WO2021191864A1 - Compléments alimentaires pour la prévention de la covid-19 - Google Patents

Compléments alimentaires pour la prévention de la covid-19 Download PDF

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WO2021191864A1
WO2021191864A1 PCT/IB2021/052534 IB2021052534W WO2021191864A1 WO 2021191864 A1 WO2021191864 A1 WO 2021191864A1 IB 2021052534 W IB2021052534 W IB 2021052534W WO 2021191864 A1 WO2021191864 A1 WO 2021191864A1
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covid
vitamin
patients
cov
sars
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PCT/IB2021/052534
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Yogesh Dound
Bhushan DOUND
Abhishek KOKANE
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Yogesh Dound
Dound Bhushan
Kokane Abhishek
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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
    • A61K31/12—Ketones
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger

Definitions

  • the present invention relates to a food/ nutraceutical supplements for the preventive management of COVID-19.
  • the present invention relates to food/ nutraceutical supplements comprising Vitamin K2-7 and/or curcuminoid, especially tetrahydrocurcumin for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the 2019-20 coronavirus pandemic is an ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the outbreak was first identified in the city of Wuhan, Hubei, China in December 2019, and was recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020.
  • WHO World Health Organization
  • Coronaviruses are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).
  • CoV is an enveloped, positive-sense single-stranded RNA (ssRNA) virus belonging to the Coronaviridae family.
  • ssRNA single-stranded RNA
  • the CoV family consists of several species and causes upper respiratory tract and gastrointestinal infections in mammals and birds. In humans, it mainly causes common cold, but complications including pneumonia and SARS can occur.
  • the known human CoV includes HCoV-229E, -OC43, -NL63, -HKU1 , and the l more widely known severe acute respiratory syndrome coronavirus (SARS- CoV) which caused a global threat with high mortality in 2003.
  • SARS- CoV severe acute respiratory syndrome coronavirus
  • WHO World Health Organization
  • COVID-19 is a new strain that was discovered in 2019 and has not been previously identified in humans.
  • Coronaviruses are zoonotic, meaning they are transmitted between animals and people. Detailed investigations found that SARS-CoV was transmitted from civet cats to humans and MERS-CoV from dromedary camels to humans.
  • Several known coronaviruses are circulating in animals that have not yet infected humans. The virus primarily spreads between people via respiratory droplets from coughing or sneezing. It is considered most contagious when people are symptomatic, although spread is possible even before symptoms appear. The time between exposure and symptom onset is typically around five days, but may range from two to fourteen days. Common symptoms include fever, cough, and shortness of breath. Common signs of infection include respiratory symptoms, fever, cough, shortness of breath and breathing difficulties. These symptoms are usually mild and begin gradually. Some people become infected but don’t develop any symptoms and don't feel unwell.
  • Vitamin K2-7 belongs to Vitamin K group.
  • the two general categories of vitamin K are Phylloquinone (K1) and Menaquinones, also referred as MK-n as per the side chains with 4-13 prenyl units. Their physiological and patho physiological roles of different menaquinones are specific.
  • Vitamin K acts as an enzymatic co-factor to carboxylate Vitamin K-dependent proteins (VKD proteins) [14]
  • VKD proteins Vitamin K-dependent proteins
  • Curcumin is a naturally derived yellow polyphenolic compound from the rhizome Curcuma longa.
  • the wide range of activities of Curcumin are attributed to its efficacy to modulate various signalling pathways, such as COX-2, MMPs, glutathione, protein kinase C, ATPase, nuclear NF-kb, AP- 1 , P-gp, MRP-1, MRP-2, ErbB2, a1-acidglycoprotein, Cyclin D1, and others.
  • signalling pathways such as COX-2, MMPs, glutathione, protein kinase C, ATPase, nuclear NF-kb, AP- 1 , P-gp, MRP-1, MRP-2, ErbB2, a1-acidglycoprotein, Cyclin D1, and others.
  • researchers have turned their attention to its reductive metabolites in an attempt to figure out the remarkable biological effects of Curcumin.
  • Curcumin The pharmacological activities of Curcumin are attributed to major metabolites of Curcumin like dimethoxycurcumin and tetrahydrocurcumin. Recently Molecular docking was performed using Autodock 4.2, with the Lamarckian Genetic Algorithm to analyse the probability of docking. COVID-19 Mpro was docked with several compounds like dimethoxycurcumin. Demethoxycurcumin appeared to have the best potential to act as COVID-19 Mpro inhibitors. There are no reports of effects of tetrahydrocurcumin against COVID-19 infection.
  • the present inventors have prepared the food/ nutraceutical supplements and analyzed the activity of Vitamin K2-7 and curcuminoid esp. tetrahydrocurcumin both severe acute respiratory syndrome coronavirus (SARS-CoV) main peptide and COVID-19 Mpro.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • An object of the present invention is to provide food/ nutraceutical supplements for the preventive management of COVID-19.
  • Another objective of the present invention is to provide food/ nutraceutical supplements comprising Vitamin K2-7 for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • Yet another objective of the present invention is to provide food/ nutraceutical supplements comprising curcuminoid especially tetrahydrocurcumin for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • curcuminoid especially tetrahydrocurcumin for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • the present invention relates to a food// nutraceutical supplement comprising Vitamin K2-7.
  • the food/ nutraceutical supplement comprising Vitamin K2-7 is used for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the present invention relates to a food/ nutraceutical supplement comprising curcuminoids especially tetrahydrocurcum in.
  • the food/ nutraceutical supplement comprising curcuminoids especially tetrahydrocurcum in is used for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) main peptide and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the food/ nutraceutical supplement can be administered in a suitable pharmaceutical dosage form or can be administered by mixing with suitable food materials.
  • Fig. 1 and Fig. 2 show the actives of the protein targets.
  • the present invention relates to a food/ nutraceutical supplements for the preventive management of COVID-19.
  • the terms used in the specification are defined as follows.
  • the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • a “subject,” “individual,” or “patient,” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also encompassed.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e.
  • condition, disorder or disease not worsening state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.
  • Some preliminary studies have investigated potential combinations which include the protease inhibitor lopinavir/ritonavir, (commonly used to treat human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome patients) for the treatment of COVID-19-infected patients.
  • Other reported antiviral treatments form human pathogenic CoVs include nucleoside analogues, neuraminidase inhibitors, remdesivir, umifenovir (arbidol), tenofovir disoproxil (TDF), and lamivudine (3TC).
  • the results from preliminary studies remain unapproved for therapeutic use in clinical settings for the treatment of COVID-19-infected patients.
  • Vitamins C act as an antioxidant that helps to destroy free radicals and support the body’s natural immune response. Vitamin C contributes to immune defence by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C also enhances white blood cell production and function. Various studies have found that vitamin C is useful in the prevention of pneumonia, a complication associated with COVID-19 mortality.
  • Vitamin K2-7 also known as Menaquinone-7. It is a menaquinone whose side-chain contains seven isoprene units in an all-trans- configutation when derived from nature. Trans isomers are shown to be safe where as Cis isomers has shown to be toxic. In fact US Pharmacopeia defined pure vitamin K2-7 to have less than 2% of Cis isomers. Currently available of vitamin K2-7 preparation contains more than 2% of Cis isomers. Trans are safe and more effective. Dound et. al., in his earlier work on Vitamin K2-7 has shown to be possessing anti viral activity against HIV and HBV.
  • Vitamin K2-7 has evaluated the activity of Vitamin K2-7 in docking studies for severe acute respiratory syndrome coronavirus (SARS-CoV) main peptide and COVID-19 Mpro. It has been observed that Vitamin K2-7 has activity viz, severe acute respiratory syndrome coronavirus (SARS-CoV) main peptide (Binding energy of -6.92 and Inhibition constant of 8.48 mM) and COVID-19 Mpro (Binding energy of -6.54 and Inhibition constant of 16.24 pM), suggesting its potential role in prevention of COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the present invention relates to a food/ nutraceutical supplement comprising Vitamin K2-7.
  • the food/ nutraceutical supplement comprising Vitamin K2-7 is used for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • Curcumin major component of Turmeric. Antiviral activity of Curcumin has been observed previously against several different viruses including hepatitis viruses, influenza viruses and emerging arboviruses.
  • Curcumin enhances immunomodulatory activity by interacting with macrophages, dendritic cells, B & T lymphocytes (Cellular immunity) and also with cytokines, transcription factors and there multiple downstream signalling pathways (Humoral immunity) such as cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kB, TNF, IL-6, IL-1, COX-2, and 5-LOX).
  • cytokines transcription factors and there multiple downstream signalling pathways
  • Humoral immunity such as cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and
  • Curcumin is the primary curcuminoid in turmeric and the compound for which most studies have been done. Curcumin undergoes metal-independent reduction of curcumin to dihydrocurcumin (DHC) as an intermediate product, followed by further reduction to tetrahydrocurcumin (THC) as an end product. Tetrahydrocurcumin (THC) exhibits many of the same physiologic and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin.
  • DHC dihydrocurcumin
  • THC tetrahydrocurcumin
  • Tetrahydrocurcumin exhibits many of the same physiologic and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin.
  • the present invention relates to a food/ nutraceutical supplement comprising curcuminoids especially tetrahydrocurcum in.
  • the food/ nutraceutical supplement comprising curcuminoids especially tetrahydrocurcum in is used for the preventive management of severe acute respiratory syndrome coronavirus (SARS-CoV) main peptide and COVID-19.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • the food / nutraceutical supplement can be administered in a suitable pharmaceutical dosage form or can be administered by mixing with suitable food materials.
  • the dosage form of the invention can be prepared combining an active pharmaceutical ingredient of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.
  • the present invention relates to administering “an effective amount of the dosage form of invention” to the subject suffering from said disease.
  • active pharmaceutical ingredient and pharmaceutical dosage form containing them may be administered using any amount, any form of pharmaceutical dosage form via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical dosage forms include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • dosage forms of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Dosage form that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • Example 1 Docking studies of Tetrahydrocurcumin and Vitamin K2-7, against COVID-19 or SARS-CoV-2.
  • COVID-19 Mpro (PDB ID: 6LU7) and SARS coronavirus main peptidase (PDB ID: 2GTB) structures were taken from PDB (https://www.rcsb.org/), in .pdb format.
  • the 6LU7 protein contains two chains, A and B, which form a homodimer.
  • the 2GTB protein contain one chain A
  • the native ligand for 6LU7 is n-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-n ⁇ 1 ⁇ -((1 r,2z)-4-(benzyloxy)- 4-oxo-1 - ⁇ [(3r)-2-oxopyrrolidin-3-yl]methyl ⁇ but-2-enyl)-l-leucinamide, where as for 2GTB native ligand is (5s,8s,14r)-ethyl 11-(3-amino-3-oxopropyl)-8-benzyl- 14-hydroxy-5-isobutyl-3,6,9, 12-tetraoxo-1 -phenyl-2-oxa-4,7, 10, 11 -tetra azapenta decan-15-oate
  • Vitamin K2-7 (CID_5287554) and tetrahydrocurcumin (CID_1240723- dimensional (3D) structures were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/), in .sdf format. PubChem is a database which store chemical substance and biological activities.
  • the active site of a protein was determined using LIGPLOT v.4.5.3 and Biovia Discovery Studio 4.5 is describing in Tablel
  • the images showing the actives site are given in supplementary images Figure 1 and Figure 2.
  • Ligand optimization was done using Marvin Tool of ChemAxon.
  • the ligands Vitamin K2-7 and tetrahydrocurcumin were docked with three dimensional structure of the Protein Target using AutoDockToola4.2. Binding modes of Vitamin K2-7 and tetrahydrocurcumin with all protein targets is shown in Table 2.
  • Example 2 Composition according to the invention
  • Example 3 Efficacy and Tolerability of composition in the management of COVID-19: A Randomised Comparative Clinical Study The composition as obtained in example 2 was used to evaluate the composition [Named hereinafter as curmune] in the management of COVID- 19 in a clinical trial.
  • the subjects had undergone a detailed history and complete physical examination along with the laboratory investigations. These include CBC, Lipid profile, Liver Profile, Pro inflammatory cytokine lnterleukin-6 (IL-6), D- Dimer, Ferritin and C Reactive Protein (CRP).
  • CBC Lipid profile
  • Liver Profile Pro inflammatory cytokine lnterleukin-6
  • CRP Ferritin
  • IL-6 Pro inflammatory cytokine lnterleukin-6
  • CRP C Reactive Protein
  • the primary outcome included clinical status as decided by the Principal Investigator based on the physical examination, laboratory investigations and signs such as axillary temperature, respiratory rate, pulse, blood pressure and symptoms which include cough, fever with or without chills and difficulty in breathing.
  • a special WHO committee arrived at this ordinal scale which measures illness severity over time. This scale has been widely used in randomized clinical trials for the management of COVID-19. The clinical status was assessed based on the symptoms at baseline and at the end point along with parameters including Pro inflammatory cytokine IL-6, D-Dimer, Ferritin and CRP.
  • the average temperature at baseline was 102.28 ⁇ 0.4°F. By the end of 48 hours, the temperature reduced to 99.39 ⁇ 0.3°F. The temperature reduced to 98.18 ⁇ 0.2°F in all the patients by day 4. The temperature continued to remain afebrile till day 10 ( Figure 1).
  • the temperature at baseline was 102.31 ⁇ 0.5°F. By the end of 48 hours, the temperature remained around 101.3 ⁇ 0.7°F. The temperature reduced to 99.32 ⁇ 0.3°F in all the patients by day 4. These patients continued to remain afebrile till day 10 from 5 days onwards ( Figure 1).
  • the average Sp02 in the Active and Standard groups at baseline was 84.86 ⁇ 0.6 and 83.44 ⁇ 0.6, respectively.
  • the average Sp02 levels in the Active group increased to 88.42 ⁇ 1.3, while in the Standard group the levels increased to 86.80 ⁇ 1.4.
  • the levels increased to 94.52 ⁇ 0.8 in the Active group and to 89.66 ⁇ 0.5 in the Standard group.
  • the Sp0 2 levels in both the groups the Sp02 levels were around 97.68 ⁇ 0.6 and 95.98 ⁇ 0.1 in all the Active and Standard Groups respectively ( Figure 2).
  • the patients in both the groups were in category 3 of the six-category ordinal scale of clinical status at baseline.
  • Category 3 refers to the patients who are hospitalized with mild to moderate disease.
  • the subjects in the Active group were in the category 0 of this scale by day 10.
  • the subjects in the Standard group were in the category 1 of this scale by day 10.
  • Category 0 refers to the patients who are not infected with no clinical or virological evidence of infection.
  • Category 1 refers to the patients who are ambulatory with no limitation of activities.
  • the Standard treatment group could not achieve category 0 on this scale by day 10.
  • the serum IL-6, Ferritin and CRP levels and plasma D-Dimer levels were very high at baseline in both the groups as compared to their respective normal range for males as well as females.
  • the IL-6 (pg/ml) levels reduced from 1272.02 ⁇ 138.7 to 318.01 ⁇ 34.7 in both males and females in the Active group within 10 days.
  • the levels reduced from 1355.22 ⁇ 20.9 to 869.34 ⁇ 124.6 by the end of day 10 ( Figure 3).
  • the CRP (mg/L) levels reduced from 30.92 ⁇ 5.5 to 4.95 ⁇ 0.9 and from 29.55 ⁇ 5.1 to 18.46 ⁇ 1.3 in the Active group and Standard group respectively ( Figure 4).
  • the Ferritin (ug/L) levels reduced from 540.18 ⁇ 94.2 to 140.45 ⁇ 24.5 in the Active group while they reduced from 574.20 ⁇ 81 .8 to 365.31 ⁇ 34.4 in the Standard group ( Figure 5).
  • the plasma D-Dimer (mg/L) levels reduced from 2.31 ⁇ 0.2 to 0.42 ⁇ 0.1 in the Active group, while it reduced from 2.36 ⁇ 0.3 to 1.40 ⁇ 0.3 in the Standard group ( Figure 6).
  • Table 3 gives a summary of the levels of these parameters in each group for males and females. There was no change in rest of the biochemical as well as organ function tests within 10 days in both the groups.
  • Table 4 Levels of serum IL-6, Ferritin and CRP levels and plasma D-Dimer levels in each group for males and females Discussion
  • Curcumin has exhibited various pharmacological activities attributed to its major metabolites like dimethoxycurcumin and tetrahydrocurcumin. Recently Demethoxycurcumin was shown to have the best potential to act as COVID- 19 M pro inhibitor. Tetrahydrocurcumin, also has shown promising antiviral effect by inhibiting SARS-CoV’s main peptide and COVID-19 M pro .
  • Vitamin C acts as an antioxidant, which destroys free radicals and supports the body’s natural immune response. Vitamin C potentially protects against infection caused by SARS-CoVs by improving the immunity, function of phagocytes, transformation of T lymphocytes and production of interferon. Vitamin C is also recommended for prevention of SARS-CoV-2 infections by the Chinese Center for Disease Control and Prevention and Chinese Nutrition Society.
  • Zinc is an essential metal involved in cell signalling, proliferation, differentiation, oxidative stress, the immune response, and numerous other important cellular processes. Various clinical studies have linked Zinc supplementation with less severe and reduced duration of symptoms along with lower recurrent infections for viral infections. Zinc is recommended by the National Institutes of Health (NIH) for inducing the immune system and preventing viral infections.
  • NASH National Institutes of Health
  • IL-6 acts as a pro-inflammatory cytokine as well as an anti-inflammatory myokine. Inflammation is closely related to severity of COVID-19 and IL-6 is one of the important therapeutic targets. It has also been shown that the serum levels of IL-6 predict the outcome in patients with COVID-19 [21] In the current study the very high levels of IL-6 at baseline reduced by approximately 75% within 10 days.
  • Ferritin plays a role in the modulation of immune function. It is known to suppress several global measures of the immune response. Laboratory investigations in the patients with severe COVID-19 showed elevated inflammatory markers, including ferritin, and hence it has been associated with critical and life-threatening illness. In the current study the high levels of Ferritin at baseline reduced approximately by 70-75 % within 10 days.
  • CRP levels are associated with the levels of inflammation, and its concentration level is unaffected by factors such as age, sex, and physical condition. CRP levels can activate the phagocytosis, thus clearing the pathogenic microorganisms which invade the body. It is an important index for the diagnosis and assessment of various infectious diseases.
  • the elevated levels of CRP are linked to the overproduction of inflammatory cytokines in severe patients with COVID-19. Higher levels of CRP are considered as a predictive marker in determining which patients with mild COVID-19 symptoms will progress to a severe case. In the current study the high levels of CRP at baseline reduced approximately by 75-80 % within 10 days.
  • D-dimer assays are routinely used as part of a diagnostics to exclude the diagnosis of thrombosis. However, any pathologic or non-pathologic process that increases fibrin production or breakdown also increases plasma D-dimer levels. D-dimer concentrations are found to be helpful to rapidly identify COVID-19 patients with high risk of pulmonary complications and venous thromboembolism, facilitating the early initiation of effective therapies. In the current study the high levels of D-dimer at baseline reduced approximately by 80% within 10 days.
  • Curmune has shown for the first time to be useful in management of COVID-19 positive patients along with improvement in the immunity, within 48 to 36 hours of starting treatment. Curmune Tablets were well tolerated without any side effects in any of the patients treated, throughout the study duration.

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Abstract

La présente invention concerne des compléments alimentaires/nutraceutiques pour la gestion préventive de la COVID-19. Spécifiquement, la présente invention concerne des compléments alimentaires/nutraceutiques comprenant de la vitamine K2-7 et/ou un curcuminoïde, en particulier la tétrahydrocurcumine pour la gestion préventive du coronavirus du syndrome respiratoire aigu sévère (SRAS-CoV) et COVID-19.
PCT/IB2021/052534 2020-03-27 2021-03-26 Compléments alimentaires pour la prévention de la covid-19 WO2021191864A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022140561A1 (fr) * 2020-12-22 2022-06-30 Ankh Life Sciences Limited Inhibition du virus de la covid-19 par des formulations à composants multiples
NL2030584B1 (en) * 2022-01-17 2023-07-27 Emphysema Solutions Bv Use of vitamin K in preventing or counteracting vaccine-related adverse events, symptoms, morbidity and/or mortality after vaccination against COVID-19 or another coronavirus

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Vitamin K2 - Vital for Health and Wellbeing", 22 March 2017, INTECH , ISBN: 978-953-51-3020-8, article HODGES STEPHEN J., PITSILLIDES ANDREW A., YTREBØ LARS M., SOPER ROBIN: "Anti-Inflammatory Actions of Vitamin K", pages: 153 - 168, XP055862959, DOI: 10.5772/63891 *
MAGGINI, S ET AL.: "Immune Function and Micronutrient Requirements Change over the Life Course", NUTRIENTS, vol. 10, no. 10, 17 October 2018 (2018-10-17), pages 1531, XP055862953, DOI: 10.3390/nu10101531 *
MCNAMARA, L: "COVID-19 - Fighting Fear and The Coronavirus Pandemic with Precautions and Quality Supplements", LADDMCNAMARA.COM, 13 March 2020 (2020-03-13), XP055862952, Retrieved from the Internet <URL:https://laddmcnamara.com/2020/03/13/covid-19-fighting-fear-and-the-coronavirus-pandemic-with-precautions-and-quality-supplements/> *
TOD COOPERMAN: "Do any supplements help with the coronavirus (COVID-19)? Do supplements like vitamin D, zinc, vitamin C, or herbals work?", CONSUMERLAB.COM, 6 March 2020 (2020-03-06), XP055862962, Retrieved from the Internet <URL:https://www.consumerlab.com/answers/do-natural-remedies-or-supplements-prevent-coronavirus/natural-remedies-coronavirus/> *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022140561A1 (fr) * 2020-12-22 2022-06-30 Ankh Life Sciences Limited Inhibition du virus de la covid-19 par des formulations à composants multiples
NL2030584B1 (en) * 2022-01-17 2023-07-27 Emphysema Solutions Bv Use of vitamin K in preventing or counteracting vaccine-related adverse events, symptoms, morbidity and/or mortality after vaccination against COVID-19 or another coronavirus

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