinaison selon l'invention caractérisé par une utilisation selon l'invention pendant au moins 5 jours à au moins 10 jours. BHT alone or in combination according to the invention characterized by use according to the invention for at least 5 days to at least 10 days.
BHT seul ou en combinaison selon l'invention caractérisé par une utilisation selon l'invention pendant au moins 5 jours à au moins 14 jours. BHT alone or in combination according to the invention characterized by a use according to the invention for at least less 5 days to at least 14 days.
Une composition selon l'invention peut être une composition alimentaire, une composition pharmaceutique ou vétérinaire. A composition according to the invention can be a food composition, a pharmaceutical or veterinary composition.
L'invention porte aussi sur une : The invention also relates to a:
- Composition selon l'invention caractérisée en ce qu'elle est administrée à individus infectés ou non par le coronavirus SARS-CoV-2, avantageusement ne présentant aucun symptôme, plus avantageusement encore par voie orale. - Composition according to the invention, characterized in that it is administered to individuals infected or not by the SARS-CoV-2 coronavirus, advantageously exhibiting no symptoms, more advantageously still orally.
- Composition selon l'invention caractérisée en ce qu'elle est utilisée chez des patients infectés par le corona- virus S.4RS-CoV-2 et présentant aucun symptôme, ou au moins un symptomes parmi toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, anosmie, agueusie, perte d'appétit, avantageusement dans une formulation galénique appropriée à une admi- nistration par voie orale. - Composition according to the invention characterized in that it is used in patients infected with the S.4RS-CoV-2 corona virus and exhibiting no symptoms, or at least one symptom among cough, dyspnea, fatigue, sore throat , gastrointestinal disturbances, intestinal pain, diarrhea, headache, anosmia, ageusia, loss of appetite, advantageously in a galenic formulation suitable for oral administration.
Composition selon l'invention caractérisé par une utilisation chez un individu infecté par le SARS-Cov-2 présentant des symptomes tels que toux et syndrome respiratoire aigu sévère, avantageusement dans une for- mulation galénique appropriée à une adm inistration par voie intraveineuse et ou par inhalation. Composition according to the invention, characterized by use in an individual infected with SARS-Cov-2 exhibiting symptoms such as cough and severe acute respiratory syndrome, advantageously in a galenic formulation suitable for administration by the intravenous route and / or by inhalation.
Composition selon l'invention pour son utilisation contre la Covid-19 dans une méthode de traitement selon l'invention. Composition according to the invention for its use against Covid-19 in a method of treatment according to the invention.
Composition comprenant de la BS selon l'invention pour son utilisation dans une méthode de traitemen de la Covid-19 selon l'invention earatérisée en ce qu'elles ne sont administrées que par voie orale. Composition comprising BS according to the invention for its use in a method of treating Covid-19 according to the invention characterized in that they are administered only orally.
Mode d'administration du BHT, NAC, BS, GSH, CAT , SOD, ATP, des compositions pharmaceutiques com- prenant du BHT pour la prévention et/ou le traitement de la Covid-19. Method of administration of BHT, NAC, BS, GSH, CAT, SOD, ATP, pharmaceutical compositions comprising BHT for the prevention and / or treatment of Covid-19.
Les compositions pharmaceutiques selon l'invention contiennent le BHT et des véhicules qui sont pharma- ceutiquement acceptables pour une formulation susceptible d'être administrée par voie entérale : orale (po), sublinguale (sl), par inhalation (in), intrarectale (ir), ou par voie parenthérale, intrapéritonéale (ip), sous cuta- née (sc), intramusculaire (im), intraveineuse (iv). The pharmaceutical compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered enterally: oral (po), sublingual (sl), by inhalation (in), intrarectal (ir ), or by parenteral, intraperitoneal (ip), subcutaneous (sc), intramuscular (im), intravenous (iv) route.
De préférence, les compositions pharmaceutiques selon l'invention contiennent le BHT et des véhicules qui sont pharmaceutiquement acceptables pour une formulation susceptible d'être administrée par voie entérale : orale (po), sublinguale (si), par inhalation (in), intrarectale (ir), ou par voie intraveineuse (iv), plus préférentiellement, les compositions pharmaceutiques selon l'invention contiennent le BHT et des véhi- cules qui sont pharmaceutiquement acceptables pour une formulation susceptible d'être administrée par voie orale (po) et/ou intrarectale (ir) pour les infections du tractus GI « bas » par le SÀRS-COV-2 ; par voie sublinguale (si), par inhalation (in) pour les infections du tractus GI «haut » par le SARS-COV-2 par voie intraveineuse (iv), et orale (po) intrarectale (ir) et sublinguale (si), par inhalation (in) pour toutes les stades de Covid-19, stade précoce (maux de gorge, rhinorrhée, nausée, diarhée), céphalée, stade avancé (in- suffisance respiratoire), chez des patients risquant de développer une forme sévère (personnes âgées (< 60 ans), souffrant de diabète, insuffisance cardiaque, insuffisance pulmonaire chez des personnes présentant des signes d'infection du TGI bas, ou (par voie intraveineuse (iv), et intrarectale (ir) et par inhalation (in) pour les patients inhibés). Preferably, the pharmaceutical compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered enterally: oral (po), sublingual (si), by inhalation (in), intrarectal ( ir), or intravenously (iv), more preferably, the pharmaceutical compositions according to the invention contain BHT and vehicles which are pharmaceutically acceptable for a formulation capable of being administered orally (po) and / or intrarectal (ir) for infections of the “low” GI tract by SÀRS-COV-2; sublingually (si), inhalation (in) for infections of the “upper” GI tract by intravenous (iv) SARS-COV-2, and orally (po) intrarectal (ir) and sublingual (si), by inhalation (in) for all stages of Covid-19, early stage (sore throat, rhinorrhea, nausea, diarrhea), headache, advanced stage (respiratory insufficiency), in patients at risk of developing a severe form (people elderly (<60 years), suffering from diabetes, heart failure, pulmonary insufficiency in people with signs of infection of low TGI, or (intravenous (iv), and intrarectal (ir) and inhalation (in) for inhibited patients).
Selon un mode de réali sation , le BHT seul ou en combinaison avec la NAC et la BS peut être administré par voie orale chez des personnes susceptibles de contracter le SARS-Cov-2 (prévention), chez des personnes asymptomatiques (SARS-Cov-2 positive sans symptôme, ou ayant au moins un signe d'infection par le SARS-Cov-2, au stade précoce, avan- cé, sévère non inhibé. According to one embodiment, BHT alone or in combination with NAC and BS can be administered orally in people at risk of contracting SARS-Cov-2 (prevention), in asymptomatic people (SARS-Cov- 2 positive without symptoms, or having at least one sign of infection with SARS-Cov-2, early, advanced, severe uninhibited.
Selon un mode de réalisation According to one embodiment
Le BHT seul ou en combinaison, soit avec la NAC et le GSH ; soit avec le GSH, SOD, CAT et ATP peut être administré par voie orale (pi, si, intranasale (in) et/ou intraveineuse iv chez des personnes susceptibles de contracter le SARS-Cov-2 (prévention), chez des personnes asymptomatiques (SARS-Cov-2 positive sans symptôme, ou ayant au moins un signe d'infection par le SARS-Cov-2, au stade précoce, avancé, sévère non intubé. BHT alone or in combination, either with NAC and GSH; either with GSH, SOD, CAT and ATP can be administered orally (pi, si, intranasal (in) and / or intravenously iv in people susceptible to contracting SARS-Cov-2 (prevention), in asymptomatic people (SARS-Cov-2 positive without symptoms, or with at least one sign of infection with SARS-Cov-2, early, advanced, severe not intubated.
Les doses actives de BHT peuvent être de 300 mg 3x/j ou 500 mg 3x/j seul ou en combinaison avec la NAC 200 mg ou 300 mg la BS est à la dose de 500 mg et au moins 40% d'acide(s)boswellique(s) le GSH 100 ou 200 mg la SOD est à la dose de 200 mg The active doses of BHT can be 300 mg 3x / d or 500 mg 3x / d alone or in combination with the NAC 200 mg or 300 mg the BS is at the dose of 500 mg and at least 40% acid (s ) boswellic (s) GSH 100 or 200 mg SOD is at a dose of 200 mg
CAT est à la dose de 100 mg CAT is at a dose of 100 mg
ATP est à la dose de 100 mg selon un mode de réalisation les doses sont exprimées en mg/kg ou en 0,lxmg/kg mg/kg signifie mg /kg en poids. ATP is at a dose of 100 mg according to one embodiment, the doses are expressed in mg / kg or in 0.1 × mg / kg mg / kg means mg / kg by weight.
Des exemples non limitatifs de doses, de posologies et de fournisseurs de principe actif(s) (pour la voie orale ou sublinguale notamment) des différents composés de l'invention sont décrits ci dessous : Non-limiting examples of doses, dosages and suppliers of active principle (s) (for the oral or sublingual route in particular) of the various compounds of the invention are described below:
NAC 200 mg ou 300 mg comprimés de l00mg (Dynveo(r)) NAC 200 mg or 300 mg 100 mg tablets (Dynveo (r))
NAC 600 mg par jour, en 3 prises Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg (ou 500 mg) 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec la MAC à la dose de 200 mg. NAC 600 mg per day, in 3 divided doses According to one embodiment, BHT is administered at a dose of 300 mg _ ± 150 mg (or 500 mg) 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ± 250 mg 3 times per day, in an individual weighing 61 to 90 kg, for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with MAC at a dose of 200 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg (ou 500 mg) 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec la NAC à la dose de 300 mg. According to one embodiment, BHT is administered at a dose of 300 mg _ ± 150 mg (or 500 mg) 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ± 250 mg 3 times per day, in an individual weighing 61 to 90 kg, for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with NAC at a dose of 300 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le GSH à la dose de 100 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ± 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 100 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg .± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le GSH à la dose de 200 mg. According to one embodiment, the BHT is administered at a dose of 300 mg 150 mg, 3 times per day, to an individual weighing between 40 to 60 kg, or 500 mg . ± 250mg 3 times a day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 200 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _+ 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le GSH à la dose de 300 mg. Sources de GSH possibles : According to one embodiment, BHT is administered at a dose of 300 mg 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 300 mg. Possible sources of GSH:
GSH (glutation réduit- actif): 100 mg (Thierry Duhec) ou 200 mg (150 mg Energetica Natura Belgique avec 50 NAC, à ajuster) GSH (reduced-active glutation): 100 mg (Thierry Duhec) or 200 mg (150 mg Energetica Natura Belgium with 50 NAC, to be adjusted)
300 mg SUBLÏNTHION Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un indi vidu pesant entre 40 à 60 kg, ou 500 mg _+ 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le GSH à la dose de 100 mg. 300 mg SUBLINTHION According to one embodiment, BHT is administered at a dose of 300 mg ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 and 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 100 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _+ 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le GSH à la dose de 200 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ + 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ± 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with GSH at a dose of 200 mg.
SGD SGD
La posologie quotidienne du SOI) pourra varier de 0,01 à 1000 mg chez l'adulte par jour. Typiquement, les compositions contiennent 0,01 ; 0,05 ; 0,1 ; 0,5 ; 1,0 ; 2,5 ; 5,0 ; 10,0 ; 15,0 ; 25,0 ; 50,0 ; 100 ; 250,0 ; 500,0 mg de SOD ; de préférence de 3 mg à environ 300 mg de SOD/j ou plus avantageusement de 100 à 200 rng/j ou de 10 à 20 mg /j The daily dosage of SOI) may vary from 0.01 to 1000 mg in adults per day. Typically, the compositions contain 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 25.0; 50.0; 100; 250.0; 500.0 mg of SOD; preferably from 3 mg to approximately 300 mg of SOD / d or more advantageously from 100 to 200 rng / d or from 10 to 20 mg / d
SOD : 200 mg Utilisée en combinaison avec le BHT comme médicament pouvant stimuler l'immunité. SOD pure (EASY NUTRITION / LABO SP) ou avec le BHT 300 ou 500mg; 2 comprimés de SOD 100 mg par prise -pour la stimulation de l'immunité, en particulier pour le traitement de la Covid-19. SOD: 200 mg Used in combination with BHT as a drug that can boost immunity. Pure SOD (EASY NUTRITION / LABO SP) or with BHT 300 or 500mg; 2 tablets of SOD 100 mg per dose -for stimulation of immunity, in particular for the treatment of Covid-19.
La posologie quotidienne du SOD pourra varier de 0,01 à 1000 mg chez l'adulte par jour. Typiquement, les compositions contiennent 0,01 ; 0,05 ; 0,1 ; 0,5 ; 1,0 ; 2,5 ; 5,0 ; 10,0 ; 15,0 ; 25,0 ; 50,0 ; 100 ; 250,0 ; 500,0 mg de SOD ; de préférence de 3 mg à environ 300 rng de SOD/j The daily dosage of SOD may vary from 0.01 to 1000 mg in adults per day. Typically, the compositions contain 0.01; 0.05; 0.1; 0.5; 1.0; 2.5; 5.0; 10.0; 15.0; 25.0; 50.0; 100; 250.0; 500.0 mg of SOD; preferably from 3 mg to about 300 rng of SOD / d
Une quantité efficace de SOD est fournie à un niveau posologique allant de 0,002 mg / kg à environ 2 mg / kg de poids corporel par jour, en particulier d'environ 0,1 mg / kg à 1 mg /kg de poids corporel par jour ; de préférence 200mg 3x/j ou 200mg 5x/j . An effective amount of SOD is provided at a dosage level ranging from 0.002 mg / kg to about 2 mg / kg of body weight per day, in particular from about 0.1 mg / kg to 1 mg / kg of body weight per day. our; preferably 200mg 3x / d or 200mg 5x / d.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _+ 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le SOD à la dose de 200 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with SOD at a dose of 200 mg.
La Catala.se (CAT) 100 mg La Catala.se (CAT) 100 mg
Une quantité efficace de CAT est fournie à un niveau posologique allant de 0,01 mg / kg à environ 1 g / kg de poids corporel par jour, en particulier environ 0,1 mg / kg à 500 mg /kg de poids corporel par jour ; de pré- férence l00mg 3x/j ou l00mg 5x/j ; 250 mg 2x/j ou 3x/j. An effective amount of CAT is provided at a dosage level ranging from 0.01 mg / kg to about 1 g / kg of body weight per day, in particular about 0.1 mg / kg to 500 mg / kg of body weight per day ; preferably 100mg 3x / d or 100mg 5x / d; 250 mg 2x / d or 3x / d.
Catalase Newpharma est une bonne source de catalase utilisable, x/j signifie fois par jour Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg .± 250mg 3 fois par jour, chez un individu pesant entre 6! à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le CAT à la dose de 100 mg. Catalase Newpharma is a good source of usable catalase, x / d means times per day According to one embodiment, the BHT is administered at a dose of 300 mg ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg. ± 250 mg 3 times per day, in an individual weighing between 6! to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with CAT at a dose of 100 mg.
ATP ATP
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _+ 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le ATP à la dose de 30 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 30 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _± 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _± 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le ATP à la dose de 100 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ ± 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ ± 250 mg 3 times per day, in an individual weighing between 61 and 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 100 mg.
Selon un mode de réalisation le BHT est administré à la dose de 300 mg _+ 150 mg , 3 fois par jour, chez un individu pesant entre 40 à 60 kg, ou 500 mg _+ 250mg 3 fois par jour, chez un individu pesant entre 61 à 90 kg, et cela pendant 5 à 10 jours, ou pendant 6 à 14 jours, ou pendant 7 à 28 jours seul ou en combinaison avec le ATP à la dose de 400 mg. According to one embodiment, the BHT is administered at a dose of 300 mg _ + 150 mg, 3 times per day, in an individual weighing between 40 to 60 kg, or 500 mg _ + 250 mg 3 times per day, in an individual weighing between 61 to 90 kg, and this for 5 to 10 days, or for 6 to 14 days, or for 7 to 28 days alone or in combination with ATP at a dose of 400 mg.
ATP 100 mg ATP 100 mg
La dose d'ATP selon T invention peuvent varier de 1 mg à 1000 mg, de préférence de 10 à 100 mg, par ex 400 mg. The dose of ATP according to the invention can vary from 1 mg to 1000 mg, preferably from 10 to 100 mg, for example 400 mg.
ATEPADENE 30mg/geiuie est une source mtéresante d'ATP pour son utilisation selon l'invention. ATEPADENE 30 mg / bottle is a metering source of ATP for its use according to the invention.
ATP Max(R) 400 mg ou PEAK ATP(TM). ATP Max (R) 400 mg or PEAK ATP (TM).
BS la dose de BS selon l'invention peuvent varier de 5 mg à 5000 mg, de préférence de 10 à 500 mg, par ex 350 mg. Forme galénique pour l'administration orale CASPEROME(R). BS the dose of BS according to the invention can vary from 5 mg to 5000 mg, preferably from 10 to 500 mg, eg 350 mg. Galenic form for oral administration CASPEROME (R).
NATTOKINASE la dose de Nattokinase selon l'invention peuvent varier de 1 mg à 500 mg, de préférence de 10 à 100 mg (2000 FU), par ex 100 mg ou 50 mg. NATTOKINASE the dose of Nattokinase according to the invention can vary from 1 mg to 500 mg, preferably from 10 to 100 mg (2000 FU), for example 100 mg or 50 mg.
QUERCETINE la dose de quercétine selon l'invention peuvent varier de 1 mg à 1000 mg, de préférence de 10 à 100 mg (2, par ex 100 mg ou 200 mg, et plus avantageusement 200 mg 3 fois par jour. QUERCETINE the dose of quercetin according to the invention can vary from 1 mg to 1000 mg, preferably from 10 to 100 mg (2, for example 100 mg or 200 mg, and more advantageously 200 mg 3 times a day.
Kit Kit
La présente invention concerne également un produit en kit comprenant : le BHT dans une formulation, et au moins l'un quelconque des principes actifs sélectionnés parmi, G.4TR dans une formulation séparée, The present invention also relates to a kit product comprising: BHT in a formulation, and at least any one of the active ingredients selected from, G.4TR in a separate formulation,
La NAC dans une formulation séparée, NAC in a separate formulation,
La BS dans une formulation séparée, The BS in a separate formulation,
La SOD dans une formulation séparée, SOD in a separate formulation,
La CAT dans une formulation séparée, CAT in a separate wording,
La GSH dans une formulation séparée, GSH in a separate formulation,
La Nattokinase dans une formulation séparée, Nattokinase in a separate formulation,
La quercétine dans une formulation séparée, ou une combinaison de trois, quatre, cinq, six, sept de ces composés ou tous ces composés. Quercetin in a separate formulation, or a combination of three, four, five, six, seven or all of these compounds.
La présente invention concerne également un produit en kit comprenant : le BHT dans une formulation, l'ATP dans une formulation séparée, The present invention also relates to a kit product comprising: BHT in one formulation, ATP in a separate formulation,
La NAC dans une formulation séparée, NAC in a separate formulation,
La BS dans une formulation séparée, The BS in a separate formulation,
La SOD dans une formulation séparée, SOD in a separate formulation,
La CAT dans une formulation séparée, CAT in a separate wording,
La GSH dans une formulation séparée, ou une combinaison de deux, trois, quatre cinq ou six de ces compo- sés. GSH in a separate formulation, or a combination of two, three, four, five or six of these compounds.
Les formes d'administration unitaires appropriées comprennent les formes par voie orale telles que compri- més, gélules, poudres, granules et suspensions ou solutions orales, formes d'administration sublinguale et buccale, aérosols, implants sous-cutanées, transdermiques, topiques, intrapéritonéales, intramusculaires, in- traveineuses, formes d'administration intrathécale, intranasale et fomies d'administration rectale. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, subcutaneous, transdermal, topical, intraperitoneal implants. , intramuscular, intravenous, intrathecal, intranasal and rectal administration forms.
L'invention porte sur, selon un aspect, sur une composition selon l'invention, comprenant le BHT et au moins une autre composition comprenant un composé choisi parmi la CAT, GSH, SOD, ATP, BS et une combinai- son de ces composés, pour une utilisation simultanée, séparée ou séquentielle pour prévenir et/ou traiter une infection par le coronavirus SARS-CoV, chez l'homme ou chez l'animal. The invention relates, according to one aspect, to a composition according to the invention, comprising BHT and at least one other composition comprising a compound selected from CAT, GSH, SOD, ATP, BS and a combination of these compounds. , for simultaneous, separate or sequential use to prevent and / or treat infection with the SARS-CoV coronavirus, in humans or animals.
Un tel produit de combinaison pourra être utilisé dans la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2, dans le cadre d'une utilisation simultanée, séparée ou séquentielle. Ainsi, les au moins deux agents actifs compris dans le produit de combinaison pourront être administrés de manière simul- tanée, séparée ou séquentielle. Il est entendu que toutes les combinaisons de deux, trois, quatre, cinq ou six composés actifs citées précé- demment peuvent chacune être sous la forme d'un produit de combinaison, en kit, c'est-à-dire que les deux, trois, quatre ou cinq composés actifs peuvent être administrés de manière simultanée, séparée ou séquentiel- le, pour prévenir et/ou traiter une infection par le coronavirus SARS-CoV-2. Such a combination product could be used in the prevention and / or treatment of an infection by the SARS-CoV-2 coronavirus, in the context of simultaneous, separate or sequential use. Thus, the at least two active agents included in the combination product can be administered simultaneously, separately or sequentially. It is understood that all the combinations of two, three, four, five or six active compounds mentioned above can each be in the form of a combination product, in a kit, that is to say that the two, three, four or five active compounds can be administered simultaneously, separately or sequentially, to prevent and / or treat infection with the SARS-CoV-2 coronavirus.
METHODE METHOD
L'invention se rapporte également à une méthode thérapeutique pour la prévention et/ou le traitement d'une infection par le coronavirus SARS-CoV-2 chez l'homme, dans laquelle on administre en plus du BHT, à un patient une quantité efficace d'un composé choisi parmi SOD, CAT GSH, ATP, NAC, BS, ou un mélange des deux, des tois des quatres, des cinq des six. The invention also relates to a therapeutic method for the prevention and / or treatment of an infection by the coronavirus SARS-CoV-2 in humans, in which, in addition to BHT, an effective amount is administered to a patient. of a compound selected from SOD, CAT GSH, ATP, NAC, BS, or a mixture of two, three of four, five of six.
Une méthode de prévention et/ou de traitement d'une maladie liée à l'infection par un coronavirus suscepti- ble de provoquer un syndrome respiratoire aigu sévère comprenant la mise à disposition de BHT ou d'une composition selon l'invention. A method of preventing and / or treating a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome comprising the provision of BHT or of a composition according to the invention.
Une méthode de prévention et/ou de traitement d'une maladie liée à l'infection par un coronavirus suscepti- ble de provoquer un syndrome respiratoire aigu sévère comprenant la mise à disposition de BHT ou d'une composition selon l'invention celle(s) comprenant de la BS étant destinée(s) à la voie orale uniquement. A method of preventing and / or treating a disease linked to infection with a coronavirus capable of causing severe acute respiratory syndrome comprising the provision of BHT or of a composition according to the invention that (s) ) comprising BS being intended for oral use only.
Méthode de prévention et/ou de traitement d'une maladie liée à l'infection parun coronavirus susceptible de provoquer un syndrome respiratoire aigu sévère comprenant une administration par voie orale, iv ou par in- halation, ou par une combinaison des voies d'administration chez des individus présentant ou non des symp- tômes, de BHT ou d'une composition selon l'invention. A method of preventing and / or treating a disease associated with coronavirus infection capable of causing severe acute respiratory syndrome comprising administration by mouth, iv or by inhalation, or by a combination of the routes of administration in individuals with or without symptoms, of BHT or of a composition according to the invention.
Méthode de prévention et/ou de traitement d'une maladie liée à l'infection par un coronavirus susceptible de provoquer un syndrome respiratoire aigu sévère selon l'invention comprenant une administration par voie orale chez tous les individus présentant ou non des symptomes, de BHT ou d'une composition selon l'inven- tion. Method for the prevention and / or treatment of a disease linked to the infection by a coronavirus capable of causing a severe acute respiratory syndrome according to the invention comprising oral administration in all individuals with or without symptoms, of BHT or of a composition according to the invention.
Méthode de prévention et/ou de traitement d'une maladie liée à l'infection parun coronavirus susceptible de provoquer un syndrome respiratoire aigu sévère comprenant une administration de BHT ou d'une composi- tion selon l'invention, chez un individu, en particulier un individu présentant au moins un des symptomes choisi parmi, toux, dys- pnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, lymphopé- nie, syndrome respiratoire aigu sévère, avantageusement une administration par voie orale et intraveineuse chez des individus présentant au moins un des symptomes choisi parmi, toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, lymphopénie, syndrome respiratoire aigu sévère, ou une adm inistration par voie orale et par inhalation chez des individus présentant au moins un des symptô- mes choisi parmi, toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, lymphopénie, syndrome respiratoire aigu sévère, ou une administration par voie orale, intraveineuse et par inhalation chez des individus présentant au moins un des symptomes choisi parmi, toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intestinale, diarrhée, céphalée, lymphopénie, syndrome respiratoire aigu sévère, ou une administration par voie intraveineuse et par inhalation chez des individus présentant au moins un des symptomes choisi parmi, toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intesti- nale, diarrhée, céphalée, lymphopénie, syndrome respiratoire aigu sévère, ou une administration par voie intraveineuse et par inhalation chez des individus présentant au moins un des symptômes choisi parmi, toux, dyspnée, fatigue, maux de gorge, troubles gastro-intestinaux, douleur intesti- nale, diarrhée, céphalée, lymphopénie, syndrome respiratoire aigu sévère. Method of preventing and / or treating a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome comprising administration of BHT or of a composition according to the invention, in an individual, in particular an individual exhibiting at least one of the symptoms selected from cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, advantageously oral administration and intravenously in individuals presenting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, or administration by the oral route and by inhalation in individuals exhibiting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, respiratory syndrome severe acute, or oral, intravenous and inhalation administration in individuals exhibiting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, intestinal pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, or intravenous and inhalation administration in individuals exhibiting at least one of the symptoms selected from, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbances, bowel pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome, or intravenous and inhalation administration in individuals with at least one of the selected symptoms among, cough, dyspnea, fatigue, sore throat, gastrointestinal disturbance, bowel pain, diarrhea, headache, lymphopenia, severe acute respiratory syndrome.
INDIVIDUS - PATIENTS - DISCLAIMER INDIVIDUALS - PATIENTS - DISCLAIMER
Dans certains cas identifiés par un médecin, si le patient souffre de syndrome cytoquinique (cytokine storm), certaines compositions selon l'invention pourraient être modifiées; n'importe quelles autres compositions se- lon l'invention pourront l'être. In certain cases identified by a doctor, if the patient suffers from cytoquine syndrome (cytokine storm), certain compositions according to the invention could be modified; any other compositions according to the invention could be.
On entend par individu un être vivant, de préférence un être humain. By individual is meant a living being, preferably a human being.
Dans la population humaine on entend par un patient, une personne infectée par un comavirus, (de préféren- ce un betacoronavirus, plus préférentiellement un virus susceptible d'induire un syndrome respiratoire aigu, encore plus pref un SARS-Cov, ou MERS-Cov, et encore plus plus pref un SARS-Cov-2) quel que soit le de- gré de la maladie - le stade de la maladie, la présence ou l'absence de symptôme. In the human population is meant by a patient, a person infected with a comavirus, (preferably a betacoronavirus, more preferably a virus capable of inducing an acute respiratory syndrome, even more preferably a SARS-Cov, or MERS-Cov , and even more pref- er a SARS-Cov-2) regardless of the degree of the disease - the stage of the disease, the presence or absence of symptoms.
Dans la population humaine, on distinguera les patients ayant des symptomes liés à l'infection de la muqueu- se du tractus gastro intestinale bas, (la muqueuse de tractus gastrointestinal haute étant la muqueuse nasale, la gorge, et /ou la muqueuse pulmonaire étant en particulier ceux ayant des nausées, ceux ayant au moins un symptôme parmi fièvre, courbatures, fatigue, tous sèche, troubles intestinaux (vomissement, nausée, diaré- hée) ceux ayant de la diarhée ; les patients âgés, (plus de 40 ans, 50 ans, 60 ans, 70 ans, 75 ans). In the human population, we can distinguish patients with symptoms related to infection of the mucous membrane of the lower gastrointestinal tract, (the upper gastrointestinal tract mucosa being the nasal mucosa, the throat, and / or the pulmonary mucosa being especially those with nausea, those with at least one symptom among fever, body aches, fatigue, all dryness, intestinal disturbances (vomiting, nausea, diarrhea) those with diarrhea; elderly patients (over 40 years old, 50 years old, 60 years old, 70 years old, 75 years old).
Les compositions selon l'invention peuvent être de type pharmaceutique, destinées à être administrées à un être humain, ou de type vétérinaire, destinées à être administrés à des animaux non humains. The compositions according to the invention can be of pharmaceutical type, intended to be administered to a human being, or of veterinary type, intended to be administered to non-human animals.
Concernant les animaux, les compositions vétérinaires selon l'invention sont notamment destinées aux mam- mifères, comme le pangolin ou la chauve-souris, ou encore le hamster doré. With regard to animals, the veterinary compositions according to the invention are in particular intended for mammals, such as the pangolin or the bat, or even the golden hamster.
Méthode de prévention et/ou de traitement d'une maladie liée à l'infection par un coronavirus susceptible de provoquer un syndrome respiratoire aigu sévère selon l'invention comprenant une administration par voie orale chez des individus présentant des symptomes tels que troubles gastro-intestinaux, douleur intestinale, diarrhée. Method for the prevention and / or treatment of a disease associated with infection with a coronavirus capable of causing severe acute respiratory syndrome according to the invention comprising oral administration in individuals exhibiting symptoms such as gastrointestinal disorders , intestinal pain, diarrhea.
L'invention porte également selon un aspect, sur des produits : 1) BHT, NAC, BS The invention also relates in one aspect to products: 1) BHT, NAC, BS
2) BHT, NAC, GSH 2) BHT, NAC, GSH
3) BHT, CAT, SOD. GSH, ATP 3) BHT, CAT, SOD. GSH, ATP
Selon l'invention une préparation (dose) formulée pour la voie orale peut être : According to the invention, a preparation (dose) formulated for the oral route can be:
• BHT: 300 MG • BHT: 300 MG
• Acétylcystéine: 200 mg • Acetylcysteine: 200 mg
• Boswellia serrata (avec au moins 40% d'acides boswelliques par rapport au poids total): 500 mg La posologie de cette composition à titre d'exemple peut être une dose deux à trois fois par jour. • Boswellia serrata (with at least 40% of boswellic acids relative to the total weight): 500 mg The dosage of this composition by way of example can be one dose two to three times a day.
Des formulations appropriées pour l' inhalation et /la voie intraveineuse font partie de l'invention. Formulations suitable for inhalation and / or intravenous use form part of the invention.
• BHT: 300 MG • BHT: 300 MG
• Quercéthine 200 mg • Quercethine 200 mg
• Boswellia serrata (avec au moins 40% d'acides boswelliques par rapport au poids total):5Q0 rng La posologie de cette composition à titre d'exemple peut être une dose deux à trois fois par jour. • Boswellia serrata (with at least 40% of boswellic acids relative to the total weight): 5q0 rng The dosage of this composition as an example can be a dose two to three times per day.
• BHT: 300 MG • BHT: 300 MG
• Quercéthine 200 mg • Quercethine 200 mg
• Nattokinase :50 mg ou 100 mg • Nattokinase: 50 mg or 100 mg
La posologie de cette composition à titre d'exemple peut être une dose deux à trois fois par jour. The dosage of this exemplary composition can be one dose two to three times per day.
Selon l'invention une préparation (dose) formulée pour la voie orale ou iv ou inhalée peut être : According to the invention, a preparation (dose) formulated for the oral or iv or inhaled route can be:
• BHT: 500 MG • BHT: 500 MG
• Glutathion: 200 mg • Glutathione: 200 mg
• Acétvl cystéine : 300 mg • Acetvl cysteine: 300 mg
Posologie : 3 fois par jours dans 250 ml de solution physiologique. Dosage: 3 times a day in 250 ml of physiological solution.
Selon l'invention une préparation (dose) formulée pour la voie orale ou iv ou inhalée peut être According to the invention a preparation (dose) formulated for the oral or iv or inhaled route can be
• BHT: 500 MG • BHT: 500 MG
• Glutathion: 100 mg • Glutathione: 100 mg
• SOD:200 mg • SOD: 200 mg
• Catalase: 100 mg • Catalase: 100 mg
• ATP: 100 mg • ATP: 100 mg
Posologie : 3 fois par jours dans 250 ml de solution physiologique. Dosage: 3 times a day in 250 ml of physiological solution.
Selon l'invention According to the invention
EXEMPLES EXAMPLES
Les exemples présentés ci-dessous démontrent que les composés cités précédemment présentent, de façon in- attendue, une activité antivirale significative contre SARS-CoV-2, in vitro sur deux modèles distincts de cel- lules de mammifères, dans des conditions de cytotoxicité modérées. The examples presented below demonstrate that the compounds cited above exhibit, unexpectedly, significant antiviral activity against SARS-CoV-2, in vitro on two distinct models of mammalian cells, under conditions of moderate cytotoxicity. .
Dans un premier temps, les composés ont été testés in vitro, à une concentration classiquement utilisée dans la litérature, dans le contexte d'une infection de cellules VERO-E6 par la souche de SARS-CoV-2 Italie, N° accession Genbank MT066156. First, the compounds were tested in vitro, at a concentration conventionally used in the literature, in the context of an infection of VERO-E6 cells by the strain of SARS-CoV-2 Italy, Genbank accession No. MT066156.
Les cellules VERO-E6 sont issues de cellules épithéliales de rein de singe, et sont sensibles à l'infection par le SARS-CoV-2. VERO-E6 cells are derived from monkey kidney epithelial cells, and are susceptible to infection with SARS-CoV-2.
Les paramètres d'infection ont été déterminés au préalable afin d'obtenir les meilleures conditions pour obser- ver un possible effet antiviral. The infection parameters were determined beforehand in order to obtain the best conditions for observing a possible antiviral effect.
Les cellules VERO-E6 ont été infectées à une MOI (Multiplicité d'infection) de 0.5 pour une durée de 24h à 37 °C sous 5 % de C02, en présence ou absence (diluant) de composés testés. The VERO-E6 cells were infected at an MOI (Multiplicity of infection) of 0.5 for a period of 24 hours at 37 ° C. under 5% C02, in the presence or absence (diluent) of compounds tested.
Après 24h d'incubation des mélanges, les titres infectieux (loglO DITC50/ml ou DITC50/mL) ont été déter- minés dans les surnageants de culture de cellules infectées. After 24 hours of incubation of the mixtures, the infectious titers (log10 DITC50 / ml or DITC50 / ml) were determined in the culture supernatants of infected cells.
Les titres infectieux sont indiqués TCID50/mL (50% Tissue Culture InfectivenDose) en FiglA (loglO TCID50/mL) et Fig IB (TCID50/mL). Ils ont été obtenus par technique d'infection par dilution limite et cal- cul par la méthode de Reed et Muench. The infectious titers are indicated TCID50 / mL (50% Tissue Culture InfectivenDose) in FiglA (log10 TCID50 / mL) and Fig IB (TCID50 / mL). They were obtained by the technique of infection by limiting dilution and calculated by the method of Reed and Muench.
Un test de cytotoxicité et un test de quantification du coronaviras sont réalisés après 24 h d'incubation. La cy- totoxicité des différents composés est déterminée à chaque essai dans une plaque de cellules non infectées par un test de viabilité (Test MTS, Promega). Ce test est basé sur la mesure de l'activité métabolique des cel- lules, qui transforme un substrat (MTS tétrazolium) en un produit (Formazan), soluble dans le milieu et dont l'absorbance mesurée à 490 nm reflète proportionnellement le nombre de cellules vivantes. Le rapport de l'absorbance dans chaque puits sur l'absorbance moyenne des puits des cellules témoins (non traitées par les composés) est calculé et indiqué sur les schémas comme un indice de viabilité cellulaire (viabilité cellulaire relative). L'effet sur la production virale in vitro est mesuré par détermination des titres infectieux (TCID50/mL) réalisée sur des cellules VERQ-E6, les titres étant calculés selon la technique de Reed et Muench. Le rapport du titre infectieux dans chaque condition a été exprimé en fonction du titre infectieux mesuré dans la condition contrôle (sans traitement). A cytotoxicity test and a coronaviras quantification test are carried out after 24 h of incubation. The cytotoxicity of the various compounds is determined for each test in a plate of uninfected cells by a viability test (MTS test, Promega). This test is based on the measurement of the metabolic activity of cells, which transforms a substrate (MTS tetrazolium) into a product (Formazan), soluble in the medium and whose absorbance measured at 490 nm proportionally reflects the number of living cells. The ratio of the absorbance in each well to the average absorbance of the wells of the control cells (not treated with the compounds) is calculated and indicated on the diagrams as an index of cell viability (relative cell viability). The effect on viral production in vitro is measured by determining the infectious titers (TCID50 / mL) carried out on VERQ-E6 cells, the titers being calculated according to the technique of Reed and Muench. The ratio of the infectious titer in each condition was expressed as a function of the infectious titer measured in the control condition (without treatment).
Les résultats sont présentés en figures IA (titres infectieux exprimés en log10 TClD50/mL) et IB (titres exprimés en TClD50/mL). The results are presented in Figures IA (infectious titers expressed in log10 TClD50 / mL) and IB (titers expressed in TClD50 / mL).
Les titres infectieux mesurés dans les conditions expérimentales en présence des composés testés sont forte- ment réduits par rapport à la condition contrôle, où les cellules ont été infectées mais non traitées. The infectious titers measured under the experimental conditions in the presence of the compounds tested are greatly reduced compared to the control condition, where the cells have been infected but not treated.
Le BHT (10 μM), la NAC (12,5 μM) et le BS (15 μM) permettent une réduction de 78,8%, 23,4% et 27,8% respectivement des titres infectieux par rapport au contrôle (cf. Figure 1). Combiné au BHT la NAC réduit 80 à 93% des titres infectieux. En résumé, les résultats montrent une activité du BHT sur des cellules cibles (exprimant le récepteur du SARS-Cov-19 et très réduite sur des cellules n'exprimant pas lee récepteur du SARS-Cov-2 de manière détectable (cytométie en flux). BHT (10 μM), NAC (12.5 μM) and BS (15 μM) allow a reduction of 78.8%, 23.4% and 27.8% respectively in infectious titers compared to the control (cf. . Figure 1). Combined with BHT, NAC reduces 80 to 93% of infectious titers. In summary, the results show an activity of BHT on target cells (expressing the SARS-Cov-19 receptor and very reduced on cells not expressing the SARS-Cov-2 receptor in a detectable manner (flow cytometry). .
Le SARS-Cov-19 est infectieux sur des cellules de rem (Figure 1), de poumon A549 (Figure 3) et d'intestin HT29 (Figure 5). L'efficacité de compositions utilisées est dose dépendante (non montré). SARS-Cov-19 is infectious on rem (Figure 1), A549 lung (Figure 3) and HT29 intestine (Figure 5) cells. The efficacy of the compositions used is dose dependent (not shown).
PROTOCOLE CLINIQUE TITLE: CLINICAL PROTOCOL TITLE:
Prévention et traitement de la COVID-19 Contexte Clinique: Prevention and treatment of COVID-19 Clinical Context:
Le virus SARS-Cov-2 cause une pneumonie alvéolaire interstitielle et dans la plupart des formes sevères une insuffisance respiratoire aigue (IRA), mitiallement hypoxique (inadéquation entre les besoins tissulaires en oxygène et les apports, et une Hypocapnie (Taux anormalement bas de dioxyde de carbone (gaz carboni- que) dans le sang, dû à une augmentation de l'échange de gaz entre l'air et le sang au niveau des poumons (ventilation pulmonaire) . The SARS-Cov-2 virus causes interstitial alveolar pneumonia and in most severe forms acute respiratory failure (ARI), which is initially hypoxic (mismatch between tissue oxygen needs and intakes, and Hypocapnia (abnormally low levels of of carbon (carbon dioxide) in the blood, due to an increase in gas exchange between air and blood in the lungs (pulmonary ventilation).
L' hypoxie-hypercapnie avec un symdrome de détresse aigue respiratoire associées avec divers degrés de compromis heamodynamiques allant jusqu'à la sepsie et à un syndrome d'effondement multiple des organes (MOFS). Ces formes sévères sont souvent précédées de diarrhée et de nausées ainsi que de variations de tem- pératures, confusion et lymphopénie, et cela à jours avant TIRA. Hypoxia-hypercapnia with a symdrome of acute respiratory distress associated with varying degrees of heamodynamic compromise up to sepsis and multiple organ collapse syndrome (MOFS). These severe forms are often preceded by diarrhea and nausea as well as changes in temperature, confusion and lymphopenia, and this even days before TIRA.
ANATOMIE PATHOLOGIQUE ESSENTIELLE ESSENTIAL PATHOLOGICAL ANATOMY
Au niveau anatomo-pathologique, des lésions étendues aux épithéliums bronchiques, des pneumocytes des cavités alvéolaires, des bouchons de mucus endobronchiques, des exsudais endoalvéol aires tendant à se con- solider et à se transformer en fibrose, des microthrombus microcirculatoires, provoqués par l'activation aveu- gle de la réponse immuno-inflammatoire ont été mis en évidence de l'organisme (SIRS). At the anatomo-pathological level, extensive lesions to the bronchial epithelia, pneumocytes of the alveolar cavities, endobronchial mucus plugs, endoalveolar exudates tending to consolidate and turn into fibrosis, microcirculatory microthrombus, caused by Blind activation of the body's immune-inflammatory response (SIRS) has been demonstrated.
PROTOCOLE PROTOCOL
Pour contrer l'évolution du tableau clinique infectieux vers TIRA, la septicémie, le choc septique, le MOFS, le protocole, qui doit être envisagé aux côtés des traitements conventionnels, et non dans leur remplacement, agit sur les trois vecteurs pathogéniques qui conditionnent, sous des formes sévères, l'aggravation de l'évolu- tion clinique de l'infection, jusqu'aux cadres d'un plus grand engagement dysfonctionnel multiorganique et multisystémique , composé de: To counter the evolution of the infectious clinical picture towards TIRA, sepsis, septic shock, MOFS, the protocol, which must be considered alongside conventional treatments, and not in their replacement, acts on the three pathogenic vectors which condition, in severe forms, the worsening of the clinical course of the infection, up to the frameworks of a greater multiorgan and multisystem dysfunctional commitment, consisting of:
- la progression de l'infection; - progression of infection;
- la progression de TIRA, avec extension du processus inflammatoire des interstices aux alvéoles pulmonai- res; - progression of TIRA, with extension of the inflammatory process from the interstices to the pulmonary alveoli;
- la progression de l'inflammation systémique (IL-6, IL2, IL-17-D-Dimer surveillés) Mécanisme d'action des composants - progression of systemic inflammation (IL-6, IL2, IL-17-D-Dimer monitored) Mechanism of action of components
Hydroxytoluène butylé, ou 2,6-di-tert-butyl-4-méthylphénoi - ( BHT ) (antiviral, antioxydant)Butylated hydroxytoluene, or 2,6-di-tert-butyl-4-methylphenoi - (BHT) (antiviral, antioxidant)
Glutathion (GSH): acide 2-amino-5-{ [2-[(carboxyméthyl)amino]- l-(mercaptométhyï)-2-oxoéthyl]amino}-5- oxopentanoïque Glutathione (GSH): 2-amino-5- {[2 - [(carboxymethyl) amino] - 1- (mercaptomethyï) -2-oxoethyl] amino} -5-oxopentanoic acid
N-acétylcystéine ou acétylcystéine (C5H9N03S ou R)-N-acétyl-L-cystéine) (NAC) est un acide aminé non essentiel, qui stimule la production de glutathion, un antioxydant N-acetylcysteine or acetylcysteine (C5H9N03S or R) -N-acetyl-L-cysteine) (NAC) is a non-amino acid essential, which stimulates the production of glutathione, an antioxidant
Superoxyde Dismutase (SOD) (classification EC 1.15.1,1) sont des métalloprotéines (à Cu Zn Fe ou Mn)Superoxide Dismutase (SOD) (EC classification 1.15.1,1) are metalloproteins (to Cu Zn Fe or Mn)
N° CAS : 9054-89-1. CAS No: 9054-89-1.
Cette enzyme intervient dans l'explosion oxydative et est également une composante essentielle du mécanis me d'élimination des radicaux libres. This enzyme is involved in the oxidative explosion and is also an essential component of the free radical elimination mechanism.
Celle utilisée ici provenant de EasyNutrition The one used here from EasyNutrition
Catalase (CAT) est une oxydoreductase àhème (N° EC 1.11.1.6) Catalase (CAT) is a haem oxidoreductase (EC No 1.11.1.6)
Adénosine triphosphate (ATP) -nucléotide de formule : [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydro- xyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate potentialise les effets des anti-oxydants Adenosine triphosphate (ATP) -nucleotide of the formula: [[(2R, 3S, 4R, 5R) -5- (6-aminopurin-9-yl) -3,4-dihydro- xyoxolan-2-yl] methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate potentiates the effects of anti-oxidants
Compositions et formulations (iv, po, in, sublingual) quantité par fomulation BHT 300 mg Compositions and formulations (iv, po, in, sublingual) amount per formulation BHT 300 mg
BHT pur (Hedinger, Allemagne) 300 mg ou 500 mg Pure BHT (Hedinger, Germany) 300 mg or 500 mg
SOD 200 SOD 200
GSH 100 ou 200 GSH 100 or 200
CAT 100 mg CAT 100 mg
NAC 200 mg ou 300 mg NAC 200 mg or 300 mg
Elffets des combinaisons : Effects of combinations:
. Capteur supérieur au radical hydroxyle . Sensor greater than hydroxyl radical
. Réduction de l'acfivité des leucocytes oxydatifs et pro-inflammatoires . Réduction de l'activité inflammatoire des éosinophiles, . Reduction in the acfivity of oxidative and pro-inflammatory leukocytes. Reduced inflammatory activity of eosinophils,
. Réduction du stress oxydatif immuno-inflammatoire sur les tissus pulmonaires . Réduction de l'évolution de la fibrose pulmonaire . Reduction of immuno-inflammatory oxidative stress on lung tissue. Reduced progression of pulmonary fibrosis
. Vasodilatation microcirculatoire. . Microcirculatory vasodilation.
PROTOCOLE CLINIQUE: CLINICAL PROTOCOL:
Patients : Patients:
Les patients hospitalisés avec COVID-19 confirmé ont été inclus dans cete étude s'ils remplissaient deux critères principaux: i) âge> 12 ans; ii) Portage du SARS-CoV-2 documenté par PCR dans échantillon nasopharyngé et / ou échantillon de matières fécales à l'admission quel que soit leur état clinique. Des personnes non porteuses ont également été incluses. Patients hospitalized with confirmed COVID-19 were included in this study if they met two main criteria: i) age> 12 years; ii) Carriage of SARS-CoV-2 documented by PCR in nasopharyngeal sample and / or fecal sample on admission regardless of their clinical condition. Non-carriers were also included.
Procédure Procedure
Les patients ont été vus au départ pour l'inscription, la collecte de données initiale et le traitement au jour 0, et à nouveau pour un suivi quotidien pendant 30 jours. Chaque jour, les patients ont reçu un examen et, si possible, un échantillon nasopharyngé a été prélevé. Patients were seen initially for enrollment, initial data collection, and treatment on day 0, and again for daily follow-up for 30 days. Each day, the patients were examined and, if possible, a nasopharyngeal sample was taken.
Toutes les données cliniques ont été collectées à l'aide de questionnaires standardisés. Tous les patients se sont vu proposer un traitement oral en prévention et / ou traitement dess formes légère de COVID-19 avec ou sans GII (posologie du traitement oral: hydroxytoluène butylé (BHT) 300 mg; acétylcystéine 200 mg; Bos- wellia serrata: 500 mg par os (po) deux fois par jour pendant 10 jours. All clinical data were collected using standardized questionnaires. All patients were offered oral treatment for prevention and / or treatment of mild forms of COVID-19 with or without GII (oral treatment dosage: butylated hydroxytoluene (BHT) 300 mg; acetylcysteine 200 mg; Bos- wellia serrata: 500 mg per bone (po) twice daily for 10 days.
Forme légère (asymptomatique, fièvre <38.5°C , fatigue) ; signe d'infection du tractus gastrointestinal « bas » nausée, vomissement, diarhée, signe d'infection du tractus gastrointestinal « haut » toux, maux de gorge, agnosie, rhinorrhée, congestion nasale). forme sévère : pneumonie, bronchite, insuffisance respiratoire, fièvre persistante Mild form (asymptomatic, fever <38.5 ° C, fatigue); sign of infection of the gastrointestinal tract “down” (nausea, vomiting, diarrhea, sign of infection of the gastrointestinal tract “up” cough, sore throat, agnosia, rhinorrhea, nasal congestion). severe form: pneumonia, bronchitis, respiratory failure, persistent fever
Dans une forme plus sévère de COVID-19, tous les patients ont été traités par formulation intraveineuse (do- se intraveineuse (iv) : trois fois par jour pendant dix jours composée de: BHT: 500 mg; Glutathion (GSH): 200 mg; Acétylcystéîne 300 mg ou In a more severe form of COVID-19, all patients were treated with intravenous formulation (intravenous (iv) dose: three times a day for ten days consisting of: BHT: 500 mg; Glutathione (GSH): 200 mg ; Acetylcysteine 300 mg or
BHT: 500 mg; Glutathion (GSH): 100 mg; Superoxyde Dismutase (SOD): 200 mg; Catalase (CAT): 100 mg; ATP: 100 mg. BHT: 500 mg; Glutathione (GSH): 100 mg; Superoxide Dismutase (SOD): 200 mg; Catalase (CAT): 100 mg; ATP: 100 mg.
Classification clinique Les patients ont été regroupés en quatre catégories: 1) asymptomatique, 2) avec infection du tractus gastro- intestinal bas, 3) infection des voies respiratoires supérieures (URTI) en cas de rhinite, de pharyngite ou de fièvre isolée de bas grade et de myalgie, et 4) infections des voies respiratoires inférieures (LRTI) en cas de symptômes de pneumonie ou de bronchite DESIGN Clinical classification Patients were grouped into four categories: 1) asymptomatic, 2) with infection of the lower gastrointestinal tract, 3) upper respiratory tract infection (URTI) in cases of rhinitis, pharyngitis or isolated low-grade fever and myalgia, and 4) lower respiratory tract infections (LRTI) for symptoms of pneumonia or bronchitis DESIGN
Type d "Etude : Etude clinique Type of Study: Clinical study
Nombre de patients estimés 360 participants : 90 asymptomatiques (1) ; 90 patients avec for- pour T étude : me modérée GI (nausée diarhée (2)), 90 patients avec URTI (3), 90 patients avec LRTI (4), Number of patients estimated 360 participants: 90 asymptomatic (1); 90 patients with for- for T study: moderate GI me (nausea diarrhea (2)), 90 patients with URTI (3), 90 patients with LRTI (4),
Allocation: hasard Allocation: chance
Intervention : Attribution parallèle Intervention: Parallel attribution
Intervention Les participants seront répartis au hasard en deux groupes d'étude; grou- Description : pe d'intervention (IG, n = 15) et groupe placebo (PG, n = 15). Des nom- bres aléatoires générés par ordinateur seront utilisés pour randomiser les participants dans l'un des deux groupes d'intervention. Intervention Participants will be randomly divided into two study groups; group Description: intervention pe (IG, n = 15) and placebo group (PG, n = 15). Computer generated random numbers will be used to randomize participants into one of the two intervention groups.
Double aveugle: Double (Participant, soignant) Description: L'intervention-QNS et i'isocalorique-NQS seont servis dans des verres opaques de même forme et couleur, les soignants (infirmières, diététis- tes) ne connaîtront pas les membres de chaque groupe ni la nature ou la composition de TONS, objectif: traitement de soutient Double blind: Double (Participant, caregiver) Description: The intervention-QNS and the isocaloric-NQS are served in opaque glasses of the same shape and color, the caregivers (nurses, dietitians) will not know the members of each group nor the nature or composition of TONS, objective: supportive treatment
Mesures premières Primary measures
1 . Taux mortalité après un mois 1-month mortality is defmed as the ratio of patients who will alive after Imonth from study start out 1. Mortality rate after one month 1-month mortality is defmed as the ratio of patients who will alive after Imonth from study start out
Mesures secondaires : Secondary measures:
1. Dosage de l' Interleukine -6 (IL-6), IL-1 b, IL-2, IL-3, IL- 17- D-Dimer dans le sang pendant un mois tous les jours, par kit ELISA commerciaux. 1. Assay of Interleukin -6 (IL-6), IL-1b, IL-2, IL-3, IL-17-D-Dimer in the blood for one month every day, by commercial ELISA kit.
2. Nombre de Lymphocyte dans le sang 2. Number of Lymphocytes in the blood
3. Dosage du complément (C3 - C4), immuno-complex (CIC), C-ANCA e P- ANCA, CRP (C-reactive protein) level [ 3. Assay of complement (C3 - C4), immuno-complex (CIC), C-ANCA e P- ANCA, CRP (C-reactive protein) level [
4. CRP 5. Mesure de la Pression partielle en oxygène (Pa02)/(Fi02) (fraction de F oxygéné inspiré, Fi02) ratio4. CRP 5. Measurement of the partial pressure of oxygen (Pa02) / (Fi02) (fraction of oxygenated F inspired, Fi02) ratio
(or P/F ratio) à partir des gaz du sang (valeurs de 300 to 100) (or P / F ratio) from blood gases (values from 300 to 100)
6. Mesure de la défaillance des organes : 6 variables, représentant chacun un système d'organes (un pour les systèmes respiratoire, cardiovasculaire, hépatique, de coagulation, rénal et neurologique), et notés de 0 (normal) à 4 (degré élevé de dysfonctionnement / échec). Ainsi, le score maximum peut varier de 0 à 24. 6. Measure of organ failure: 6 variables, each representing an organ system (one for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems), and rated from 0 (normal) to 4 (high degree malfunction / failure). Thus, the maximum score can vary from 0 to 24.
7. Nombre de participants présentant des effets secondaires liés au traitement, tels qu'évalués par les critères de terminologie communs pour les événements indésirables (CTCAE) version 5.0 [Délai: pendant le traitement et jusqu'à 30 jours après la dernière dose de traitement] classé selon CTCAE ci- teria (v5.0) 8. Réponse radiologique [Délai: au départ (facultatif), après sept jours et si cliniquement indiqué (jus- qu'à 1 mois)] Scanner thoracique ou thorax XR 7. Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [Timeframe: during treatment and up to 30 days after last dose of treatment ] classified according to CTCAE ci- teria (v5.0) 8. Radiological response [Time limit: at baseline (optional), after seven days and if clinically indicated (up to 1 month)] Chest or chest XR scanner
9. Durée d'hospitalisation [Délai: de la ligne de base jusqu'à la sortie du patient (jusqu'à 1 mois)] Jours d'hospitalisation 9. Duration of hospitalization [Timeframe: from baseline until discharge of the patient (up to 1 month)] Days of hospitalization
10. Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] 11. temps de ventilation mécanique invasive (s'il n'a pas été initié auparavant) calculé de la ligne de base à l'intubation 10. Remission of respiratory symptoms [Timeframe: up to 1 month] 11. invasive mechanical ventilation time (if not initiated previously) calculated from baseline to intubation
12. Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] 12. Remission of respiratory symptoms [Delay: up to 1 month]
13. temps jusqu'à l'extubation définitive calculé de l'intubation (à tout moment) à l'extubation en jours13. time to final extubation calculated from intubation (at any time) to extubation in days
14. Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] temps jusqu'à l'indépendance de la ventilation mécanique non invasive calculé en jours. Rémission des symp- tômes respiratoires [Délai: jusqu'à 1 mois] 14. Remission of respiratory symptoms [Time limit: up to 1 month] time to independence of non-invasive mechanical ventilation calculated in days. Remission of respiratory symptoms [Delay: up to 1 month]
15. temps jusqu'à l'indépendance de l'oxygénothérapie en jours 15. time until independence of oxygen therapy in days
16. Charge virale par PCR [Délai: jusqu'à 1 mois] CRITÈRES Critère d'inclusion: 16. Viral load by PCR [Timeframe: up to 1 month] CRITERIA Inclusion criteria:
N'importe quel sexe plus de 12 ans Any sex over 12 years old
Consentement éclairé pour participer à l'étude Confidentialité Informed consent to participate in the study Confidentiality
Diagnostic virologique de l'infection Sars-CoV2 (PCR) Virological diagnosis of Sars-CoV2 infection (PCR)
Saturation en oxygène au repos dans l'air ambiant <93% (valable pour les patients non intubés et pour la pha- se 2 et la cohorte d'observation) Oxygen saturation at rest in ambient air <93% (valid for non-intubated patients and for phase 2 and the observation cohort)
Intubé moins de 24 heures avant l'inscription (éligible pour la phase 2 uniquement - le critère n ° 6 ne s'appli- que pas dans ce cas) Intubated less than 24 hours before registration (eligible for phase 2 only - criterion n ° 6 does not apply in this case)
Intubé plus de 24 heures avant l'inscription (éligible à la cohorte d'observation uniquement - le critère n ° 6 ne s'applique pas dans ce cas) Intubated more than 24 hours before registration (eligible for the observation cohort only - criterion n ° 6 does not apply in this case)
Patients déjà en traitement préventif Patients already on preventive treatment
Critère d'exclusion: Exclusion criteria:
En cas de maladies rénales: pas plus de 200 mg de BHT au total / jour femmes enceintes In case of kidney disease: not more than 200 mg of BHT in total / day pregnant women
Les tout premiers résultats laissent penser que le BHT (300mg et 500mg 3x/j) en bloquant la réplication du SARS-Cov-2, réduit la dissémination du virus dans l'organisme permet un rétablissement plus rapide et évite les complications pulmonaires. La stratégie d'administration semble déterminante. The very first results suggest that the BHT (300mg and 500mg 3x / d) by blocking the replication of SARS-Cov-2, reduces the dissemination of the virus in the body allows a faster recovery and avoids pulmonary complications. The administration strategy seems decisive.
La voie sublinguale et/ou orale est particulièrement intéressante, même si les formulations ne sont pas évi- dentes à préparer probablement en lien avec le propriétés du BHT. The sublingual and / or oral route is particularly interesting, even if the formulations are not easy to prepare probably in connection with the properties of BHT.
Méthodologie : Evaluation de l'inhibition de la réplication virale du BHT et BHT en combinaison dans la gamme 0,5 à 50 μM sur le SARS-CoV2 dans les VeroE6 TMPRSS2. Le protocole suivi est décrit dans Touret, F., Gilles, M., Barrai, K. et ai. In vitro screening of a FDA approved Chemical library reveals poten- tiel inhibitors of SARS-CoV-2 réplication. Sci Rep 10, 13093 (2020). https://doi.org/10.1038/s41598-020- 70143-6 Methodology: Evaluation of the inhibition of viral replication of BHT and BHT in combination in the range 0.5 to 50 μM on SARS-CoV2 in VeroE6 TMPRSS2. The protocol followed is described in Touret, F., Gilles, M., Barrai, K. et al. In vitro screening of an FDA approved Chemical library reveals potential inhibitors of SARS-CoV-2 replication. Sci Rep 10, 13093 (2020). https://doi.org/10.1038/s41598-020- 70143-6
En bref, le virus est incubé 20 à 30 minutes en présence des produits 1 et 2. Le mix est ensuite utilisé pour in- fecter une culture de VeroE6 TMPRSS2. Après 48h, l'inhibition de la réplication virale est définie par real ti- me RTPCR quantifiant le nombre de copies du génome viral avec ou sans composé testé. 0% d'inhibition correspondant à la rélication viral sans inhibiteur, 100% correspondant aux cellules non infectées. Briefly, the virus is incubated for 20 to 30 minutes in the presence of products 1 and 2. The mix is then used to infect a culture of VeroE6 TMPRSS2. After 48 h, the inhibition of viral replication is defined by real time RTPCR quantifying the number of copies of the viral genome with or without the compound tested. 0% inhibition corresponding to viral re-application without inhibitor, 100% corresponding to uninfected cells.
Les produits 1 et 2 présentent une activité antivirale modérée dans la gamme 10- 50μM. l'activité antiviarale est détectable à partir de ImM Un autre modèle d'infection in vivo est utilisé : le hamster doré infecté par le SARS-COV2 tel que décrit dans Driouich, JS,, Cochin, M., Lingas, G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun 12, 1735 (2021). https://doi.org/10.1038/s41467-021-21992-w. Products 1 and 2 exhibit moderate antiviral activity in the 10- 50μM range. antiviaral activity is detectable from ImM Another model of infection in vivo is used: the golden hamster infected with SARS-COV2 as described in Driouich, JS ,, Cochin, M., Lingas, G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun 12, 1735 (2021). https://doi.org/10.1038/s41467-021-21992-w.
Dans ce modèle le BHT seul administré par voie intranasale permet de réduire de 50 % le nombre d'indivi- dus développant un syndrome respiratoire aigue et permet aux animaux de maintenir leur poids, In this model, BHT alone administered intranasally makes it possible to reduce the number of individuals developing an acute respiratory syndrome by 50% and allows the animals to maintain their weight,
ESSAI N°2 OBJECTIF TEST N ° 2 OBJECTIVE
Effet d'une nouvelle formulation multimodale comprenant du BHT et basée sur des composants dotés d'une capaci té de ciblage actif contre le SARS-Cov2, Effect of a new multimodal formulation comprising BHT and based on components with active targeting capacity against SARS-Cov2,
TEST PRÉCLINIQUE (in vitro et in vivo) POUR ÉVALUER LA SÉCURITÉ ET L'EFFICACITÉ CONTRE LE VIRUS: PRECLINICAL TEST (in vitro and in vivo) TO ASSESS THE SAFETY AND EFFECTIVENESS AGAINST THE VIRUS:
Test antiviral par CPE Antiviral test by CPE
Ce test est destiné au dépistage initial de composés potentiellement antiviraux. L'activité antivirale du com- posé est évaluée sur la base de la capacité du composé à empêcher le virus de provoquer un CPE viral dans la culture de cellules de mammifères. Huit dilutions du composé d'essai seront testées et la concentration an- tivirale efficace sera déterminée par analyse de régression. This test is intended for the initial screening of potentially antiviral compounds. The antiviral activity of the compound is evaluated on the basis of the ability of the compound to prevent the virus from causing viral CPE in the culture of mammalian cells. Eight dilutions of the test compound will be tested and the effective antiviral concentration will be determined by regression analysis.
La toxicité du composé d'essai est déterminée dans l'intervalle de temps. Le CPE est déterminé par observa- tion microscopique de monocouches de culture cellulaire ainsi que par absorption de colorant rouge neutre. The toxicity of the test compound is determined over the time interval. The CPE is determined by microscopic observation of cell culture monolayers as well as by absorption of neutral red dye.
In vivo In vivo
Matériaux: 1. Nutriments (l'une des combinaison(s) selon l'invention) fournis par MSD Materials: 1. Nutrients (one of the combination (s) according to the invention) supplied by MSD
2. Coronavirus PED fourni par Nam Khoa 2. Coronavirus PED provided by Nam Khoa
3. Fourniture de pigmies (cochon pygmée) par Nam Khoa 3. Supply of pigmies (pygmy pig) by Nam Khoa
4. Fourniture de nourriture pour les cochons pygmées par Nam Khoa 4. Provision of food for pygmy pigs by Nam Khoa
Méthodes: Pour le test Anti-V 6-1 Compound, utilisez 10 pigmies avec formule orale, 10 p. pour formule IV avec respectivement 10 p. utilisation de contrôle oral et 10 p. pour le contrôle IV. Methods: For the Anti-V 6-1 Compound test, use 10 pigmies with oral formula, 10 p. for formula IV with respectively 10 p. use of oral control and 10 p. for IV control.
Pour l'étude, nourrir quotidiennement le pygmée avec de la nourriture ou une injection IV à fournir en fonc- tion de la dose et de la durée selon la demande du promoteur. For the study, feed the pygmy daily with food or an IV injection to be provided according to the dose and duration according to the request of the promoter.
Pour le contrôle, nourrir uniquement les aliments sans ajout de nutriments ou utiliser une solution saline nor- male pour IV ou SC For control, feed only foods without added nutrients or use normal saline solution for IV or SC.
Après 1 ou deux semaines, défiez tous les pigmies avec PED par voie orale. After 1 or two weeks challenge all pigmies with oral PED.
Observez le développement, de la diarrhée pendant 1 semaine. Après une semaine, tuez tous les pigmies à l'observation macroscopique et microscopique de la muqueuse nasale, de l'intestin grêle. Observe the development of diarrhea for 1 week. After a week, kill all pigmies on gross and microscopic observation of the nasal mucosa, small intestine.
2- La nécessité d'utiliser des animaux et le manque d'alternatives réalistes 2- The need to use animals and the lack of realistic alternatives
Bien que l'utilisation des suppléments proposés ait révélé leur innocuité et leur efficacité in vitro ou in vivo chez l'homme, c'est la première fois qu'ils seont associés dans une solution à administrer par voie orale ou IV. Afin d'évaluer le degré de toxicité et de sécurité, nous avons donc besoin d'utiliser des animaux. Although the use of the proposed supplements has revealed their safety and efficacy in vitro or in vivo in humans, this is the first time that they have been combined in a solution to be administered orally or IV. In order to assess the degree of toxicity and safety, therefore, we need to use animals.
3- Choix des espèces d'animaux à utiliser 3- Choice of animal species to use
Dans ce projet seront utilisés des porcs pygmées, une espèce très connue qui a été utilisée dans des expérien- ces précédentes réalisées dans nos laboratoires et parrainées par SANOFT Vietnan pour différentes gammes de suppléments et de nutraceutiques. In this project will be used pygmy pigs, a well-known species which has been used in previous experiments carried out in our laboratories and sponsored by SANOFT Vietnan for different ranges of supplements and nutraceuticals.
4- Type d'animal (s), par exemple, souche, sans pathogène, génétiquement modifié ou mutant 4- Type of animal (s), for example, strain, pathogen-free, genetically modified or mutant
Le porc miniature, partage de nombreuses similitudes physiologiques avec les humains, offre plusieurs avan- tages d'élevage et de manipulation (par rapport aux primates non humains), ce qui en fait une espèce optima- le pour l'expérimentation préclinique. Le présent projet offre plusieurs exemples tirés de la recherche actuelle dans l'espoir de convaincre notre partisan que le modèle animal porcin a pris une importance considérable dans la recherche biomédicale au cours des dernières années. Les exemples cités sont tirés des domaines d'in- vestigation suivants: la physiologie de la réponse immunitaire aux viras Corona Family Member, où les porcs sont utilisés pour étudier les anomalies immunitaires et / ou l'efficacité contre les attaques virales suite au traitement avec notre nouveau composé. The miniature pig, shares many physiological similarities with humans, offers several breeding and handling advantages (over non-human primates), making it an optimal species for preclinical experimentation. This project offers several examples drawn from current research in the hope of convincing our proponent that the porcine animal model has gained considerable importance in biomedical research in recent years. The examples cited are drawn from the following areas of investigation: the physiology of the immune response to Corona Family Member viruses, where pigs are used to study immune abnormalities and / or efficacy against viral attacks following treatment with our new compound.
5- Conception expérimentale prévue et sa justification 5- Planned experimental design and its justification
Le projet actuel est destiné à observer et étudier l'effet de notre solution de traitement contre le virus PEDV, donc pour cette étude seront utilisés 15 porcs pygmées à la fois pour l'étude de groupe et le contrôle. Chaque pigmy pig sera inoculé avec le virus et sera ensuite évalué après le traitement quotidiennement et pendant une période de 2 semaines. Chaque cochon pygmée sera sacrifié et un examen histopathologique sera effec- tué pour confirmer l'état tissulaire et moléculaire de chaque animal. The current project is intended to observe and study the effect of our treatment solution against the PEDV virus, therefore for this study 15 pygmy pigs will be used for both the group study and the control. Each pigmy pig will be inoculated with the virus and will then be evaluated after treatment daily and for a period of 2 weeks. Each pygmy pig will be sacrificed and a histopathological examination will be carried out to confirm the tissue and molecular state of each animal.
Prévention des biais - randomisation et mise en aveugle Preventing bias - randomization and blinding
1- Les porcs recevant le médicament ou le traitement factice seront randomisés à l'aide d'un générateur de nombres aléatoires. Le personnel administrant le médicament ou le traitement factice sera différent de ceux qui évaluent les effets. Les souris et les échantillons de sang et de tissus ultérieurs seront étiquetés de sorte que le personnel évaluant les effets du traitement et analysant les résultats ne sache pas qui a reçu le médica- ment ou le traitement factice. 1- Pigs receiving the drug or dummy treatment will be randomized using a random number generator. The staff who administer the drug or sham treatment will be different from those who assess the effects. Mice and subsequent blood and tissue samples will be labeled so that personnel assessing the effects of treatment and analyzing the results do not know who received the drug or dummy treatment.
Exemples qui couvrent la sélection, les études pilotes pour déterminer la taille de l'effet, la justification de la taille de l'effet et la taille de l'échantillon 1- Pour l'expérience pilote, la taille de l'effet pigmy pig ne dépasse pas 10 kg, seront suffisants pour accepter le résultat comme méritant d'être étudié en raison de leurs caractéristiques biologiques uniques dans la re- cherche translationnelle, les modèles chirurgicaux et la formation procédurale et sont de plus en plus utilisés comme une alternative au chien ou au singe comme choix d'espèces non rongeurs en toxicologie préclinique, tests de produits pharmaceutiques, il y a des avantages uniques à l'utilisation des porcs dans ce contexte étant donné qu'ils partagent avec les humains des caractéristiques anatomiques et immunophysiologiques similai- res impliquant les systèmes cardiovasculaire, urinaire, tégumentaire et digestif. Nous avons besoin de 15 ani- maux pour la souche PEDV et de 15 pour le contrôle, pour un nombre total de 30 animaux pour déterminer l'écart-type avec une précision. Examples that cover screening, pilot studies to determine effect size, rationale for effect size and sample size 1- For the pilot experiment, the size of the pigmy pig effect does not exceed 10 kg, will be sufficient to accept the result as worthy of study due to their unique biological characteristics in translational research, models surgical and procedural training and are increasingly used as an alternative to the dog or monkey as a non-rodent species choice in preclinical toxicology, pharmaceutical testing, there are unique advantages to the use of pigs in this context since they share similar anatomical and immunophysiological characteristics with humans involving the cardiovascular, urinary, integumentary and digestive systems. We need 15 animals for the PEDV strain and 15 for the control, for a total number of 30 animals to determine the standard deviation with precision.
2- Le modèle de porc diabétique hypercholestérolémique induit par la streptozotocine a été utilisé avec suc- cès pour induire l'athérosclérose coronarienne et partage de nombreuses caractéristiques de la physiopatholo- gie de la vasculopathie hyperlipidémique chez l'homme. Il existe diverses modifications à ce modèle impli- quant différents régimes d'administration de streptozotocine et des modifications du régime alimentaire, mais les lésions vasculaires peuvent inclure des plaques athéromateuses dans les gros vaisseaux ainsi que des mo- difications hypertrophiques des parois des vaisseaux plus petits [1], Par rapport au P450 total pour les chiens, les singes et les humains ont bien sur noté quelques différences, avec des activités d'oxygénation plus élevées dépendant de la flavine monooxygénase (FMQ) dans les microsomes hépatiques minipig et une activité CYP-2A plus faible. La castration des miniporcs mâles entraînerait une multiplication par 10 de l'activité du CYP-2A, ce qui indique que l'activité est régulée sexuellement. Cependant, l'activité d'oxydation des médica- ments dépendant des CYP-1A, 2B, 2C, 2E et 3A s'est avérée présente et relativement comparable chez les mini-porcs. Comme chez les rongeurs, le métabolisme hépatique dans le minipig est sensible à l'induction (par exemple, induction du CYP-1A à l'aide de l'oméprazole), entraînant une augmentation potentielle du métabolisme de certains médicaments et composés, mais cela n'a pas posé de problème majeur dans la modé- lisation ou l'interprétation pharmacocinétique comparative. [2-5], Il existe une quantité croissante de littératu- re sur l'utilisation des mini-porcs dans la recherche, y compris des aperçus de leur utilisation en toxicologie. L'existence de quantités importantes de données de base, dïm point de vue réglementaire et du point de vue des bonnes pratiques de laboratoire, fournit un solide soutien à l'utilisation de cette espèce dans la recherche courante [6-8]. 2- The streptozotocin-induced hypercholesterolemic diabetic pig model has been used successfully to induce coronary atherosclerosis and shares many features of the pathophysiology of hyperlipidemic vasculopathy in humans. There are various modifications to this pattern involving different regimens of streptozotocin and changes in diet, but vascular lesions can include atheromatous plaques in large vessels as well as hypertrophic changes in the walls of smaller vessels. [1], Compared to total P450 for dogs, monkeys and humans noted some differences, of course, with higher flavin monooxygenase (FMQ) dependent oxygenation activities in minipig hepatic microsomes and CYP activity. -2A lower. Castration of male minipigs would result in a 10-fold increase in CYP-2A activity, indicating that the activity is sexually regulated. However, the oxidative activity of CYP-1A, 2B, 2C, 2E and 3A dependent drugs was found to be present and relatively comparable in mini pigs. As in rodents, hepatic metabolism in the minipig is sensitive to induction (eg, induction of CYP-1A using omeprazole), leading to a potential increase in the metabolism of some drugs and compounds, but this did not pose any major problem in modeling or comparative pharmacokinetic interpretation. [2-5] There is a growing body of literature on the use of mini-pigs in research, including overviews of their use in toxicology. The existence of significant amounts of basic data, from a regulatory point of view and from a good laboratory practice point of view, provides strong support for the use of this species in current research [6-8].
Données normalement distribuées, comparaison de plus de deux groupes à un moment donné Notre résultat principal est d'évaluer les réponses immunitaires au traitement nutraceutique à 1 semaine et les mesures des organes internes des poumons, du cœur, de la rate, du foie et des reins lorsque les animaux sont abattus à 2 semaines. Dans nos travaux précédents, tous les résultats et mesures étaient à peu près normale- ment distribués avec un écart type des deux groupes et, nous testerons la différence entre les groupes d'étude et de contrôle en utilisant une analyse unidirectionnelle de la variance. Notre deuxième point final est d'ob- server et de compter la présence de tissu anormal dans N sections d'un seul organe prélevé sur chaque ani- mal, Cette variable n'est pas normalement distribuée, nous allons donc utiliser un test de MannWhitney de la différence entre nos deux groupes, il s'agit d'un test non paramétrique. Ce test est moins puissant qu'un test de données normalement distribuées, nous devrons donc gonfler la taille de notre échantillon au-dessus de celle requise pour les données normalement distribuées. Normally distributed data, comparison of more than two groups at one time Our primary outcome is to assess immune responses to nutraceutical treatment at 1 week and measures of internal organs of the lungs, heart, spleen, liver and kidneys when the animals are slaughtered at 2 weeks. In our previous work, all results and measures were roughly normally distributed with one standard deviation of the two groups, and we will test the difference between the study and control groups using unidirectional analysis of variance. Our second end point is to observe and count the presence of abnormal tissue in N sections of a single organ taken from each animal, This variable is not normally distributed, so we will use a MannWhitney test of the difference between our two groups, this is a non-parametric test. This test is less powerful than a test normally distributed data, we will therefore need to inflate our sample size above that required for normally distributed data.
Résultats préliminaires et méthodes pré-clmiqueS Preliminary results and pre-clinical methods
Solution buvable en gélules pour les cas infectieux bénins Oral solution in capsules for mild infectious cases
BHT: 300 mg Acétylcystéine: 2.00 mg Boswellia serrata: 500 mg BHT: 300 mg Acetylcysteine: 2.00 mg Boswellia serrata: 500 mg
Solution buvable en gélules pour les cas infectieux légers / graves Oral solution in capsules for mild / severe infectious cases
BHT: 250 mg BHT: 250 mg
Acétylcystéine: 50 mg Acetylcysteine: 50 mg
Superoxyde Disrnutase (SOD): 100 rng Superoxide Disrnutase (SOD): 100 rng
Nattokinase: 50 mg Glutatione: 50 mg. Nattokinase: 50 mg Glutatione: 50 mg.
Solution IV 1 g dans 100 ml de solution saline /NaCl / Ringer L IV solution 1 g in 100 ml of saline / NaCl / Ringer L solution
BHT: 250 mg BHT: 250 mg
Acétylcystéine: 50 mg Acetylcysteine: 50 mg
Superoxyde Disrnutase (SOD): 100 mg Superoxide Disrnutase (SOD): 100 mg
Nattokinase: 50 mg Nattokinase: 50 mg
Glutatione: 50 mg. Glutation: 50 mg.
Évaluation des effets thérapeutiques de la formulation nommée groupe 1 (administration orale, BHT, Ace, Bowellia serrata), 2 (administration orale BHT, Ace, SOD, NAT, Glu), 3 (administration IV BHT, Ace, SOD, NAT, Glu), Les animaux ont été divisés en 3 groupes chacun avec un groupe témoin et un groupe d'étude. Pour évaluer l'effet de la procédure proposée, les animaux seront sacrifiés après l'administration de kétamine / xylazme, les organes internes, le cœur, le foie, la rate, les poumons et les tissus rénaux des porcs seront pho- tographiés et pesés. Le profil des cytokines / interleukines et. la charge virale seront également, mesurés dans chaque échantillon histologique pour déterminer la teneur en cellules sanguines de différents groupes des deux groupes d'étude et de contrôle. Evaluation of the therapeutic effects of the formulation named group 1 (oral administration, BHT, Ace, Bowellia serrata), 2 (oral administration BHT, Ace, SOD, NAT, Glu), 3 (IV administration BHT, Ace, SOD, NAT, Glu ), The animals were divided into 3 groups each with a control group and a study group. To assess the effect of the proposed procedure, the animals will be sacrificed after administration of ketamine / xylazme, the internal organs, heart, liver, spleen, lungs and kidney tissue of the pigs will be photographed and weighed. . The cytokine / interleukin profile and. Viral load will also be measured in each histological sample to determine the content of blood cells from different groups of both study and control groups.
Les résultats seront donc évalués en mesurant le poids entre les deux groupes d'animaux au moment du der- nier traitement, le nombre de cellules sanguines et de cytokines et d'interleukines sera également évalué entre les 2 groupes ainsi WBC, LY, MO, MPV, MCH et La teneur en PLT plus TNF-a, IFN-y, IL-6, IL-2 IL-1 β, IL-10-D-dimères et. la charge virale seront, évalués et collectés. Phase In Vivo, étude clinique sous trois types de traitement: formes légères, modérées, sévères The results will therefore be evaluated by measuring the weight between the two groups of animals at the time of the last treatment, the number of blood cells and cytokines and interleukins will also be evaluated between the 2 groups thus WBC, LY, MO, MPV, MCH and PLT content plus TNF-α, IFN-γ, IL-6, IL-2 IL-1 β, IL-10-D-dimers and. viral load will be, evaluated and collected. Phase In Vivo, clinical study under three types of treatment: mild, moderate, severe
A cet égard, afin de contraster la diffusion entre les différences et donc le risque potentiel mortel décrit dans l'infection, le protocole expérimental d'association nutraceutique modifiée visant, en complément et non en substitution par rapport aux thérapies conventionnelles, est présenté: In this regard, in order to contrast the diffusion between the differences and therefore the potential fatal risk described in the infection, the experimental protocol of a modified nutraceutical combination aiming, as a complement and not as a replacement compared to conventional therapies, is presented:
• dans les formes cliniques légères → prévenir la progression de la maladie vers les stades de plus grande sé- vérité clinique, tels que les stades d'insuffisance respiratoire aiguë, de sepsie sévère, de choc septique et de syndrome de défaillance multi-organique (MOFS); • in mild clinical forms → prevent the progression of the disease to the stages of greater clinical truth, such as the stages of acute respiratory failure, severe sepsis, septic shock and multi-organ failure syndrome ( MOFS);
• dans les formes cliniques modérées et sévères ----> réduire la mortalité, réduire la durée de séjour en cas d'in- tensité de soins intermédiaires (unité opératoire de pneumologie) et de haute intensité de soins (unité opéra- toire de soins intensifs), réduire les autres issues dysfonctionnelles à un niveau multi-organique-multisystè- me, comme la fibrose pulmonaire résiduelle. • in moderate and severe clinical forms ----> reduce mortality, reduce the length of stay in the event of intensive intermediate care (pneumology operating unit) and high intensity care (surgical unit of intensive care), reduce other dysfunctional outcomes at a multi-organ-multi-system level, such as residual pulmonary fibrosis.
COVID-19 → mécanismes d'action essentiels de l'expérimentation nutraceutique COVID-19 → essential mechanisms of action of nutraceutical experimentation
L'expérimentation nutraceutique soutenant les stratégies thérapeutiques de contraste contre COVID-19 que nous présentons une justification scientifique essentielle qui s'exprime, une seconde des différentes compo- santes contrôlées dans l'association, et donc prenant en compte leur action synergique globale, comme les ac- tions biologiques documentées , au niveau cellulaire, vasculaire, organique et multisystémique, équipé d'un mécanisme direct, intégré et synergique, sur les 2 déterminants physiopathologiques essentiels du syndrome, qualifiés viraux directs et divers aspects moléculaires, biologiques et immunitaires de la réponse inflamma- toire systémique incontrôlée (SIRS ). The nutraceutical experimentation supporting the therapeutic strategies of contrast against COVID-19 that we present an essential scientific justification which is expressed, a second of the different components controlled in the association, and therefore taking into account their overall synergistic action, such as documented biological actions, at the cellular, vascular, organic and multisystem level, equipped with a direct, integrated and synergistic mechanism, on the 2 essential physiopathological determinants of the syndrome, qualified as direct viral and various molecular, biological and immune aspects of the syndrome. uncontrolled systemic inflammatory response (SIRS).
Les composants nutraceutiques de l'expérimentation possèdent, l'application, l'action: The nutraceutical components of the experiment have, the application, the action:
• antiviral • antiviral
• antioxydant • antioxidant
• anti-inflammatoire • anti-inflammatory
• lymphoprolifératif • lymphoproliferative
• fibrinolytique • fibrinolytic
• antithrombotique • antithrombotic
• agent antiplaquettaire • antiplatelet agent
• antifibrotique • antifibrotic
Enumérez les hypothèses cliniques. List the clinical assumptions.
HYPOTHÈSE DU PROTOCOLE CLINIQUE: Les patients Les patients hospitalisés avec COVID-19 confirmé ont été inclus dans cette étude s'ils remplissaient deux critères principaux: i) âge> 12 ans; ii) Le portage du SARS-CoV-2 documenté par PCR prélèvement nasopharyngé à l'admission quel que soit leur état clinique. CLINICAL PROTOCOL ASSUMPTION: Patients Patients hospitalized with confirmed COVID-19 were included in this study if they met two main criteria: i) age> 12 years; ii) The carriage of SARS-CoV-2 documented by PCR nasopharyngeal swab on admission regardless of their clinical condition.
Procédure Procedure
Les patients ont été vus au départ pour le recrutement, la collecte initiale des données et le traitement au jour 0, et à nouveau pour un suivi quotidien pendant 14 jours. Chaque jour, les patients ont reçu une clinique standardi- sée examen et lorsque cela était possible, un échantillon nasopharyngé a été prélevé. Patients were seen initially for enrollment, initial data collection and processing on day 0, and again for daily follow-up for 14 days. Each day, patients received a standardized clinical examination and when possible, a nasopharyngeal sample was taken.
Toutes les données cliniques ont été collectées à l'aide de questionnaires standardisés. Tous les patients ont été proposés par voie orale en prévention et / ou sous fonne légère COVID-19 (butyîhydroxytoluène BHT 300 mg; acétylcystéine 200 mg; Bosvvellia serrata: 500 mg) deux fois par jour pendant dix jours (dans cette phase préliminaire, nous n'avons pas recruté d'enfants dans le groupe de traitement sur la base de données in- diquant que les enfants développent des symptômes bénins du COVID-19). Dans la forme sévère de CO- VID-19, tous les patients ont été traités par fonnulation intraveineuse (posologie: trois fois par jour pendant dix jours composée de: BHT: 500 mg; Glutathion (G SH): 200 mg; Acetilcisteina: 300 rng ou BHT: 500 mg ; Glutathion (GSH): 100 mg; Superoxyde Dismutase (SOD): 200 mg; Catalase (CAT): 100 mg; ATP: 100 mg Dans les Etats où l'utilisation de la catalase (CAT) et de l'adénosine triphosphate (ATP) n'est pas autorisée, le protocole pour les patients présentant des symptômes légers nécessite l'utilisation d'une formulation orale (posologie: trois fois par jour pendant dix jours composée de): BHT: 250 mg; Acétylcystéine: 50 mg; Super- oxyde Dismutase (SOD): 100 mg; Nattokinase: 50 mg; Glutatione: 50 mg. Alors que chez les patients pré- sentant des symptômes sévères, le protocole nécessite l'utilisation d'une formulation intraveineuse (posolo- gie: trois fois par jour pendant dix jours composée de): BHT: 250 mg; Acétylcystéine: 50 mg; Superoxyde Dismutase (SOD): 100 mg; Nattokinase: 50 mg; Glutarione: 50 mg. All clinical data were collected using standardized questionnaires. All the patients were offered orally for prevention and / or in mild form COVID-19 (butyîhydroxytoluene BHT 300 mg; acetylcysteine 200 mg; Bosvvellia serrata: 500 mg) twice a day for ten days (in this preliminary phase, we did not recruit children to the treatment group based on data indicating that children develop mild symptoms of COVID-19). In the severe form of CO-VID-19, all patients were treated with intravenous formulation (dosage: three times a day for ten days consisting of: BHT: 500 mg; Glutathione (G SH): 200 mg; Acetilcisteina: 300 rng or BHT: 500 mg; Glutathione (GSH): 100 mg; Superoxide Dismutase (SOD): 200 mg; Catalase (CAT): 100 mg; ATP: 100 mg In states where the use of catalase (CAT) and adenosine triphosphate (ATP) is not permitted, the protocol for patients with mild symptoms requires the use of an oral formulation (dosage: three times a day for ten days consisting of): BHT: 250 mg ; Acetylcysteine: 50 mg; Superoxide Dismutase (SOD): 100 mg; Nattokinase: 50 mg; Glutatione: 50 mg. While in patients with severe symptoms, the protocol requires the use of an intravenous formulation (dosage: three times a day for ten days consisting of): BHT: 250 mg; Acetylcysteine: 50 mg; Superoxide Dismutase (SO D): 100 mg; Nattokinase: 50 mg; Glutarione: 50 mg.
Classification clinique Clinical classification
Les patients ont été regroupés en trois catégories: infection asymptomatique des voies respiratoires supérieu- res The patients were grouped into three categories: asymptomatic upper respiratory infection
(URTÏ) en cas de rhinite, de pharyngite ou de fièvre isolée de bas grade et de myalgie, et infections des voies respiratoires inférieures (LRTI) en cas de symptômes de pneumonie ou bronchite. (URTÏ) in cases of rhinitis, pharyngitis or isolated low-grade fever and myalgia, and lower respiratory tract infections (LRTI) in case of symptoms of pneumonia or bronchitis.
Le syndrome COVID-19 suit, au niveau physiopathologique, deux déterminants essentiels qui, avec un mé- canisme d'amplification intégré et réciproque, consistent en: * réplication systémique et propagation du virus --> invasion tissulaire multiorganique / multisystémique avec cytolyse / apoptose massive · incontrôlée ex- pression et amplification de la réponse immunitaire -inflammatoire de l'hôte (SIRS - MQDS - MOFS) → pa- nendothélite maligne avec occlusion microvasculaire systémique COVID-19 → classification clinique Le syndrome COVID-19 peut être classé, au niveau clinique, dans les tonnes cliniques suivantes: • Légère (80%) → découverte de fièvre, toux, mal de gorge, asthénie et absence d'insuffisance respiratoire aiguë (la valeur minimale normale de Pa02 détectée avec l'analyse des gaz du sang dans l'air ambiant est supposée → 80 mmHg). * Modérée (15%) → détection d'une pneumonie avec insuffisance respiratoire aiguë modérée (80 <Pa02 dans l'air ambiant> 60 mmHg). * Sévère (5%) → détection d'une pneumonie avec présence d'une in- suffisance respiratoire aiguë sévère (Pa02 dans l'air ambiant <60 mmHg) avec A R DS (Pa02 / Fi02 <200 mmHg), choc septique (TA systolique <90 mmHg et / ou diastolique TA <60 mmHg malgré un volume suffi- sant de remplissage, acide lactique> 2 mmol / L) et dysfonctionnement mufti -organes (par exemple insuffi- sance rénale aiguë, avec diurèse <03 mL / Kg / h). The COVID-19 syndrome follows, at the pathophysiological level, two essential determinants which, with an integrated and reciprocal amplification mechanism, consist of: * systemic replication and propagation of the virus -> multiorgan / multisystem tissue invasion with cytolysis / apoptosis massive uncontrolled expression and amplification of the host's immune-inflammatory response (SIRS - MQDS - MOFS) → malignant panendothelitis with systemic microvascular occlusion COVID-19 → clinical classification COVID-19 syndrome can be classified as clinical level, in the following clinical tons: • Mild (80%) → discovery of fever, cough, sore throat, asthenia and absence of acute respiratory failure (the normal minimum value of Pa02 detected with analysis of blood gases in ambient air is assumed → 80 mmHg). * Moderate (15%) → detection of pneumonia with moderate acute respiratory failure (80 <Pa02 in ambient air> 60 mmHg). * Severe (5%) → detection of pneumonia with the presence of severe acute respiratory insufficiency (Pa02 in ambient air <60 mmHg) with AR DS (Pa02 / Fi02 <200 mmHg), septic shock (TA systolic <90 mmHg and / or diastolic TA <60 mmHg despite sufficient filling volume, lactic acid> 2 mmol / L) and mufti-organ dysfunction (eg acute renal failure, with diuresis <03 mL / Kg / h).
Matériaux et instruments Materials and instruments
Matériaux Materials
Article de test: Test article:
Numéro de lot: la partie A fournit. Lot number: part A supplies.
Pureté: la partie A fournit. Purity: Part A provides.
Apparence:. Appearance:.
Stockage: Stocké à 2-8 °C, à l'abri de la lumière. Storage: Stored at 2-8 ° C, protected from light.
Procédure d'enregistrement: la quantité, la date, l'utilisateur et le but d'utilisation de l'échantillon d'essai sont enregistrés à chaque fois: Recording procedure: the quantity, date, user and purpose of use of the test sample are recorded each time:
La solution a été préparée à l'avance en fonction de la dose à administrer, et conservée à 4 oC dans l'obscu- rité. The solution was prepared in advance according to the dose to be administered, and stored at 4 ° C in the dark.
Médicament témoin positif: Positive control drug:
Numéro de lot: Batch number:
Fabricant: . Maker: .
Stockage: scellé et stocké à une température inférieure à 4 °C. Storage: sealed and stored at a temperature below 4 ° C.
Procédure d'enregistrement: le numéro, la date, l'utilisateur et le but de chaque échantillon de test sont enre- gistrés. Recording procedure: the number, date, user and purpose of each test sample are recorded.
BHT, Acétyl cystéine., Glutathion, Nattokine., Bowellia serrata, solution (100 mM) BHT, Acetyl cysteine., Glutathione, Nattokine., Bowellia serrata, solution (100 mM)
Fabricant: . Maker: .
Numéro de produit: BSA04-001. Product number: BSA04-001.
Réactifs spéciaux pour analyseur de sang animal HEMAVET950FS Marque: DREW. Special reagents for animal blood analyzer HEMAVET950FS Brand: DREW.
Fabricant: Drevv Scientiflc, Inc., États-Unis. Manufacturer: Drevv Scientiflc, Inc., United States.
Kit de détection de cytokines Marque: Biolegend. Cytokine detection kit Brand: Biolegend.
Fabricant: Biolegend, États-Unis. Manufacturer: Biolegend, USA.
Matrice de membrane de sous-sol Cultrex® haute concentration, 10X Fabricant: Corning, États-Unis. Cultrex® High Concentration Basement Membrane Matrix, 10X Manufacturer: Corning, USA.
EDTA dipotassique Fabricant: SIGMA, USA. Saline Dipotassium EDTA Manufacturer: SIGMA, USA. Saline
Numéro de lot: ; Batch number: ;
Fabricant: . Maker: .
PB S en poudre Fabricant: SIGMA, USA. PB S powder Manufacturer: SIGMA, USA.
Paraform aldéhyde Numéro de lot:. Paraform aldehyde Batch number :.
Fabricant: . Isoflurane Maker: . Isoflurane
Période de validité: 2019-12-28; Validity period: 2019-12-28;
Fabricant: . Maker: .
Instruments Instruments
Balance de pesée animale Numéro de série: PL3001-s. Animal weighing scale Serial number: PL3001-s.
Fabricant: Mettler - Toîedo instruments (Shanghai) Co., LTD. Manufacturer: Mettler - Toîedo instruments (Shanghai) Co., LTD.
Analyseur de sang animal HEMAVET 950 Modèle: HEMAVET 950FS. HEMAVET 950 animal blood analyzer Model: HEMAVET 950FS.
Fabricant: Drew Scientific, Inc., Etats-Unis. Manufacturer: Drew Scientific, Inc., USA.
Analyseur biochimique automatique Modèle: 7100. Automatic biochemical analyzer Model: 7100.
Marque: Hitachi. Brand: Hitachi.
Cytomètre en flux BD Accuri C6 Marque: société BD. BD Accuri C6 flow cytometer Brand: BD company.
Système d'imagerie par ultrasons haute résolution pour petits animaux (VisualSonics) Marque: Canadian VisualSonics. High resolution ultrasound imaging system for small animals (VisualSonics) Brand: Canadian VisualSonics.
Modèle: Vevo2100, sonde MS400 (fréquence 30 MHz). Model: Vevo2100, MS400 probe (frequency 30 MHz).
Spectromètre de masse à plasma à couplage inductif (ICAP-Q) Inductively Coupled Plasma Mass Spectrometer (ICAP-Q)
Marque: American Thermo Company. Brand: American Thermo Company.
Plaque chauffante de type DB-3EFS Heating plate type DB-3EFS
Marque: Tianjin Gongxing Laboratory Instrument Co., Ltd. Brand: Tianjin Gongxing Laboratory Instrument Co., Ltd.
Système de traitement d'eau ultrapure Milli-Q Marque: American Millipore Company Milli-Q ultrapure water treatment system Brand: American Millipore Company
Animaux d'essai Espèce: porcs pygmées: Test animals Species: pygmy pigs:
Souche: pigmy; Strain: pigmy;
Grade: SPF; Grade: SPF;
Genre masculin; Age: Des porcs miniatures croisés KCG seront utilisés à un âge moyen de 5 à 7 semaines et 10 kg de poids corporel. Male gender; Age: KCG crossbred miniature pigs will be used at an average age of 5-7 weeks and 10 kg body weight.
Nombre d'animaux: Les animaux ont été répartis au hasard en 6 groupes, 3 études (n = 10, n = 10, n ::: 10) et 3 contrôles (n = 5, n = 5, n-5): Number of animals: The animals were randomly divided into 6 groups, 3 studies (n = 10, n = 10, n ::: 10) and 3 controls (n = 5, n = 5, n-5):
Etude orale sur infection modérée du 1er groupe (n = 10) + contrôle (n = 5) groupe: BHT: 300 mg Acétylcystéine: 200 mg Boswellia serrata: 500 mg Oral study on moderate infection of the 1st group (n = 10) + control (n = 5) group: BHT: 300 mg Acetylcysteine: 200 mg Boswellia serrata: 500 mg
Solution buvable en gélules pour les cas infectieux légers / graves Étude orale sévère modérée du 2e groupe (n = 10) + contrôle (n = 5) Oral solution in capsules for mild / severe infectious cases Severe moderate oral study of the 2nd group (n = 10) + control (n = 5)
BHT: 250 mg Acétylcystéine: 150 mg Superoxyde Dismuta.se (SOD): 150 mg Nattokinase: 50 mg Gîutatione: 100 mg BHT: 250 mg Acetylcysteine: 150 mg Superoxide Dismuta.se (SOD): 150 mg Nattokinase: 50 mg Gututation: 100 mg
Solution IV pour les cas infectieux légers / sévères IV solution for mild / severe infectious cases
Etude orale sévère modérée du 3e groupe (n = 10) + contrôle (n = 5) Severe moderate oral study of the 3rd group (n = 10) + control (n = 5)
BHT: 250 mg Acétylcystéine: 150 mg Superoxyde Dismutase (SOD): 150 mg Nattokinase: 50 mg Gîutatione: 100 mg. BHT: 250 mg Acetylcysteine: 150 mg Superoxide Dismutase (SOD): 150 mg Nattokinase: 50 mg Gututation: 100 mg.
Numéro de licence de production animale: SCXK, Laboratoires Nam-Khoa du SYT-Health and Medical Umts et Laboratory Animal Center of Ho Chi Mmh City Vietnam. Animal production license number: SCXK, Nam-Khoa Laboratories of SYT-Health and Medical Umts and Laboratory Animal Center of Ho Chi Mmh City Vietnam.
Numéro de certificat animal: Non.; Non.; Animal certificate number: No .; No.;
Numéro de licence d'utilisation des animaux: sera attribué au SCXK, aux laboratoires Nam-Khoa du SYT- Health and Medical Units et au Laboratory Animal Center de Ho Chi Minh City Vietnam, Animal use license number: will be assigned to SCXK, the Nam-Khoa laboratories of SYT-Health and Medical Units and the Laboratory Animal Center in Ho Chi Minh City Vietnam,
Les animaux seront nourris dans une animalerie de qualité SPF des laboratoires Nam-Khoa de HCM City Vietnam. Les porcs miniatures croisés KCG ont eu libre accès à la nourriture et à l'eau tout au long de l'expé- rience et ont été logés dans des conditions de lumière / obscurité de 12 h 12 dans un environnement à tempé- rature contrôlée (23 ± 3 oC) et l'humidité étant contrôlée à 40-70%. Les procédures expérimentales ont été menées conformément au BYT-MOH et au NIH de la République socialiste du Vietnam et ont été approu- vées par le comité d'éthique des animaux expérimentaux de SYT-HCM City Vietnam. The animals will be fed in an SPF quality animal facility at the Nam-Khoa laboratories in HCM City Vietnam. The KCG crossbred miniature pigs had free access to food and water throughout the experiment and were housed in 12:12 light / dark conditions in a temperature-controlled environment ( 23 ± 3 oC) and humidity controlled at 40-70%. The experimental procedures were carried out in accordance with BYT-MOH and NIH of the Socialist Republic of Vietnam and were approved by the Ethics Committee of Experimental Animals of SYT-HCM City Vietnam.
Méthodes expérimentales Après être entrés dans le centre expérimental de niveau SPF, les porcs pygmées seront hébergés en stricte conformité avec les exigences techniques pertinentes du centre des animaux expérimentaux du MOH du cen- tre de santé de la municipalité de HCM City SYT. La durée de l'étude était de 10 jours. L'aspect général et les conditions d'exercice, y compris l'état de conscience, la démarche, la réponse à la stimulation, l'équilibre de la marche et la coordination des membres chez l'animal, doivent être observés et enregistrés, Experimental methods After entering the SPF level experimental center, pygmy pigs will be housed in strict accordance with the relevant technical requirements of the MOH Experimental Animal Center of HCM City SYT Municipality Health Center. The duration of the study was 10 days. The general appearance and conditions of exercise, including state of consciousness, gait, response to stimulation, balance of gait and coordination of limbs in the animal should be observed and recorded,
... De différents groupes seront administrés par voie intraveineuse une fois tous les 3 jours (injection à 10:00 am). la formulation a été administée pdt 3 semaines. ... Different groups will be administered intravenously once every 3 days (injection at 10:00 am). the formulation was administered for 3 weeks.
Indicateurs de détection Detection indicators
Observer l'état général, le poids corporel et l'indice d'organes des souris nude Observe the general condition, body weight and organ index of nude mice
La situation générale de la souris nude comprend l'activité, l'état mental, la couleur de la peau, le régime ali- mentaire, la consommation d'eau et la production d'urine. Le poids corporel (BW) a été pesé tous les 3 jours. A la fin de l'expérience, les cœurs, le foie, la rate, les poumons, les reins et les tumeurs ont été séparés et pe- sés avec précision après que les souris nues aient été sacrifiées, et le cœur, le foie, la rate, les poumons, les reins et les tumeurs ont été calculés. Autrement dit, poids du tissu (mg) / poids corporel (g) = poids du tissu / poids corporel. The general status of the nude mouse includes activity, mental state, skin color, diet, water intake and urine production. Body weight (BW) was weighed every 3 days. At the end of the experiment, the hearts, liver, spleen, lungs, kidneys and tumors were separated and weighed precisely after the nude mice had been sacrificed, and the heart, liver, spleen, lungs, kidneys and tumors were calculated. In other words, tissue weight (mg) / body weight (g) = tissue weight / body weight.
Détection de la numération globulaire totale Total blood count detection
Des échantillons de sang total ont été prélevés sur des tubes EDTA et analysés avec un analyseur de sang ani- mal automatisé HEMAVET950FS pour déterminer les concentrations de globules blancs (WBC), de globules rouges (RBC), d'hémoglobine (HGB), d'hématocrite (HCT), de volume corpusculaire moyen. (MCV), hémo- globine corpusculaire moyenne (MCH), concentration corpusculaire moyenne d'hémoglobine (MCHC), pla- quettes (PLT), lymphocytes (LY), monocyte (MONO), granulocyte neutrophile (NEUT), largeur de distribu- tion du volume plaquettaire (PDW), plaquete moyenne volume (MPV) et le plus grand rapport de cellules plaquettaires (P-LCR). Whole blood samples were taken from EDTA tubes and analyzed with a HEMAVET950FS automated animal blood analyzer to determine the concentrations of white blood cells (WBC), red blood cells (RBC), hemoglobin (HGB), d hematocrit (HCT), medium corpuscular volume. (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets (PLT), lymphocytes (LY), monocyte (MONO), neutrophil granulocyte (NEUT), distribution width tion of platelet volume (PDW), average platelet volume (MPV) and greatest platelet cell ratio (P-LCR).
Test à base de billes multiplex pour la cytokine pro-inflammatoire Multiplex Bead Assay for Pro-inflammatory Cytokine
Après avoir recueilli le sang total, laissez le sang coaguler en le laissant sans perturbation à température am- biante pendant 1 h, et le surnageant a été recueilli par centrifugation à 3500 tr / min pendant 10 min. Les taux sériques de cytokine pro-inflammatoire ont été mesurés en utilisant le test à base de billes multiplex BioLe- gend LEGENDplexTM (# 740007) de BioLegend (San Diego, CA, USA), analyses statistiques After collecting the whole blood, allow the blood to clot, leaving it undisturbed at room temperature for 1 hour, and the supernatant was collected by centrifugation at 3500 rpm for 10 minutes. Serum pro-inflammatory cytokine levels were measured using the BioLegend LEGENDplexTM Multiplex Bead Assay (# 740007) from BioLegend (San Diego, CA, USA), statistical analyzes
L'analyse statistique des données expérimentales a été réalisée par le logiciel GraphPad Prism 5.0. Les don- nées ont été exprimées en moyenne ± SEM. Des méthodes de test ANOVA et Tukey à un facteur ont été utili- sées pour la comparaison entre les groupes. Les résultats ont été considérés comme statistiquement significa- tifs lorsque p <0,05. Statistical analysis of the experimental data was performed by GraphPad Prism 5.0 software. Data were expressed as mean ± SEM. One-way ANOVA and Tukey test methods were used for comparison between groups. The results were considered statistically significant when p <0.05.
Les effets de la formulation sur les cellules sanguines The effects of the formulation on blood cells
Les cellules sanguines des souris seront évaluées avec un système de comptage sanguin. Comme mentionné ci-dessus dans tous les groupes avant et après la période d'expérience, identifier et comparer les mêmes para- mètres entre les groupes d'étude et de contrôle. The blood cells of the mice will be assessed with a blood count system. As mentioned above in all the groups before and after the experiment period, identify and compare the same parameters between the study and control groups.
Les effets de la formulation sur les cytokines Les cytokines sériques seront évaluées par analyse de cytométrie en flux. Une comparaison sera effectuée en- tre les groupes d'étude et de contrôle IL- 1a , IL-Ib , IL- 10 , IL-6 , TNFy , IFN β sérum
Figure imgf000062_0001
The effects of the formulation on cytokines Serum cytokines will be assessed by flow cytometric analysis. A comparison will be made between the study and control groups IL-1a, IL-Ib, IL-10, IL-6, TNFy, IFN β serum
Figure imgf000062_0001
Mesures des résultats Outcome measures
Mesures des résultats primaires: Primary outcome measures:
Taux de mortalité à un mois [Période: jusqu'à 1 mois] One-month death rate [Period: up to 1 month]
La mortalité à 1 mois est définie comme le ratio de patients qui vivront après 1 mois à compter du début de l'étude par rapport à ceux enregistrés au départ. Mortality at 1 month is defined as the ratio of patients who will live after 1 month from the start of the study compared to those recorded at baseline.
Mesures des résultats secondaires: Secondary outcome measures:
Taux d'interleukine-6, IL-1 β, IL-2, IL-3, IL-17-IL 10, D-Dimer [Période: ligne de base, pendant le traite- ment (cycles 1 et 2 toutes les 12 heures) jusqu'à 1 mois] Interleukin-6, IL-1 β, IL-2, IL-3, IL-17-IL 10, D-Dimer [Period: baseline, during treatment (cycles 1 and 2 every 12 hours) up to 1 month]
Les niveaux d'IL-6 seront évalués à l'aide de la méthode ELISA commerciale. Nombre de lymphocytes [Période: ligne de base, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à 1 mois] IL-6 levels will be assessed using the commercial ELISA method. Lymphocyte count [Period: baseline, during treatment (cycles 1 and 2 every 12 hours) up to 1 month]
Numération lymphocytaire évaluée par la détermination de la formule sanguine utilisée en routine complément (C3 - C4), immuno-complexe (CIC), C-ANCA et P-ANCA, niveau de CRP (protéine C-réacti- ve) [Délai: ligne de base, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à 1 mois ]; TNF a. La CRP est évaluée par la détermination de la CRP couramment utilisée Lymphocyte count evaluated by determining the blood formula used in routine complement (C3 - C4), immunocomplex (CIC), C-ANCA and P-ANCA, level of CRP (C-reactive protein) [Time limit: line basic, during treatment (cycles 1 and 2 every 12 hours) up to 1 month]; TNF a. CRP is assessed by determining the commonly used CRP
Rapport Pa02 (pression partielle d'oxygène) / Fi02 (fraction d'oxvgène inspiré, Fi02) (ou rapport P / F) [Pé- riode: référence, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à 1 mois] calculé à partir d'analyses des gaz du sang artériel (valeurs de 300 à 100) Ratio Pa02 (partial pressure of oxygen) / Fi02 (fraction of inspired oxygen, Fi02) (or P / F ratio) [Period: reference, during treatment (cycles 1 and 2 every 12 hours) until 1 month] calculated from arterial blood gas analyzes (values from 300 to 100)
Changement du SOFA (Sequential Organ Faiîure Assessment) [Délai: départ, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à 1 mois] Il évalue 6 variables, chacune représentant un système organique (une pour les systèmes respiratoire, cardio- vasculaire, hépatique, de coagulation, rénal et neurologique), et notées de 0 (normal) à 4 (degré élevé de dys- fonctionnement / échec). Ainsi, le score maximum peut varier de 0 à 24. Change in SOFA (Sequential Organ Faiîure Assessment) [Timeframe: start, during treatment (cycles 1 and 2 every 12 hours) up to 1 month] It evaluates 6 variables, each representing an organ system (one for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems), and rated from 0 (normal) to 4 (high degree of dysfunction / failure). . Thus, the maximum score can vary from 0 to 24.
Nombre de participants présentant des effets secondaires liés au traitement, tel qu'évalué par les Critères de terminologie communs pour les événements indésirables (CTCAE) version 5.0 [Délai: pendant le traitement et jusqu'à 30 jours après la dernière dose de traitement] classé selon CTCAE citeria (v5.0) Number of participants with treatment-related side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [Timeframe: during treatment and up to 30 days after last dose of treatment] classified according to CTCAE citia (v5.0)
Réponse radiologique [Délai: au départ (facultatif), après sept jours et si cliniquement indiqué (jusqu'à 1 mois)] Radiological response [Timeframe: at baseline (optional), after seven days and if clinically indicated (up to 1 month)]
Scanner thoracique ou Chest XR Chest XR or chest scanner
Durée de l'hospitalisation [Période: du départ jusqu'à la sortie du patient (jusqu'à 1 mois)]. Duration of hospitalization [Period: from departure until discharge (up to 1 month)].
Jours d'hospitalisation. Days of hospitalization.
1. Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] délai avant la ventilation mécanique invasive (si elle n'a pas été initiée précédemment) calculé de la ligne de base à l'intubation 1. Remission of respiratory symptoms [Delay: up to 1 month] Delay before invasive mechanical ventilation (if not initiated previously) calculated from baseline to intubation
Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] délai jusqu'à l'extubation définitive calculé de l'intubation (à tout moment) à l'extubation en jours Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] délai d'indépendance par rapport à la ventilation mécanique non invasive calculé en jours Remission of respiratory symptoms [Time: up to 1 month] Time until final extubation calculated from intubation (at any time) to extubation in days Remission of respiratory symptoms [Time: up to 1 month] time to independence from non-invasive mechanical ventilation calculated in days
Rémission des symptômes respiratoires [Délai: jusqu'à 1 mois] délai d'indépendance par rapport à l'oxygénothérapie en jours Remission of respiratory symptoms [Delay: up to 1 month] delay of independence from oxygen therapy in days
CRITÈRES CRITERIA
Critère d'intégration: Integration criteria:
Tout genre Pas de limite d'âge Any gender No age limit
Consentement éclairé pour la participation à l'étude. Informed consent to participate in the study.
La formulation thérapeutique nutraceutique anti-COVÏD-19 a été modulée en trois protocoles d'accompagne- ment thérapeutique, visant respectivement à aider au traitement des fonnes cliniques: The anti-COVID-19 nutraceutical therapeutic formulation has been modulated into three therapeutic support protocols, aimed respectively at helping in the treatment of clinical forms:
• léger --> protocole 1 * modéré → protocole 2 ° sévère → protocole 3 • light -> protocol 1 * moderate → protocol 2 ° severe → protocol 3
Protocole 1 pour forme légère → forme clinique rationnelle et mécanisme d'action des composants Le proto- cole de support nutraceutique 1 vise à aider au traitement de la forme clinique légère du COVID-19: * Tonne clinique légère (80%) → découverte de fièvre, toux, mal de gorge, asthénie et absence d'insuffisance respira- toire aiguë (la valeur minimale normale de Pa02 détectée avec l'analyse des gaz du sang dans l'air ambiant est supposée → 80 mmHg). Protocol 1 for mild form → rational clinical form and mechanism of action of the components Nutraceutical support protocol 1 aims to help in the treatment of the mild clinical form of COVID-19: * Mild clinical tonne (80%) → discovery of fever, cough, sore throat, asthenia and absence of acute respiratory failure (the normal minimum value of Pa02 detected with analysis of blood gases in ambient air is assumed to be → 80 mmHg).
Protocole 2 (forme modérée) → forme clinique rationnelle et mécanisme d'action des composants Le proto- cole de support nutraceutique 2 vise à aider au traitement de la forme clinique modérée du COVID-19: • Mo- déré (15%) → détection d'une pneumonie avec insuffisance respiratoire aiguë (80 <Pa02 dans l'air ambiant> 60 mmHg). Protocol 2 (moderate form) → rational clinical form and mechanism of action of the components Nutraceutical support protocol 2 aims to help in the treatment of the moderate clinical form of COVID-19: • Mo- derated (15%) → detection of pneumonia with acute respiratory failure (80 <Pa02 in ambient air> 60 mmHg).
Composantes de l'association nutraceutique du protocole 2 Components of the nutraceutical combination of protocol 2
• BHT · acétylcystéine · Glutathion • Superoxyde Dismutase (SOD) · nattokinase Composantes de l'association nutraceutique du protocole 2 en alternative • BHT · acetylcysteine · Glutathione • Superoxide Dismutase (SOD) · nattokinase Components of the nutraceutical combination of protocol 2 as an alternative
• BHT * quercétine • nattokinase • BHT * quercetin • nattokinase
Conception de l'étude: Estimation des patients: 75 patients: * 25 sans insuffisance respira- toire aiguë → protocole 1 * 2.5 avec insuffisance respiratoire aiguë modérée → protocole 2 · 25 avec insuffisance respiratoire sévère et / ou choc → protocole 3 Study design: Patient estimate: 75 patients: * 25 without acute respiratory failure → protocol 1 * 2.5 with moderate acute respiratory failure → protocol 2 · 25 with severe respiratory failure and / or shock → protocol 3
Profils de support nutraceutique par catégories → • Protocole 1 → gélules → posologie → 2 cp administrés par voie orale toutes les 12 heures · Protocole 2 ----> gélules → posologie → 2 cp administrés par voie orale toutes les 12 heures · Protocole 3 ----> gélules ----> posologie ----> 2 gélules du protocole 2 administrées par sonde nasale gastrique toutes les 8 heures Nutraceutical support profiles by category → • Protocol 1 → capsules → dosage → 2 tabs administered orally every 12 hours · Protocol 2 ----> capsules → dosage → 2 tabs administered orally every 12 hours · Protocol 3 ----> capsules ----> dosage ----> 2 capsules of protocol 2 administered by gastric nasal tube every 8 hours
Composition de 1 gélule * BHT: 150 mg * Acétylcystéine: 100 mg Bosweîlia serrata: 250 mg per os Voie d'administration * Via Orale. * De préférence l'estomac plein et immédiatement après avoir ingéré une cuil- lère à café d'huile d'olive extra vierge (le BHT est bien mieux absorbé dans les milieux à faible teneur en ma- tière grasse), dosage 2 gélules toutes les 12 heures Durée 30 jours Etat Disponible sous 10 jours Composition of 1 capsule * BHT: 150 mg * Acetylcysteine: 100 mg Bosweîlia serrata: 250 mg per os Route of administration * Via Oral. * Preferably on a full stomach and immediately after ingesting a teaspoon of extra virgin olive oil (BHT is much better absorbed in environments with a low fat content), dosage 2 capsules every 12 hours Duration 30 days Status Available within 10 days
Protocole 2 → per os Composition de 1 gélule * BHT: 250 mg « Acétylcystéine: 50 mg · Superoxyde Dismu- tase (SOD): 100 mg · Nattokinase: 50 mg · Glutathion: 50 mg. Voie d'administration Orale » De préférence l'estomac plein et immédiatement après l'ingestion d'une cuillère à café d'huile d'olive extra vierge (le BHT est bien mieux absorbé dans les milieux à faible teneur en matière grasse), posologie * Par voie orale 2 gélu- les toutes les 12 heures Durée 21 jours État NON disponible → à préparer (7 semaines). Protocol 2 → orally Composition of 1 capsule * BHT: 250 mg “ Acetylcysteine: 50 mg · Superoxide Dismutase (SOD): 100 mg · Nattokinase: 50 mg · Glutathione: 50 mg. Route of administration Oral »Preferably on a full stomach and immediately after ingestion of a teaspoon of extra virgin olive oil (BHT is much better absorbed in low fat environments), dosage * Oral 2 capsules every 12 hours Duration 21 days Status NOT available → to be prepared (7 weeks).
Alternative Protocole 2 per os Composition de 1 gélule * BHT: 250 mg · Quercétine: 200 mg * Nattokina- se: 50 mg • Voie d'administration Orale * De préférence l'estomac plein et immédiatement après l'ingestion d'une cuillère à café d'huile d'olive extra vierge (le BHT est bien mieux absorbé dans les milieux à faible te- neur en matière grasse), posologie « Par voie orale 2 gélules toutes les 12 heures Durée 21 jours État NON disponible — » à préparer (7 semaines). Alternative Protocol 2 per os Composition of 1 capsule * BHT: 250 mg · Quercetin: 200 mg * Nattokina- sis: 50 mg • Route Oral * Preferably with a full stomach and immediately after ingestion of a tablespoon. coffee with extra virgin olive oil (BHT is much better absorbed in environments with a low fat content), dosage " Oral 2 capsules every 12 hours Duration 21 days Status NOT available -" to be prepared (7 weeks).
Protocole 3 → pour SNG Composition de 1 capsule ° BHT: 250 mg · Acétylcystéine: 50 mg * Superoxyde Dismutase (SOD): 100 mg * Nattokinase: 50 mg ° Glutathion: 50 mg. Voie d'administration Dosage de SNG 2 cp toutes les 8 heures Durée 14 jours Etat NON disponible → à préparer (7 semaines). Alternative Protocole 3 → pour SNG Composition de 1 capsule · BHT: 250 mg • Quercétine 100 mg * Natto- kinase: 50 mg * Voie d'administration Dosage de SNG 2 cp toutes les 8 heures Durée 14 jours État NON dis- ponible → à préparer (7 semaines). Protocol 3 → for SNG Composition of 1 capsule ° BHT: 250 mg · Acetylcysteine: 50 mg * Superoxide Dismutase (SOD): 100 mg * Nattokinase: 50 mg ° Glutathione: 50 mg. Route of administration Dosage of SNG 2 tabs every 8 hours Duration 14 days Status NOT available → to be prepared (7 weeks). Alternative Protocol 3 → for SNG Composition of 1 capsule · BHT: 250 mg • Quercetin 100 mg * Nattokinase: 50 mg * Route of administration Dosage of SNG 2 tabs every 8 hours Duration 14 days Status NOT available ponible → to prepare (7 weeks).
Paramètres d'évaluation primaires de l'évolution clinique: * Taux de mortalité à 1 mois Paramètres d'évalua- tion secondaires de l'évolution clinique: • Interleukine-6, 1L-1 b, IL -2, IL-3, IL-10-D-Dimères [Période: de base valeurs, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à un mois]; Les niveaux d'IL-6 doivent être dosés à l'aide du test ELI SA commercial. • Nombre de lymphocytes [Durée: valeurs de base, pendant le traitement (cycle 1 et 2 toutes les 12 heures) jusqu'à un mois] • Complément (C3 - C4), immuno- complexes circulants (CIC), C-ANCA et P-ANCA, anti- anticorps phospholipidiques (LAC - ACA) - niveau de PCR (protéine C-réactive) [Time Trame: valeurs de base, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à un mois]; TNF α. Primary endpoints for clinical outcome: * Mortality rate at 1 month Secondary endpoints for clinical outcome: • Interleukin-6, 1L-1b, IL -2, IL-3, IL -10-D-Dimers [Period: baseline values, during treatment (cycles 1 and 2 every 12 hours) up to one month]; IL-6 levels should be determined using the commercial ELI SA test. • Number of lymphocytes [Duration: baseline, during treatment (cycle 1 and 2 every 12 hours) up to one month] • Complement (C3 - C4), circulating immunocomplexes (CIC), C-ANCA and P-ANCA, anti-phospholipid antibodies (LAC - ACA) - PCR level (C-reactive protein) [Time Frame: baseline values, during treatment (cycles 1 and 2 every 12 hours) up to one month] ; TNF α.
Rapport P / F: rapport Pa02 (pression partielle d'oxygène) / Fi()2 (fraction d'oxygène inspiré, Fi02) [Time Frame: valeurs de base, pendant le traitement (cycles 1 et 2 toutes les 12 heures) jusqu'à un mois] déterminé par EGA (valeurs de 300 à 100 mmHg) P / F ratio: Pa02 (partial pressure of oxygen) / Fi () 2 (fraction of inspired oxygen, Fi02) ratio [Time Frame: baseline values, during treatment (cycles 1 and 2 every 12 hours) up to 'at one month] determined by EGA (values from 300 to 100 mmHg)
Modifications du score SOFA (Sequential Organ Failure Assessment) pour les patients classés en catégorie 2 et 3 [Time Frame: valeurs de base, pendant le traitement (cycle 1 et 2 toutes les 12 heures) jusqu'à un mois] Surveillance de 6 paramètres, chaque organe spécifique (système respiratoire, cardiovasculaire, hépatique, hémocoagulant, rénal et neurologique), classé avec un score allant de 0 (indicatif du paramètre normal glo- bal) à 4 (degré élevé de dysfonctionnement / défaillance d'organes). Le score peut donc varier d'un minimum de 0 à un maximum de 24. Changes in the SOFA (Sequential Organ Failure Assessment) score for patients classified in category 2 and 3 [Time Frame: baseline, during treatment (cycles 1 and 2 every 12 hours) up to one month] Monitoring of 6 parameters , each specific organ (respiratory, cardiovascular, hepatic, hemocoagulant, renal and neurological system), classified with a score ranging from 0 (indicative of the overall normal parameter) to 4 (high degree of organ dysfunction / failure). The score can therefore vary from a minimum of 0 to a maximum of 24.
Nombre de patients présentant des effets indésirables attribuables au traitement selon la classification de la version 5.0 des Critères de terminologie communs pour les événements indésirables (CTCAE) [Délai: pen- dant le traitement et jusqu'à un maximum de 30 jours après la dernière admini stration de celui-ci]Number of patients with treatment-attributable adverse reactions according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 classification [Timeframe: during treatment and up to a maximum of 30 days after the last administration stration of it]
Évaluation radiologique [Délai: début (facultatif), après 7 jours et si cliniquement indiqué à 1 mois, par TDM du thorax ou radiographie du thorax. Radiological evaluation [Timeframe: start (optional), after 7 days and if clinically indicated at 1 month, by chest CT or chest x-ray.
Durée de l'hospitalisation [Délai: de l'hospitalisation à la sortie (jusqu'à 1 mois)] jours d'hospitalisation Rémission des symptômes respiratoires [Délai: dans un délai de 1 mois] délai d'indépendance vis-à-vis de la ventilation mécanique non invasive, calculé en jours à compter de son début (chez les patients non intubés par la suite et soumis à une ventilation mécanique) Duration of hospitalization [Time: from hospitalization to discharge (up to 1 month)] days of hospitalization Remission of respiratory symptoms [Time: within 1 month] period of independence from non-invasive mechanical ventilation, calculated in days from the start (in patients not subsequently intubated and undergoing mechanical ventilation)
Rémission des symptômes respiratoires [Délai: dans un délai d'un mois] temps d'extubation définitif calculé les jours d'extubation avant la sortie de l'hôpital. Remission of respiratory symptoms [Time limit: within one month] final extubation time calculated on the days of extubation before discharge from hospital.
Rémission des symptômes respiratoires [Délai: dans un délai de 1 mois] Délai d'indépendance par rapport à l'oxygénothérapie, calculé en jours • Présence du génome viral par PCR [Délai: dans un délai de 1 mois]. Remission of respiratory symptoms [Time: within 1 month] Time to independence from oxygen therapy, calculated in days • Presence of the viral genome by PCR [Time: within 1 month].

Claims

REVENDICATIONS
1. Un principe actif sélectionné parmi 2,6-di-tert-butyl-4-méthyl-phénol (BHT), BG1, BG2, BG3, BG4, N- acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOI)), gluthation (GSH), Adénosine triphosphate (ATP), quercétine, une combinaison de ces principes actifs, pour la prévention et/ou le traitement d'une infection par un coronavirus SARS-CoV-2. 1. An active principle selected from 2,6-di-tert-butyl-4-methyl-phenol (BHT), BG1, BG2, BG3, BG4, N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOI ) ), gluthation (GSH), Adenosine triphosphate (ATP), quercetin, a combination of these active ingredients, for the prevention and / or treatment of infection with a SARS-CoV coronavirus. 2.
2. Principe actif pour son utilisation selon la revendication 1, dans une formulation galénique destinée à une voie d'administration sélectionnée parmi administration orale, intranasale, sublinguale, intraveineuse, intra- rectale, intraoculaire, en inhalation, ou une combinaison de ces voies d'administration. 2. Active principle for its use according to claim 1, in a galenic formulation intended for a route of administration selected from oral, intranasal, sublingual, intravenous, intra-rectal, intraocular, inhalation, or a combination of these routes. 'administration.
3. Composition comprenant un principe actif selon la revendication 1 ou kit comprenant un mois deux prin- cipe actif selon la revendication 1 ou 2 et un excipient acceptable. 3. Composition comprising an active principle according to claim 1 or a kit comprising one month two active principle according to claim 1 or 2 and an acceptable excipient.
4. Composition ou kit selon la revendication 3 comprenant le BHT et l'un quelconque des principes actifs sé- lectionnés parmi N-acétylcystéine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxi- de dismutase (SOD), gluthation (GSH), Adénosine triphosphate (ATP), quercétine, une combinaison de ces principes actifs 4. Composition or kit according to claim 3 comprising BHT and any one of the active principles selected from N-acetylcysteine (NAC), Boswellia Serrata (BS), Nattokinase, Catalase (CAT), Superoxide dismutase (SOD). ), gluthation (GSH), Adenosine triphosphate (ATP), quercetin, a combination of these active ingredients
5. Composition ou kit selon la revendication 4 caractérisé en ce que le BHT est à une dose de 0,01 mg à 1g, de 0.1 mg à 10 mg, de 1 mg à 100 mg, de 100 mg à 900 mg, de 300 mg à 500 mg, avantageusement adminis- tré à une dose de 0,1 mg/kg à lg/kg, de 1 mg/kg à 0.1g/kg, de 10 mg/kg à 800 mg/kg, de 10Gmg/kg à 900mg/kg ; de 300mg/kg à 500 mg/kg en poids. 5. Composition or kit according to claim 4 characterized in that the BHT is at a dose of 0.01 mg to 1g, from 0.1 mg to 10 mg, from 1 mg to 100 mg, from 100 mg to 900 mg, from 300 mg to 500 mg, advantageously administered at a dose of 0.1 mg / kg to 1g / kg, from 1 mg / kg to 0.1g / kg, from 10 mg / kg to 800 mg / kg, from 10Gmg / kg at 900mg / kg; from 300 mg / kg to 500 mg / kg by weight.
6. Composition ou kit selon la revendication 4 caractérisé en ce que la BS est administrée à un individu à la dose de 250 mg, l'Acéthylcystéine à la dose de 100 mg, le BHT est à une dose de 150 mg, en combinaison avec de l'huile végétale, la composition ou le kit étant admmsitré deux fois par jour pendant 30 jours, 6. Composition or kit according to claim 4 characterized in that the BS is administered to an individual at a dose of 250 mg, Acethylcysteine at a dose of 100 mg, BHT is at a dose of 150 mg, in combination with vegetable oil, the composition or the kit being administered twice a day for 30 days,
7. Composition ou kit selon la revendication 4 caractérisé en ce que la SOD est administrée par voie orale à un individu à la dose de 100 mg, FAcéthylcystéine à la dose de 50 mg, le BHT est à une dose de 250 mg, en combinaison avec de l'huile végétale, la Nattokinase est administrée à la dose de 50 mg, le gluthation est ad- ministré à la dose de 50mg, la composition ou le kit étant adminsitré toutes les 12 heures pendant 21 jours. 7. Composition or kit according to claim 4 characterized in that the SOD is administered orally to an individual at a dose of 100 mg, FAcethylcysteine at a dose of 50 mg, BHT is at a dose of 250 mg, in combination with vegetable oil, the nattokinase is administered at a dose of 50 mg, the gluthation is administered at a dose of 50 mg, the composition or the kit being administered every 12 hours for 21 days.
8. Composition ou kit selon la revendication 4 caractérisé en ce que la SOD est administrée par voie orale à un individu à la dose de 100 mg, FAcéthylcystéine par voie orale à la dose de 50 mg, le BHT par voie orale est à une dose de 250 mg, en combinaison avec de l'huile végétale, la Nattokinase par voie orale est adminis- trée à la dose de 50 mg, le gluthation est administré par voie orale à la dose de 50mg, la composition ou le kit étant adminsitré toutes les 8 heures pendant 14 jours. 8. Composition or kit according to claim 4 characterized in that the SOD is administered orally to an individual at a dose of 100 mg, FAcethylcysteine orally at a dose of 50 mg, the oral BHT is at a dose. of 250 mg, in combination with vegetable oil, oral nattokinase is administered at a dose of 50 mg, gluthation is administered orally at a dose of 50 mg, the composition or the kit being administered all 8 hours for 14 days.
9. Composition ou kit pour son utilisation selon l'une quelconque des revendications 5, 6 ou 7 caractérisé en ce que le BHT est combiné en outre à de TAdénosine TriPhosphate (ATP), avantageusement ATP à la dose de 50mg ou 100 mg. 9. Composition or kit for its use according to any one of claims 5, 6 or 7 characterized in that the BHT is further combined with TAdenosine TriPhosphate (ATP), advantageously ATP at a dose of 50 mg or 100 mg.
10. Composition ou kit pour son utilisation selon l'une quelconque des revendications précédantes caractéri- sé en ce que le BHT est combiné en outre à la quercétine, avantageusement la quercétine à la dose de l00mg ou 200 mg trois fois par jour. 10. Composition or kit for its use according to any one of the preceding claims, characterized in that the BHT is further combined with quercetin, advantageously quercetin at a dose of 100 mg or 200 mg three times a day.
11. Composition ou kit pour son utilisation selon la revendication 6 chez des patients présentant des sympto- mes modérés - et pas de syndrome respiratoire aigüe, ou pour son utilisantion selon la revendication 7 ou 8 pour des patients SARS-Cov-2 positifs présentant un syndrome respiratoire aigüe non inhibés. 11. Composition or kit for its use according to claim 6 in patients exhibiting moderate symptoms - and no acute respiratory syndrome, or for its use according to claim 7 or 8 for positive SARS-Cov-2 patients exhibiting an acute respiratory syndrome. uninhibited acute respiratory syndrome.
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