WO2021240375A1 - Méthotrexate destiné à être utilisé dans la prévention et/ou le traitement pharmaceutique ou vétérinaire d'infections virales - Google Patents

Méthotrexate destiné à être utilisé dans la prévention et/ou le traitement pharmaceutique ou vétérinaire d'infections virales Download PDF

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WO2021240375A1
WO2021240375A1 PCT/IB2021/054558 IB2021054558W WO2021240375A1 WO 2021240375 A1 WO2021240375 A1 WO 2021240375A1 IB 2021054558 W IB2021054558 W IB 2021054558W WO 2021240375 A1 WO2021240375 A1 WO 2021240375A1
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methotrexate
preceeding
veterinary
treatment
pharmaceutical
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PCT/IB2021/054558
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English (en)
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Lilia Alberghina
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Blueprint Pharma S.R.L.
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Priority claimed from IT102020000012325A external-priority patent/IT202000012325A1/it
Priority claimed from IT102020000012343A external-priority patent/IT202000012343A1/it
Application filed by Blueprint Pharma S.R.L. filed Critical Blueprint Pharma S.R.L.
Publication of WO2021240375A1 publication Critical patent/WO2021240375A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 or pantothenic 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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/33—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • 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
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns the use of methotrexate in the pharmaceutical or veterinary treatment of viral infections.
  • Viruses are smaller and simpler in construction than unicellular microorganisms, and they contain as genetic material only one type of nucleic acid, either DNA or RNA. They replicate only within cells of the host that they infect. Many relevant human diseases are caused by viruses. Animal virology developed largely from the need to control viral diseases in livestock farming. Viruses, like other infectious agents, enter the animal body through one of its surfaces. They then spread either locally on one of the body surfaces or through lymphatic and blood vessels to produce systemic infections.
  • a virus When a virus enters the body, it triggers the body's immune defences. These defences begin with white blood cells, such as lymphocytes, which attack and destroy the virus or the cells it has infected. If the body survives the viral infection, the lymphocytes "remember" the invader and can respond more quickly and effectively to a later infection with the same virus. This is the basis of adaptive immunity. Adaptive immunity can also be produced by vaccination .
  • Antiviral drugs Drugs that fight viral infections are called antiviral drugs.
  • Antiviral drugs work by interfering with viral replication.
  • Respiratory tract infections are common infections of the upper respiratory tract (e.g., nose, ears, sinuses, and throat) and lower respiratory tract (e.g., trachea, bronchial tubes, and lungs) .
  • Symptoms of upper respiratory tract infection include runny or stuffy nose, irritability, restlessness, poor appetite, decreased activity level, coughing, and fever.
  • the infection causing microorganism e.g., virus, bacterium, or fungus
  • the infection causing microorganism may be resistant or develop resistance to the administered therapeutic agent or combination of therapeutic agents.
  • microorganisms that develop resistance to administered therapeutic agents often develop pleiotropic drug or multidrug resistance, that is, resistance to therapeutic agents that act by mechanisms different from the mechanisms of the administered agents.
  • pleiotropic drug or multidrug resistance that is, resistance to therapeutic agents that act by mechanisms different from the mechanisms of the administered agents.
  • methotrexate an inhibitor of DNA and RNA synthesis in human and animal cells
  • methotrexate an inhibitor of DNA and RNA synthesis in human and animal cells
  • the present invention discloses methotrexate as a medicament for the prevention and/or the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • methotrexate is disclosed as a medicament for the treatment and/or the prevention of viral infections caused by RNA viruses.
  • the present invention discloses methotrexate as a medicament for the prevention and/or the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses, together with additional metabolic cofactors.
  • the present invention discloses a pharmaceutical or veterinary composition for the prevention and/or the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • the present invention discloses a method for the prevention and/or the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • Figure 1 shows the inhibition mechanism of methotrexate on RNA synthesis.
  • Figure 2 shows the results of the assay on the antiviral activity of methotrexate against CVA3.
  • Figure 3 shows the results of the assay on the antiviral activity of methotrexate against BHV-1.
  • Methotrexate is a known chemotherapy agent and immune system suppressant, also known as amethopterin, 4-amino-10-methyl folic acid and also briefly referred to as MTX in the following description.
  • prevention shall be intended as the prevention of the onset of the disease.
  • Prevention shall also include a prophylaxis treatment, wherein a subject at risk of being contaged with a virus can prevent the development of the disease.
  • treatment shall be intended as the curing the disease caused by a virus.
  • viral infections shall be intended as diseases caused by a virus.
  • Viral infections are particularly, but not exclusively, represented by respiratory tract infections.
  • respiratory tract infection has its general meaning in the art and is intended to designate infections of the upper respiratory tract (e.g., nose, ears, sinuses, and throat) and lower respiratory tract (e.g., trachea, bronchial tubes, and lungs).
  • Other viral infections can be treated with methotrexate according to the present invention; in fact, other tissues, such as the liver, comprise high expression of the folate transported (FOLR1) or of the dihydrofolate reductase, and therefore have high sensibility towards the treatment with methotrexate.
  • FOLR1 folate transported
  • dihydrofolate reductase dihydrofolate reductase
  • virus shall include both DNA virus and RNA virus.
  • methotrexate is also active against DNA virus, as it blocks the mRNA synthesis and DNA synthesis.
  • RNA virus is meant to comprise a negative single-strand RNA virus, a positive single-strand RNA virus and a double-strand RNA virus.
  • virus shall include enveloped and non-enveloped viruses.
  • Viruses are the predominant cause of respiratory tract illnesses and include DNA and RNA viruses.
  • RNA viruses include: such as respiratory syncytial virus, influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus.
  • Human respiratory syncytial virus also known as human orthopneumovirus, or HRSV, or just RSV
  • HRSV human orthopneumovirus
  • a prophylactic medication, palivizumab can be employed to prevent HRSV in preterm (under 35 weeks gestation) infants, infants with certain congenital heart defects (CHD) or bronchopulmonary dysplasia (BPD), and infants with congenital malformations of the airway. Treatment is limited to supportive care, including oxygen therapy and more advanced breathing support with CPAP or nasal high flow oxygen, as required.
  • Severe HRSV infections have increasingly been found among elderly patients. Young adults can be re infected every five to seven years, with symptoms looking like a sinus infection or a cold (infections can also be asymptomatic).
  • Gammainfluenzavirus can be identified by antigenic differences in their nucleoprotein and matrix protein.
  • Vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections.
  • Vaccines are composed of either inactivated or live attenuated virions of the H1N1 and H3N2 human influenza A viruses, as well as those of influenza B viruses. Because the antigenicities of the wild viruses evolve, vaccines are reformulated annually by updating the seed strains.
  • HPIVs Human parainfluenza viruses
  • HPIVs are the viruses that cause human parainfluenza.
  • HPIVs are a paraphyletic group of four distinct single-stranded RNA viruses belonging to the Paramyxoviridae family.
  • HPIVs remain the second main cause of hospitalisation in children under 5 years of age suffering from a respiratory illness (only Human orthopneumovirus causes more respiratory hospitalisations for this age group).
  • Human parainfluenza viruses include:
  • HPIV-1 Human parainfluenza virus type 1
  • HPIV-2 Human parainfluenza virus type 2 (HPIV-2), which causes croup and other upper and lower respiratory tract illnesses,
  • HPIV-3 Human parainfluenza virus type 3
  • HPIV-4 Human parainfluenza virus type 4
  • HPIVs belong to two genera: Respirovirus (HPIV-1 & HPIV-3) and Rubulavirus (HPIV-2 & HPIV-4).
  • HMPV Human metapneumovirus
  • HMPV Human metapneumovirus
  • RSV Human orthopneumovirus
  • the peak age of hospitalization for infants with HMPV occurs between 6-12 months of age, slightly older than the peak of RSV, which is around 2-3 months.
  • the clinical features and severity of HMPV are similar to those of RSV. HMPV is also an important cause of disease in older adults.
  • the virus is distributed worldwide and, in temperate regions, has a seasonal distribution generally following that of RSV and influenza virus during late winter and spring.
  • Rhinovirus Rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures of 33-35 °C (91-95 °F), the temperatures found in the nose. Rhinoviruses belong to the genus Enterovirus in the family Picornaviridae.
  • the three species of rhinovirus include around 160 recognized types of human rhinovirus that differ according to their surface proteins (serotypes).
  • ICAM-1 Intercellular adhesion molecule 1
  • Enterovirus are picornaviruses (pico, or small RNA viruses). All enteroviruses are antigenically heterogeneous and have a wide geographic distribution. Enteroviruses include:
  • Echoviruses human orphan cytopathic enteric viruses 1 to 7, 9, 11 to 21, 24 to 27 and 29 to 33
  • Enteroviruses are found in respiratory secretions and feces and are sometimes present in the blood and cerebrospinal fluid of infected patients.
  • Infection typically spreads through direct contact with respiratory secretions or stool, but can be transmitted from environmental contaminated sources (eg, water). Infection transmitted from a mother during childbirth can cause severe disseminated neonatal infection, which can include hepatitis or liver necrosis, meningoencephalitis, myocarditis, or a combination of these, and can lead to sepsis or death. Enteroviruses can cause various diseases: epidemic pleurodynia, hand-foot-mouth disease, herpangin, poliomyelitis.
  • An exemplary enterovirus is represented by Coxsackievirus (A3): CV-A3.
  • Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, and MERS.
  • Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria. They are enveloped viruses with a positive-sense single- stranded RNA genome and a nucleocapsid of helical symmetry.
  • Coronaviruses vary significantly in risk factor.
  • Coronaviruses can cause colds with major symptoms, such as fever, and a sore throat from swollen adenoids. Coronaviruses can cause pneumonia (either direct viral pneumonia or secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or secondary bacterial bronchitis).
  • SARS-CoV which causes severe acute respiratory syndrome (SARS)
  • SARS severe acute respiratory syndrome
  • HCV-OC43 Human coronavirus OC43 (HCoV-OC43), b-CoV,
  • HKU1 HKU1
  • HKUl Human coronavirus HKU1
  • b-CoV b-CoV
  • HCV-229E Human coronavirus 229E (HCoV-229E), -CoV,
  • HCV-NL63 Human coronavirus NL63
  • a-CoV Human coronavirus NL63
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • b-CoV Severe acute respiratory syndrome coronavirus
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), b-CoV.
  • Veterinary viral infections are caused by both DNA viruses and RNa viruses.
  • RNA virus causing viral infections is selected from the group comprising: Arteriviridae, Roniviridae, Tobaniviridae, Toroviridae, Picornaviridae, Caliciviridae, Reoviridae, Togaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, Retroviridae, Bunyaviridae, Arenaviridae, Coronaviridae, and Birnaviridae.
  • the veterinary treatment according to the present invention is particularly suitable against viral infections in pigs.
  • Coronaviridae including the genera Alphacoronavirus, Betacoronavirus and Gammacoronavirus
  • Toroviridae including the genera Torovirus and Bafinivirus may cause in pigs different diseases, such as transmissible gastroenteritis (TGE), haemagglutinating encephalomyelitis (HEV), porcine epidemic diarrhoea (PED), porcine respiratory coronavirus (PRCV), deltacoronavirus (PDCoV).
  • TGE transmissible gastroenteritis
  • HEV haemagglutinating encephalomyelitis
  • PED porcine epidemic diarrhoea
  • PRCV porcine respiratory coronavirus
  • PDCoV deltacoronavirus
  • Porcine respiratory coronavirus is associated with respiratory problems, and the HEV virus gives rise to two different syndromes, vomiting and wasting disease and encephalomyelitis.
  • the TGE virus is a coronavirus that has rarely been found since the late 20th century. First reported in 1946, it reached its highest prevalence in the 1970, 80s, and 90s in both Europe and the USA, with over 95% of European farms seropositive in the 80s. It is a highly infectious virus that causes diarrhoea, dehydration, and occasionally vomiting as a distinctive symptom, and causes high mortality in young pigs.
  • the TGE virus has been completely sequenced and only one serotype is known. Homologies exist between TGE virus and bovine coronavirus, as well as with porcine respiratory coronavirus. From an epidemiological point of view, there are both epidemic and endemic cases.
  • thermostable virus It is a relative thermostable virus, and is resistant to low pH and to many disinfectants. At 37°C, it is inactivated in less than two hours. It is very sensitive to light and highly resistant to freezing. The virus survives for long periods of time in frozen carcasses. This means that most outbreaks of the disease occur during cold months.
  • the piglets die dehydrated, with a distended stomach, milk and haemorrhagic petechiae in the small intestine, hypertrophied mesenteric nodes (characteristic lesion), atrophy of intestinal microvilli (duodenum, jejunum and ileum) with thinner walls, and necrosis of enterocytes in the jejunum with reduced enzymatic activity and yellowish content.
  • co-infections with gastrointestinal bacteria such as E. coli and Clostridium spp are frequent, worsening and prolonging the clinical picture.
  • Porcine epidemic diarrhoea is a highly contagious disease.
  • the virus has a genomic structure and replication very similar to those affecting other animals.
  • the virulence of the viruses isolated in different countries during clinical cases was similar, with minimum genetic dispersion. Only one serotype is known.
  • Morbidity at any stage of production can reach 100%, and is more variable in breeding sows.
  • Mortality in nursing piglets can be as high as 100%, with rates normally between 30 and 50%.
  • the main clinical sign is watery diarrhoea leading to death from dehydration within 2-4 days in nursing piglets, in addition to vomiting and poor appetite.
  • Weaned piglets and fattening pigs can recover from diarrhoea after one week, showing anorexia, lethargy, and considerable growth retardation.
  • After a clinical infection in breeding sows they acquire a strong immunity, which they pass on to their piglets via colostrum.
  • the course of the disease on a breeding farm usually lasts a maximum of one month, varying according to farm size and production system. This period can be prolonged if secondary complications arise from gastrointestinal infectious agents such as
  • Escherichia coli Clostridium perfringens, Rotavirus, Isospora suis, Salmonella spp, Lawsonia intracellularis or Brachispira spp. It should be noted that the lesions are found exclusively in the small intestine, which appears distended with yellowish watery contents, and the stomach is found empty. There is up to 70% atrophy of intestinal villi and vacuolization of enterocytes with reduced enzymatic activity.
  • the treatment has been only through supportive care, with the priority being hydrating nursing and weaned piglets using saline, electrolyte agents, and milk replacers.
  • the transmission of specific IgA via colostrum from the sow to the piglets is critical. Therefore, the rapid exposure of the virus to gestating sows, infecting them with piglet feces to stimulate rapid lactogenic immunity (depending on the production phase where the infection started), allows us to shorten the duration of the clinical picture and lessen the spread to the different production areas as much as possible.
  • Porcine respiratory coronavirus is a variant of the TGE virus family that infects the respiratory tract, and is not excreted via feces. Porcine respiratory coronavirus produces antibodies that neutralize the TGE virus. The virus infects animals of all ages, either by direct contact or by aerosol transmission, being more prevalent in areas with a high pig density.
  • Clinical signs include coughing, dyspnea, abdominal breathing, lethargy, anorexia and slight growth retardation; symptoms similar to most problems within the porcine respiratory disease complex (PRDC). Worsening of the symptoms occurs in cases combined with PRRS virus or bacterial infectious agents, which in these cases cause pneumonia that can be severe.
  • the respiratory coronavirus can be located in both the upper and lower respiratory tract.
  • the most characteristic lesions which are not pathognomonic, are lung consolidation, broncho- interstitial and broncho-catarrhal pneumonia, bronchiolar epithelial hyperplasia with loss of epithelial cells, infiltration of leukocytes, lymphocytes and macrophages into the alveolar septum.
  • Bovine herpes virus 1 (BHV-1)
  • Bovine herpes virus 1 has a tropism for the mucous membranes of the upper respiratory tract and genitals and causes infectious rhinotracheitis, conjunctivitis and vulvovaginitis, pustular balanoposthitis and less frequently, also abortion, systemic neonatal infection, encephalitis, infertility.
  • An important feature of the virus is the ability to cause latent infection. It is responsible for respiratory forms (IBR) and infections of the genital system: vulvovaginitis (IPV) and pustular balanoposthitis (BPH); in addition: abortion, systemic neonatal infection, encephalitis and infertility. Incubation of 2-5 days is followed by an acute phase of 5-10 days, respiratory symptoms (cough, nasal discharge, conjunctivitis) are related to a sharp drop in production lactea, possible bacterial complications (pneumonia) may occur.
  • the present invention concerns a medicament having a pan antiviral potential application.
  • the present invention discloses methotrexate for use as a medicament for the prevention and/or for the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • methotrexate for use as a medicament for the prevention and/or for the treatment of viral infections in humans, wherein said virus is a DNA virus or an RNA virus.
  • RNA virus is selected from the group comprising RNA virus causing viral respiratory tract infections is selected from respiratory syncytial virus, influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus .
  • said RNA virus is represented by Coxsackie A3 virus (CVA3).
  • methotrexate for use as a medicament for the prevention and/or for the treatment of viral infections in animals, wherein said virus is a DNA or an RNA virus.
  • said DNA virus is represented by Herpesvirus and more in particular by Bovine herpesvirus 1 (BHV-1).
  • said RNA virus is selected form the group comprising Arteriviridae, Roniviridae, Tobaniviridae, Picornaviridae, Caliciviridae, Reoviridae, Togaviridae, Toroviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, Retroviridae, Bunyaviridae, Arenaviridae, Coronaviridae, and Birnaviridae.
  • said RNA virus is represented by Coronaviridae and Toroviridae .
  • animals include livestock animals.
  • livestock animals comprise: poultry, horse, donkey, cattle, zebu, yak, buffalo, gayal, mink, sheep, goat, reindeer, camel, llama, alpaca, pig, rabbit, or deer.
  • animals are represented by pigs.
  • methotrexate for use as a medicament for the pharmaceutical or veterinary prevention and/or treatment of viral infections wherein the dosage is about 150-300 pg/week per kg of weight (human body or animal weight).
  • said weekly dose is administered in fractioned amounts.
  • the prevention and/or treatment dosage regimen is according to the known "metronomic" regimen.
  • methotrexate is administered to a human or animal in need thereof at the earliest appearance of symptoms.
  • methotrexate is disclosed for use as a medicament for the prevention and/or for the treatment of viral infections in humans or in animals, together with one or more additional pharmaceutical or veterinary compounds.
  • said one or more additional pharmaceutical or veterinary compounds may be selected from the group comprising: anti-inflammatory compounds (steroidal or FANS).
  • said additional pharmaceutical or veterinary compounds may be administered before, together or after the administration of methotrexate.
  • methotrexate is disclosed for use as a medicament for the prevention and/or for the treatment of viral infections in humans or in animals, with the proviso that the treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses, together with a coadjuvant compound.
  • said coadjuvant compound is represented by a metabolic cofactor.
  • said metabolic cofactor may be selected from the group comprising: carnitine, N- acetylcysteine, nicotinamide, biotin, serine, vitamin B complex, nicotinic acid, or derivatives thereof.
  • a carnitine derivative is represented by L- carnitine tartrate.
  • a nicotinamide derivative is represented by nicotinamide riboside.
  • Vitamin B complex may be administered according to the below dosage per day:
  • said metabolic cofactor may be administered before, together or after the administration of methotrexate.
  • methotrexate is administered via nasal, oral, subcutaneous or intramuscular administration.
  • the pharmaceutical composition is administered via nasal administration.
  • the veterinary composition is administered via oral administration.
  • the present invention discloses a pharmaceutical or veterinary composition for the prevention and/or for the treatment of viral infections in humans or in animals, with the proviso that the prevention and/or treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • said pharmaceutical or veterinary composition may include one or more additional pharmaceutical or veterinary compounds may be selected from the group comprising anti-inflammatory compounds (steroidal or FANS).
  • anti-inflammatory compounds steroidal or FANS
  • said pharmaceutical composition is a nasal, oral, subcutaneous or intramuscular composition.
  • the pharmaceutical composition of the invention is represented by a nasal composition.
  • said pharmaceutical composition is in the form of sealed in soft-gel capsules or in a solid form, such as a tablet, mini-tablet, micro-tablet, granule, micro- granule, pellet, multiparticulate, or micronised particulate, or powder or in the form of a solution, emulsion, gel, vial, drops, aerosol or spray.
  • the pharmaceutical composition of the invention is represented by an aerosol.
  • aerosol refers to the delivery of a drug to the body, for either topical or systemic effect, via the airways by delivering it in an aerosolised form.
  • This pharmaceutical form is the use of smaller doses and thus, minimal systemic adverse effects, besides giving a rapid response.
  • the particle size (expressed as mass median aerodynamic diameter) is of critical importance as the drug delivery depends on the same to a major extent.
  • Several devices such as metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulisers are available.
  • MDI metered dose inhaler
  • DPI dry powder inhaler
  • nebulisers are available.
  • MMAD mass median aerodynamic diameter
  • Another characteristic that may modify the penetration of the drug is the shape of aerosol where a more aerodynamically shaped droplet is likely to be associated with greater penetration.
  • the velocity at which the aerosol is generated also affects the fraction delivered to the lower airways. Those aerosols that are generated at a very high velocity tend to get deposited in the upper airways and consequently the delivery to the lower airways is compromised.
  • An MDI is a typical example of a generator that produces aerosols at a high velocity, which are in the range of 10-100 m/s.
  • dry powder and nebulizers produce aerosols with relatively low velocities. Slower flow minimises oropharyngeal and upper airway deposition and enhances distal delivery and depositing.
  • the advantages connected to an aerosol administration are well-know and in particular are represented by the facts that: i) the aerosol doses are generally smaller than systemic doses, ii) the onset of effect with inhaled drugs is faster than with oral dosing, iii) the drug is delivered directly to the airways, with minimal systemic exposure, iv) the systemic side effects are less frequent and severe with inhalation when compared to systemic delivery, v) the spray and powder forms may inadvertently deposit in the eyes and result in eye irritation.
  • inhaled aerosol delivered with a face mask allows to avoid these problems and increases the amount of drug delivered to the distal airways, and vi) the inhaled drug therapy is less painful than injection and is relatively comfortable.
  • said veterinary composition is a nasal, oral, subcutaneous or intramuscular composition.
  • the pharmaceutical composition of the invention is represented by an oral composition.
  • the pharmaceutical composition of the invention is represented by a tablet.
  • the pharmaceutical or veterinary composition of the invention comprises one or more suitable pharmaceutical or veterinary excipients according to the route of administration.
  • Suitable excipients include: acidifiers, acidity regulators, anti-caking agents, antioxidants, bulking agents, firming agents, gelling agents, coating agents, modified starches, sequestrants, thickeners, sweeteners, diluents, disintegrants, glidants, colourings, binders, lubricants, stabilisers, adsorbents, preservatives, humectants, flavourings, filmogenic substances, emulsifiers, wetting agents, release retardants and mixtures thereof.
  • said excipients are potassium sorbate, sodium benzoate, e-polylysine, sucralose, maltodextrin, citric acid, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium stearate, stearic acid, polyethylene glycol, natural starch, partially hydrolysed starch, modified starch, maize starch, potato starch, lactose, lactose monohydrate, calcium phosphate, calcium carbonate, calcium sulphate, polyvinylpyrrolidone, silica, colloidal silica, precipitated silica, magnesium silicates, aluminium silicates, sodium lauryl sulphate, magnesium lauryl sulphate, methacrylate copolymers, sodium dehydroacetate, xanthan gum, guar gum, tara gum, locust bean gum, fenugreek gum, gum arabic, alginic acid, sodium alginate, propylene glycol alginate, sodium croscarmellose
  • compositions of the present invention may be prepared by using methods known to a person skilled in the art.
  • the present invention discloses a method for the prevention and/or for the treatment of viral infections in humans or in animals comprising the step of administering to a human or to an animal in need thereof of a pharmaceutically or veterinary effective dose of methotrexate according to one or more of the embodiment of the above description, with the proviso that the prevention and/or treatment in humans is excluded for viral infections caused by SARS-CoV2 and ZIKA viruses.
  • the method for the prevention and/or treatment of viral infections comprises the administration of a dose of methotrexate of about 150-300 pg/week per kg of weight (human body or animal weight).
  • said weekly dose is administered in fractioned amounts.
  • the method for the prevention and/or treatment of viral infections may further comprise the administration of one or more additional pharmaceutical or veterinary compounds.
  • said one or more additional pharmaceutical or veterinary compounds may be selected from the group comprising anti-inflammatory compounds (steroidal or FANS).
  • the method for the prevention and/or treatment of viral infections may further comprise the administration of a coadjuvant compound.
  • said coadjuvant compound is represented by a metabolic cofactor.
  • said metabolic cofactor may be selected from the group comprising: carnitine, N- acetylcysteine, nicotinamide, biotin, serine, vitamin B complex, nicotinic acid, or derivatives thereof.
  • a carnitine derivative is represented by L- carnitine tartrate.
  • a nicotinamide derivative is represented by nicotinamide riboside.
  • the above compounds may be administered with the following indicative dosage:
  • Vitamin B complex may be administered according to the below dosage per day:
  • said metabolic cofactor may be administered together with methotrexate during the prevention and/or treatment regimen.
  • said metabolic cofactor may be administered according to a different posology regimen.
  • FIG. 1 shows the results of the assay performed on CVA3 virus.
  • Coxsackie A3 is a Picornaviridae, single- stranded positive-sense RNA viruses and it is nonenveloped .
  • the plateau of efficacy is reached at about 25 mM methotrexate and IC50 is 6.25 mM.
  • Figure 3 shows the results of the assay performed on BHV-1 virus.
  • Bovine herpesvirus 1 (BHV-1) is a Herpesviridae double-stranded DNA genome virus and it is enveloped. The plateau of efficacy is reached at about 1.5 mM methotrexate and IC50 is 0.19 mM.
  • the assays carried out show that methotrexate is effective both against DNA and RNA viruses.
  • methotrexate is a well-known compound used in the chemiotherapic treatment of neoplasia. None in the art had ever suggested that methotrexate could find application for the prevention and/or for the treatment of viral infections .
  • MTX has shown high efficacy in inhibiting viral reproduction, with negligible effects on host cell viability.
  • the inhibition of viral replication occurs at a concentration of mM, which is significantly lower, reduced by about one to two orders of magnitude, compared to the cytotoxic dose in the host cell.
  • methotrexate has shown to provide an antiviral effect both in the pharmaceutical and in the veterinary field. Thus, it can be administered both to a human or to an animal in need thereof at the earliest appearance of symptoms .
  • methotrexate can be administered in a prophylaxis treatment when an epidemic is diffusing and widespreading, so to effectively prevent viral replication and diffusion of the infection.
  • methotrexate is effective towards both DNA and RNA viruses, it is expected that it is also effective against most of the DNA and RNA viruses.
  • Methotrexate is commercially largely available and it is not expensive, thereby it may represent a socially convenient pan-viral medicament.

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Abstract

La présente invention concerne l'utilisation de méthotrexate en tant que médicament dans le traitement pharmaceutique ou vétérinaire d'infections virales provoquées par des virus d'ADN ou d'ARN chez l'homme ou l'animal, sous réserve que le virus de l'ARN du SARS-Cov-2 et le virus de l'ARN ZIKA soient exclus de la prévention et/ou du traitement pharmaceutique chez l'homme.
PCT/IB2021/054558 2020-05-26 2021-05-26 Méthotrexate destiné à être utilisé dans la prévention et/ou le traitement pharmaceutique ou vétérinaire d'infections virales WO2021240375A1 (fr)

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IT102020000012325A IT202000012325A1 (it) 2020-05-26 2020-05-26 Metotrexato per l’uso nel trattamento di infezioni virali in animali da allevamento
IT102020000012325 2020-05-26
IT102020000012343 2020-05-26
IT102020000012343A IT202000012343A1 (it) 2020-05-26 2020-05-26 Metotrexato per l’uso nel trattamento farmaceutico di infezioni virali del tratto respiratorio

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WO1993018776A1 (fr) * 1992-03-16 1993-09-30 Chiesi Farmaceutici S.P.A. Combinaisons de composes a activite antivirale
US20050049220A1 (en) * 2003-08-18 2005-03-03 Stuyver Lieven J. Dosing regimen for Flaviviridae therapy
WO2016077282A1 (fr) * 2014-11-13 2016-05-19 Eli Lilly And Company Effets antiviraux du narasin dans de la nourriture pour porcs
EP3246024A1 (fr) * 2015-01-17 2017-11-22 Genifarm Laboratories Inc Utilisation de taurine pour la prévention et/ou le traitement de maladies virales à coronavirus et/ou rotavirus
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WO1993018776A1 (fr) * 1992-03-16 1993-09-30 Chiesi Farmaceutici S.P.A. Combinaisons de composes a activite antivirale
US20050049220A1 (en) * 2003-08-18 2005-03-03 Stuyver Lieven J. Dosing regimen for Flaviviridae therapy
WO2016077282A1 (fr) * 2014-11-13 2016-05-19 Eli Lilly And Company Effets antiviraux du narasin dans de la nourriture pour porcs
EP3246024A1 (fr) * 2015-01-17 2017-11-22 Genifarm Laboratories Inc Utilisation de taurine pour la prévention et/ou le traitement de maladies virales à coronavirus et/ou rotavirus
WO2019220453A1 (fr) * 2018-05-15 2019-11-21 National Centre For Cell Science Composés médicamenteux antiviraux et composition associée

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CARUSO ARNALDO ET AL: "Methotrexate inhibits SARS-CoV-2 virus replication "in vitro"", JOURNAL OF MEDICAL VIROLOGY, vol. 93, no. 3, 1 March 2021 (2021-03-01), US, pages 1780 - 1785, XP055819965, ISSN: 0146-6615, DOI: 10.1002/jmv.26512 *
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