CN101340902B - Materials and methods for treating viral infections with a cysteamine compound - Google Patents
Materials and methods for treating viral infections with a cysteamine compound Download PDFInfo
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- CN101340902B CN101340902B CN2006800443056A CN200680044305A CN101340902B CN 101340902 B CN101340902 B CN 101340902B CN 2006800443056 A CN2006800443056 A CN 2006800443056A CN 200680044305 A CN200680044305 A CN 200680044305A CN 101340902 B CN101340902 B CN 101340902B
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Abstract
The subject invention provides materials and methods for treating various health conditions, including the prevention and/or treatment of a viral infection. In a preferred embodiment, a cysteamine compound is administered to a subject to treat an influenza virus infection. More preferably, a cysteamine compound is administered to a subject to treat influenza A, influenza B, influenza C virus infections, including avian influenza virus subtypes (such as H5N1 avian influenza virus).
Description
The cross reference of related application
The application requires U.S. Provisional Application sequence number 60/740,584 (submissions on November 28th, 2005), sequence number 60/810,773 (submissions on June 2nd, 2006), sequence number 60/818,885 (submission on July 6th, 2006) and sequence numbers 60/847, the rights and interests of 020 (2006 on JIUYUE 25, submit to), more than all these comprise that its any accompanying drawing and/or form all incorporate into herein by reference.
Background technology
Virus is a kind of little parasite of being made up of the nucleic acid (RNA or DNA) that is wrapped in the protein coat.Virus only can and guide the more viruses of host cell systems generation to duplicate by infecting the susceptible host cell.Glycoprotein (being arranged in protein coat) mediation virus is to the absorption and the intrusion of susceptible host cell.
Generation approach based on nucleic acid type that forms between replicative phase and mRNA is divided into big class with most of viruses.Usually, as its hereditary material, its amplifying nucleic acid can be strand or two strands to virus with RNA or DNA.
Important DNA type Viraceae (also be divided into I class and II viroid---referring to Harvey, L.et al.,
Molecular Cell BiologyFourth Edition, W.H.Freeman andCompany (2000)) comprises Adenoviridae (adenoviridae), herpetoviridae (herpesviridae), Poxviridae (poxviridae), papovaviridae (papovaviridae), densovirus subfamily (densovirinae) and parvovirus subfamily (parvovirinae).Typical R NA type Viraceae (also be categorized as the III-VI class, referring to
Molecular Cell Biology) comprise birnavirus section (birnaviridae), Reoviridae (reoviridae), Astroviridae (astoviridae), Arterivirus (arterivirus), Caliciviridae (caliciviridae), coronaviridae (coronaviridae), flaviviridae (flaviviridae), Picornaviridae (picornaviridae), Togaviridae (togaviridae), poliovirus (polioviruses), that Viraceae of glass (bornaviridae), filamentous virus section (filoviridae), paramyxovirus subfamily (paramyxovirinae), pneumonitis virus subfamily (pneumovirinae), Rhabdoviridae (rhabdoviridae), bunyaviridae (bunyaviridae) and orthomyxoviridae family (orthomyxoviridae).
Influenza is also referred to as " influenza " usually, is a kind of infectious disease that is caused by influenza virus, and influenza virus belongs to orthomyxoviridae family.Known have 3 kinds to infect human influenza virus type: first, second, influenza virus C.Except that the mankind, also from multiple animal species, isolate influenza A virus, and found that second and influenza virus C mainly infect the mankind.
Influenza virus is the enveloped virus that contains the minus strand single stranded RNA, wherein RNA be merogenesis and wrapped up by capsid.The feature of influenza virus peplos is to have two kinds of surface glycoproteins: hemagglutinin and neuraminidase.First type and Influenza B virus are pantomorphic, and typically have a diameter from 80-120nm.The influenza virus C particle has multiple remarkable characteristic, thereby is different from first and the B virus particle that is closely related.
Influenza viruse attack human respiratory (that is: nose, larynx and lung).For example, infect the acute respiratory disease that first type or influenza B often cause hyperinfection.Influenza infection generally includes following symptom: heating, headache, tired (can be extremely), dry cough, laryngalgia, nasal obstruction and physical distress.
According to estimates in the U.S. resident of 10-20% of the annual millions of people of the U.S.-approximately-suffer from influenza.Major part gets final product rehabilitation at 1-2 in week usually among this crowd.Yet in some cases, influenza infection can lead to complications.Suffering from the highest crowd of influenza complication risk comprises: the age surpasses 50 years old people, 6 to 23 months child, conceived women more than 3 months, the people who lives in long-term care facility or mechanism, the people who suffers from the chronic heart, lung or nephropathy, diabetes or immune system fragility.Pneumonia, bronchitis, encephalitis, otitis media, rhinitis and sinusitis only are the several examples in the complication that causes of influenza infection.And influenza can make chronic health problem more serious.For example, the people who suffers from asthma can suffer asthma attack when catching a cold, and suffers from the people of chronic heart failure because exciting of influenza can make worse off.
In the U.S., there are about 36,000 people to die from influenza every year on average, annual 114,000 people are in hospital because of influenza.Therefore, influenza virus has a significant impact the sickness rate that causes hospitalization and outpatient service amount to increase.For example, usually observe a high proportion of hospitalization greater than 65 years old object and age in less than 5 years old child at the age.
In addition, the propagation of influenza virus in the crowd can cause epidemic diseases, can cause significant impact to economy.During influenza pandemic in 1957,1968 and 1977, because influenza infection causes a high proportion of mortality rate (Volume 1 for Fields Virology, Second Edition, pp.1075-1152 (1990)).Influenza virus periodically causes worldwide popular.For example, the flu outbreak that it is reported 1918 causes the about 2,000 ten thousand people's death in the whole world, wherein dead about 500,000 people of the U.S. (
Medical Microbiology, Fourth Edition, University of Texas MedicalBranch at Galveston (1996)).
Influenza virus mainly is (also the claiming droplet transmission) that the respiratory tract spittle that sprays during between men by cough and/or sneeze is propagated.Influenza virus in the respiratory tract spittle can suspend in air 3 hours; But to thermo-responsive and more than 50 ℃ the time rapid deactivation.Virus can be survived 24-48 hour at hard pore-free surface (that is: telephone receiver, computor-keyboard, door handle, kitchen countertops, toy); Survived 8 hours at cloth, paper and tissue; Survive 5 minutes on hand (referring to Muir, P, " Treatment of Influenza.Essential CPE.Continuing Education from the Pharmaceutical Society of Australia, " Paragon Printers, Australasia, ACT (2002)).Typical circulation way comprise with the mucosa of the infectiousness anemophily respiratory tract spittle contact, contact contacts with pollutant (that is: the tissue of infected nose and larynx ejection pollution) between individuality.
Can pass through respiratory tract droplet transmission influenza virus the previous day that occurs the influenza related symptoms as far back as individuality.Symptom is first occur after, the adult can after 3 to 7 days in continuation to other people transmitted virus.Different with the adult, the child can surpass transmitted virus in 7 days longer time.Usually after virus enters 1 to 4 day of body symptom appears.Under some situation, individual infective virus does not but show symptom.During this period, these crowds still can give other people with virus disseminating.
Seldom have method to infect by flu-prevention, its Therapeutic Method also still remains to be developed.The method that flu-prevention infects comprises vaccination and antiviral therapy.Ratify three kinds of antiviral drugs (amantadine, rimantadine and Oseltamivir (oseltamivir)) and commercial offers in the U.S. and be used for prevention or treatment influenza virus disease.Yet these chemical compounds are the most effective when being used to prevent, and this can make the rapid resistance that obtains all these chemical compounds of influenza virus.Referring to U.S. Patent No. 3,352,912 and 3,152,180.It is reported that other chemical compounds with anti-influenza virus activity have been disclosed in U.S. Patent No. 6,271,373; 5,935,957; 5,821,243; 5,684,024; 3,592,934; 3,538,160; 3,534,084; 3,496,228 and 3,483,254.
New treatment to the treatment virus disease has very big demand.On the Therapeutic Method of treatment bacterial infection, obtained huge progress, yet the feasible Therapeutic Method of treatment virus is less.As mentioned above, antiviral drugs and vaccine are the main method that prevents and/or treats influenza infection.Ganciclovir, acyclovir and foscarnet sodium (foscarnet) are used for the treatment of herpesvirus infection at present.Yet,, thereby significant side effects is arranged because that these Therapeutic Method duplicate host cell DNA is harmful or only effective to limited viral infection.In addition, virus as can be known as implied above can produce resistance to treatment, thereby causes therapeutic efficiency to descend gradually.
So far, still do not have the report cysteamine compound and can be used for treating viral infection.
Summary of the invention
The invention provides the material and the method that are used for the treatment of the object that is diagnosed with viral infection and prophylaxis of viral infections outbreak.In one embodiment, the invention provides and be used for the treatment of viral related indication method.In another embodiment, the invention provides the method that is used to prevent or delay viral related complication generation.
Therefore, the present invention by use to object cysteamine compound provide treat and/or prevent I to V viroid infect (referring to Lodish, H.et al., Molecular Cell Biology, FourthEdition, W.H.Freeman and Company (2000)).More specifically, the invention provides the method that is used for the treatment of and/or prevents the infection of I to V viroid, alleviate the relevant symptom of I to V viroid infection and prevent or delay the generation of I to V viroid infection-related complication.
Treat and/or prevent the viral infection that causes by following type virus by using cysteamine compound disclosed herein.Described virus comprises double-stranded DNA (dsDNA), single stranded DNA (ssDNA), double-stranded geneome RNA (dsRNA), strand positive chain RNA and minus-strand RNA virus, is such as but not limited to influenza virus, adenovirus, herpesvirus, human papillomavirus, parvovirus, reovirus, picornavirus, coronavirus, banzi virus, togavirus, influenza virus, Bu Niya disease, rhabdovirus and paramyxovirus.
The present invention especially can be applicable to humans and animals health, especially infects the animal that the I-V viroid is arranged.For example, virus tabulation and associated diseases to the common following indefiniteness of non-human mammal can treat and/or prevent with the present invention: 2 porcine circovirus, picornavirus, influenza virus, coronavirus, togavirus, paramyxovirus, rhabdovirus and reovirus comprise its any mutant.
Concrete illustrationally be to use cysteamine compound to be used for the treatment of and/or the flu-prevention viral infection herein.According to the present invention, before influenza virus infection, use cysteamine compound and can help object of protection to avoid influenza infection, or guarantee that at least the degree that the influenza virus disease related symptom takes place compares when not using cysteamine compound littler to object.
In another embodiment, use cysteamine compound and prevent and/or delay having excessive risk to suffer from these complication of generation in the object of influenza related complication.For example, according to the present invention, by using cysteamine compound can reduce the influenza related complication, such as encephalitis, bronchitis, tracheitis, myositis, rhinitis, sinusitis, asthma, bacterial infection (that is: golden yellow streptococcus (Streptococcus aureus) bacterial infection, hemophilus influenza (haemophilusinfluenzae) bacterial infection, pneumonia staphylococcus (staphylococcal pneumonia) bacterial infection), cardiac complication (that is: quiver by the atrium, myocarditis, pericarditis), the Lei Er Cotard (Reye ' sSyndrome), neurological complication (that is: mental disorder, faint from fear, psychosis, the neuritis, the Guillain-Barre syndrome, stupor, transection myelitis, encephalitis, encephalomyelitis), toxic shock syndrome, myositis, myoglobinuria and renal failure, croup, otitis media, viral infection (being viral pneumonia), pulmonary fibrosis, bronchiolitis obliterans, bronchiectasis, asthma increases the weight of, chronic obstructive pulmonary disease increases the weight of, lung abscess, empyema, pulmonary aspergillosis, myositis and myosin mass formed by blood stasis, heart failure, anemia of pregnant woman's early stage and foetal death in late period, birth defect when increase of anemia of pregnant woman's perinatal mortality and birth.
In another embodiment of the invention, object from influenza infection to diagnosis that suffer from is used cysteamine compound and is alleviated the influenza related symptoms.Cysteamine compound both can be used separately, also can with other known being used for the treatment of/flu-prevention virus disease (that is: vaccination, antiviral drugs) or treatment influenza related symptoms (that is: antitussive, mucolytic and/or expectorant; Antipyretic analgesic and nose decongestant) medicament use simultaneously.
In one embodiment, use separately or use cysteamine compound simultaneously with the medicament of other known being used for the treatment of/prophylaxis of viral infections.Preferably, before the contact influenza virus, among or use cysteamine compound of the present invention and known being used for the treatment of/flu-prevention virus disease (that is: vaccine, antiviral drugs) or treatment influenza related symptoms (that is: antitussive, mucolytic and/or expectorant simultaneously to object afterwards; Antipyretic analgesic and nose decongestant) medicament.
In a related embodiment, use separately or with other known are used for the treatment of and/or medicament that birds flu-preventing virus (AIV) infects is used cysteamine compound simultaneously.According to the present invention, can or orally use described cysteamine compound to object and treat and/or prevent AIV and infect by injection.
Preferably, use separately or with other known are used for the treatment of and/or the medicament of the various hypotypes of birds flu-preventing virus is used cysteamine compound simultaneously.More preferably, use separately or knownly be used for the treatment of and/or prevent the medicament of H5N1 AIV to use cysteamine compound of the present invention simultaneously with other.Can use 0.1mg/mL cysteamine hydrochloride at least, more preferably 1mg/mL cysteamine hydrochloride even more preferably any AIV hypotype of listing above treating and/or preventing of the dosage of 2mg/mL cysteamine hydrochloride at least at least to object, preferred H5N1 type AIV infects.
In some preferred embodiment, the dosage that treats and/or prevents the cysteamine hydrochloride of being used in the H5N1 type AIV infection is relevant with the concentration of virus in the object.More preferably, it is relevant with the initial concentration that is approximately LD50 to treat and/or prevent the dosage of the cysteamine hydrochloride that H5N1 type AIV used in infecting.
According to the present invention, using the daily dose that cysteamine compound comes object of protection to avoid viral infection to object before viral infection can be about 10mg to 3000mg.The preferred cysteamine compound of using about 50mg to 1500mg every day.In a preferred embodiment, use the outbreak that the cysteamine hydrochloride of about 200mg to 900mg comes preventing/treating influenza (as bird flu virus, influenza A virus, Influenza B virus and influenza virus C or its any mutant) virus disease every day to object.
According to the present invention, in case the symptom relevant with viral infection occur, then daily dose from cysteamine compound to object that use can be about 10mg to 3000mg.Preferably, use the cysteamine compound of about 200mg to 1500mg every day.In a preferred embodiment, cysteamine hydrochloride from every day to object that use about 450mg to 900mg is treated and/or is alleviated influenza (as bird flu virus, influenza A virus, Influenza B virus and influenza virus C or its any mutant) the related indication order of severity of virus disease.
According to the present invention, the daily dose of the cysteamine compound of using to the object of the risk that ill malicious infection-related complication is arranged is about 10mg to 3000mg.Preferably, use the cysteamine compound of about 200mg to 1500mg every day.In a preferred embodiment, cysteamine hydrochloride from every day to object that use about 450mg to 900mg prevents and/or delays the outbreak of influenza (as bird flu virus, influenza A virus, Influenza B virus and influenza virus C or its any mutant) virus disease related complication.
Description of drawings
Fig. 1 represents the cysteamine as the coenzyme A component.
Fig. 2 represents the metabolic pathway of cysteamine.
The specific embodiment
The invention provides the material and the method that are used for the treatment of viral infection.Particularly, the invention provides material and the method that is used for following situation: prevention I-V viroid infects; Treatment/improvement is infected relevant symptom with the I-V viroid; And/or prevent/delay the outbreak of I-V viroid infection-related complication.In some preferred embodiments, the invention provides the method that is used for following situation: symptom that flu-prevention infects, treatment/improvement is relevant with influenza infection and the outbreak that prevents/delay the influenza infection related complication at high-risk patient.
Term used herein " symptom " indicated object is suffered from the common sign or the sign of particular condition or disease.For example, viral infection related symptoms described herein represents to infect common sign or the sign in the object that the I-V viroid is arranged.The influenza related symptoms of herein mentioning include but not limited to heating, headache, tired/weak, myalgia, joint aches, zest shed tears (irritated wateringeye), uncomfortable (malaise), feel sick and/or vomiting, shiver with cold, chest pain, sneeze and respiratory symptom (that is: scorching hot under respiratory mucosa inflammation, the breastbone, rhinorrhea, throat be hoarse/pain, dry cough, hyposmia).
According to the present invention, after infection, the influenza infection related symptoms can occur in 24 to 48 hours and can break out.Shiver with cold or sensation cold often are the initial signs of influenza.Usually can generate heat in the middle of several leading day, temperature can reach 102 ℉ to 103 ℉.Under a lot of situations, object is felt very uncomfortable bed many days that need; The common whole body pain of object, the back of the body and shank are the most remarkable.
To be illustrated in what take place during the disease or the patient's condition be not the pathological process or the incident of necessity part of the disease or the patient's condition to term " complication " as used herein; Both can cause also that reason can be arranged in addition by disease/patient's condition.Therefore, the term complication is illustrated in and diagnoses observed medical science/clinical problem in the object that the infection of I-V viroid is arranged.A complication of influenza infection is that influenza infection can increase the weight of chronic health problem.For example, relevant with viral infection complication includes but not limited to: encephalitis, bronchitis, tracheitis, myositis, rhinitis, sinusitis, asthma, bacterial infection (that is: golden yellow streptococcus (Streptococcus aureus) bacterial infection, hemophilus influenza (haemophilus influenzae) bacterial infection, pneumonia staphylococcus (staphylococcalpneumonia) bacterial infection), cardiac complication (that is: quiver by the atrium, myocarditis, pericarditis), Lei Er Cotard (Reye ' s Syndrome), neurological complication (that is: mental disorder, faint from fear, psychosis, the neuritis, the Guillain-Barre syndrome, stupor, transection myelitis, encephalitis, encephalomyelitis), toxic shock syndrome, myositis, myoglobinuria and renal failure, croup, otitis media, viral infection (being viral pneumonia), pulmonary fibrosis, bronchiolitis obliterans, bronchiectasis, asthma increases the weight of, chronic obstructive pulmonary disease increases the weight of, lung abscess, empyema, pulmonary aspergillosis, myositis and myosin mass formed by blood stasis, heart failure, anemia of pregnant woman's early stage and foetal death in late period, birth defect when increase of anemia of pregnant woman's perinatal mortality and birth.
Term " influenza ", " influenza virus " or " influenza " are represented the RNA viruses of orthomyxoviridae family as used herein, and it comprises first type, B-mode and influenza virus C and mutant thereof.Influenza virus described herein is included in the virus that there is two kinds of antigenicity glycosylases (neuraminidase and hemagglutinin) on its surface.Can include but not limited to H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7 hypotype with the various hypotypes of the influenza virus of material of the present invention and method treatment, comprise the hypotype of following being commonly referred to as " spanish influenza ", " Asia influenza ", " Mao flu ", " bird flu ", " swine flue ", " equine influenza " and " dog influenza ".
Term used herein " object " is described a kind of utilization compositions according to the present invention to its biology that treatment is provided, and comprises people and mammal.The mammalian species of benefiting from the disclosed Therapeutic Method of the present invention includes but not limited to that ape, chimpanzee, orangutan, people, monkey and domestic animal (being house pet) are as dog, cat, mice, rat, Cavia porcellus, pig and hamster.
Term used herein " is used simultaneously " and is comprised that using the chemical compound or the Therapeutic Method that are suitable for using together with the inventive method (using cysteamine compound) is used for the treatment of the infection of I-V viroid or is used for the treatment of the relevant symptom/complication of I-V viroid infection.
For diagnosis the object of influenza infection is arranged, cysteamine compound can be used simultaneously with vaccine, antiviral drugs, antitussive, mucolytic and/or expectorant, antipyretic analgesic and nose decongestant.For example, chemical compound can mix mutually with cysteamine compound to be provided, as in pharmaceutical composition; Perhaps the chemical compound that can be used as separately of chemical compound and cysteamine provides, for example successively, simultaneously or the independently pharmaceutical composition of using at different time.Preferably, if separate administration cysteamine compound and being used for the treatment of/flu-prevention infects and/or the known pharmaceutical agents (or Therapeutic Method) of treatment influenza related symptoms/complication, use their time and separate not farly, in order to avoid cysteamine compound and described known agent (method) can not interact.
In certain embodiments of the invention, cysteamine compound can be simultaneously and following medicine (but being not limited thereto) use together: vaccine, antiviral drugs such as amantadine, rimantadine, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, foscarnet sodium, zidovudine, didanosine, zalcitabine, stavudine, famciclovir, Oseltamivir and valaciclovir (material and/or the method that are used for the treatment of viral infection); Or antitussive, mucolytic and/or expectorant; Antipyretic analgesic and nose decongestant (being used for the treatment of the related indication material of influenza infection).
As an example, can mix mutually with described cysteamine compound with chemical compound that cysteamine compound of the present invention uses together provides, such as in pharmaceutical composition.As an alternative, described chemical compound and cysteamine can be used as independently that chemical compound provides, for example successively, simultaneously or the independently pharmaceutical composition of using at different time.Preferably, if the described cysteamine compound of separate administration and being used for the treatment of/flu-prevention infects and/or the known pharmaceutical agents (or Therapeutic Method) of treatment influenza related symptoms/complication, use their time and separate not farly, in order to avoid cysteamine compound and described known agent (method) can not interact.
As used herein, " cysteamine compound " comprise cysteamine, various cysteamine salt (officinal salt that comprises cysteamine compound) and can be for example easily in vivo metabolism produce the cysteamine prodrug of cysteamine.Analog, derivant, conjugate and the metabolic precursor thereof (as cysteine, cystamine, pantoyl cysteamine etc.) and the metabolite (as taurine, hypotaurine etc.) that also comprise cysteamine within the scope of the invention, they are as described herein, and have the ability stress (stress) and stress related symptoms/complication by reducing cortisol levels and improving that immunocompetence treats and/or prevents.Those skilled in the art are familiar with and use various cysteamine analog, derivant, conjugate and metabolite easily, and for example they comprise U.S. Patent No. 6,521, and 266,6,468,522,5,714, chemical compound, compositions and the delivering method mentioned in 519 and 5,554,655.
As described here, cysteamine compound comprises pantothenic acid.Pantothenic acid is naturally occurring vitamin, and it is converted into coenzyme A in mammal, and coenzyme A is the necessary materials of a lot of physiological reactions.Cysteamine is the component of coenzyme A, and the level of cysteamine increased during the increasing of coenzyme A level caused circulating.Alkali metal salt such as magnesium phosphate and magnesium sulfite (Epsom salts) strengthen the formation of coenzyme A.In addition, coenzyme A is degraded to cysteamine and is strengthened owing to the existence of Reducing agent such as citric acid.Therefore, the combination of pantothenic acid and alkali metal salt causes the generation of coenzyme A to increase, and has also increased the generation of cysteamine simultaneously.
Term used herein " officinal salt " expression is pharmaceutically useful and significantly do not reduce or suppress any salt of the active cysteamine compound of cysteamine compound.Suitable example comprises the acid-addition salts with organic or inorganic acid, such as acetate, tartrate, trifluoroacetate, lactate, maleate, fumarate, citrate, mesylate, sulfate, phosphate, nitrate or chloride.
Therefore, in one embodiment of the invention, as described here, can promote endogenous to produce the advantage that cysteamine is realized cysteamine such as the effect by coenzyme A or as the precursor and/or the metabolite (referring to Fig. 1 and 2) of cysteine by the natural metabolism process.For example, this can realize by using pantothenic acid.
Term used herein " effective dose " expression causes the necessary amount of biological respinse of expectation.According to the present invention, the effective dose of cysteamine compound is following necessary amount: treatment/prevention I-V viroid infects; Treat/improve the I-V viroid and infect relevant symptom; And/or prevent/delay/improve the outbreak of I-V viroid infection-related complication.In a preferred embodiment, the effective dose of cysteamine compound is following necessary amount: treatment/flu-prevention infects; Treat/improve the relevant symptom of influenza infection; And/or in suffering from the high patient of influenza infection related complication risk, prevent/delay/improve the outbreak of complication.The improvement of the symptom and/or the complication order of severity can be that the order of severity reduces by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%.
As used herein, term " I-V viroid " expression is formed dissimilar virus fixed and that the mRNA synthesis strategy is divided by genome, for example referring to Lodish, and H.et al.,
Molecular Cell Biology, Fourth Edition, W.H.Freeman and Company (2000).The I-V viroid is as follows:
-I viroid contains the double-stranded DNA of a part;
-II viroid contains the single stranded DNA of a part;
-III viroid contains double-stranded geneome RNA;
-IV viroid contains the virus mRNA (being also referred to as positive strand genomic rna) of a chain, wherein virus mRNA coded protein and himself have infectivity; And
-V viroid contain one with the complementary single stranded RNA sequence of genomic viral mRNA (being also referred to as negative strand gene group RNA), wherein geneome RNA is as the template of synthetic mRNA, but himself coded protein not.
The invention provides by use cysteamine compound to object and treat and/or prevent material and the method that the I-V viroid infects.Treat and/or prevent the viral infection that is caused by following type virus by using cysteamine compound disclosed herein.Described virus comprises double-stranded DNA (dsDNA), single stranded DNA (ssDNA), double-stranded geneome RNA (dsRNA), strand positive chain RNA and minus-strand RNA virus.The virus that can treat according to the present invention that is contained includes but not limited to arbovirus (including but not limited to dengue virus, yellow fever etc.); Adenovirus (including but not limited to acute respiratory disease, pneumonia, conjunctivitis, gastroenteritis, pharyngitis, acute hemorrhagic cystitis, African swine fever, pig circular ring virus, first, the second and the third type porcine adenovirus); Herpesvirus (including but not limited to herpes simplex virus, varicella zoster virus (chickenpox and herpes zoster), Epstein-Barr virus); Human papillomavirus's (including but not limited to HPV 1-65 type); Parvovirus (including but not limited to assays for parvovirus B 19, Canine Parvovirus); Reovirus (including but not limited to ring-type, rotavirus, aquatic reovirus, colti virus); Picornavirus (including but not limited to enterovirus, rhinovirus, hepatovirus (hepatovirus)); Coronavirus (including but not limited to coronavirus and curved virus (torovirus)); Banzi virus (including but not limited to Pestivirus (petsivirus), hepatitis C sample Tobamovirus (hepatitis C-like virus)); Togavirus (including but not limited to Alphavirus and rubella virus); Influenza virus (including but not limited to first, second and influenza virus C, bird flu virus, Thotogo virus); Bunyavirus (including but not limited to Hantaan virus, Nairovirus (Nairovirus), Phlebovirus); Rhabdovirus (include but not limited to rabies virus, fever virus (Ephemerovirus), vesicle virus (vesiculovirus)) in short-term; And paramyxovirus (including but not limited to Measles virus and mumps virus).
The present invention is particularly useful for the health of inhuman object, and the inhuman object of I-V viroid is arranged especially for infection.For example, the common patient's condition in the virus of following indefiniteness tabulation and the inhuman object that caused can treat and/or prevent with the present invention: picornavirus (avian encephalomyelitis, duck liver inflammation and Ka Lixi virus (Calicivirus) (cat) infect); Influenza virus (fowl plague and bird flu (H5N1)); Coronavirus (canine coronavirus in the infectious bronchitis in the poultry and coronavirus enteritis and the Canis familiaris L.); Togavirus (pheasant encephalitis); Paramyxovirus (Avian pneumo-encephalitis virus in the poultry and canine distemper in the dog and parainfluenza); Rhabdovirus (viral hemorrhagic diseases in rabies and the Fish) and reovirus (tame poultry infectious bursal disease).
For human subjects, the present invention is particularly useful for treating and/or preventing influenza infection, especially avian influenza.According to the present invention, cysteamine compound can be used for treating and/or preventing various bird flu strains, comprises H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7 subtype virus.In one embodiment of the invention, use cysteamine hydrochloride to object (human or animal) and treat and/or prevent H5N1 type avian influenza.Can use the known pharmaceutical agents that cysteamine hydrochloride also can be used for the treatment of with other and/or flu-prevention infects separately uses simultaneously.
In a related embodiment, use separately or use cysteamine compound (example hydrochloric acid cysteamine) simultaneously with other known agent that are used for the treatment of and/or birds flu-preventing virus (AIV) infects.Can or orally use described cysteamine compound by injection to object.
Preferably, use at least the cysteamine hydrochloride of 0.1mg/mL dosage to object and treat and/or prevent H5N1 type AIV and infect, the more preferably cysteamine hydrochloride of 1mg/mL at least, even the more preferably cysteamine hydrochloride of 2mg/mL at least.
In some preferred embodiment, it is relevant to treat and/or prevent the virus concentration that exists in dosage that AIV infects the cysteamine hydrochloride that (virus that comprises H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7 hypotype) used and the object.More preferably, it is relevant to treat and/or prevent the virus concentration that is approximately LD50 that exists in dosage that H5N1 type AIV infects the cysteamine hydrochloride used and the object.
Compositions of the present invention can be used by number of ways, for example comprises Orally administered form, such as tablet, capsule etc. or by parenteral, intravenous, intramuscular, transdermal, oral cavity, subcutaneous, suppository or other approach.These compositionss are referred to as " pharmaceutical composition " herein.Usually, they can be and one or more other medicinal ingredients unit dosage form that is the diluent or carrier coupling, described unit dosage form is also promptly: be suitable for the discrete unit of physics that makes the human dosage unit, each unit contains the active component of scheduled volume, and it can produce desired therapeutic effect as calculated.
Cysteamine compound of the present invention can be prepared by the known method that is used to prepare Pharmaceutical composition.The resource that has a lot of those skilled in the art to know and be easy to obtain is described dosage form.For example, Remington ' s Pharmaceutical Science (Martin EW[1995] Easton Pennsylvania, Mack Publishing Company, 19th ed.) has described and can be used for dosage form of the present invention.The dosage form that is applicable to parenteral administration for example comprises the aseptic injection aqueous solution, and it can contain antioxidant, buffer agent, antibacterial and solute, makes the blood etc. of this dosage form and target recipient ooze; And sterilized water and non-aqueous suspensions, this can comprise suspending agent and thickening agent.Described dosage form can provide in unit dose or multi-dose container, for example Mi Feng ampoule and bottle, and can preserve in lyophilization (lyophilizing) condition, this need face with for example condition of water for injection of sterile liquid carrier is before arranged.Instant injection solution and suspension can be from preparations such as sterilized powder, granule, tablets.Should know, except the above composition of specifically mentioning, dosage form of the present invention can comprise other reagent commonly used in the relevant preparation type field.
The described dosage form that contains cysteamine compound comprises the dosage form that is applicable to that oral, rectum, nose, part (comprising oral cavity and Sublingual), vagina, parenteral (comprising subcutaneous, intramuscular, intravenous, Intradermal, intrathoracic and exterior dura) are used and eyes are used.Described dosage form can provide with unit dosage form easily and can prepare by the known any method of pharmaceutical field.These methods comprise the step that described cysteamine compound is combined with the carriers that constitute one or more kind auxiliary elements.Usually by prepare described dosage form to get off: evenly closely described cysteamine compound is combined with liquid-carrier or the accurate solid carrier that separates or both, then, make product shaping in case of necessity.In certain embodiments, described cysteamine compound can be provided with the dosage form that is used for skin patch.
According to the present invention, can any suitable method and technology present by those skilled in the art or that expection is understood use cysteamine compound.In a preferred embodiment, cysteamine compound is mixed with patentability and wieldy peroral dosage form, such as pill, lozenge, tablet, colloid (gum), beverage etc.The experience stress event at that time, before or after and/or when the needs enhance immunity is active (that is: after diagnosis suffers from influenza infection) use described dosage form.
According to the present invention, compositions comprises as the cysteamine of the effective dose of active component and one or more plants non-toxic pharmaceutical carrier or diluent.The example that is used for these carriers of the present invention comprises ethanol, dimethyl sulfoxine, glycerol, silica gel, aluminium oxide, starch, sorbitol, inositol, xylitol, D-xylose, mannitol, Powderd cellulose, microcrystalline Cellulose, Pulvis Talci, silica sol, calcium carbonate, magnesium carbonate, calcium phosphate, calcium aluminium silicate, aluminium hydroxide, sodium starch phosphate, lecithin and carrier that is equal to and diluent.
In order to provide these dosage to be applied to desired therapeutic, compositions of the present invention accounts for about 0.1% to 95% of total composition (comprising carrier or diluent) usually.Used dosage can change according to age, body weight, health or the sex of individuality to be treated.
In one embodiment, be about 10mg every day about 3000mg extremely for the dosage that causes the cysteamine that expected response uses to the patient.The reaction of expectation can comprise that (1) prevention I-V viroid infects; Preferred influenza infection; (2) reduce the I-V class and infect the related indication order of severity, duration or intensity, preferred influenza infection related symptoms; And the order of severity, duration or the intensity of I-V viroid infection-related complication, influenza infection related complication are prevented, delay or reduced in (3).Preferably, the cysteamine hydrochloride of using about 50mg to 1000mg every day causes the reaction of expectation.In a preferred embodiment, the dosage of the cysteamine hydrochloride of using to the patient for the reaction that causes expectation is about 200mg to 900mg every day.
Following is the embodiment that illustrates the process of implementing the present invention.These embodiment shall not be understood as limiting.Unless otherwise, all percentage ratios are by weight calculation, and the ratio of all solvent mixtures is according to volume calculation.
Embodiment
The related indication treatment of embodiment 1-influenza
The male of an influenza virus infection presents influenza infection related symptoms (watery nasal discharge, fever, tired), earlier with OTC (over-the-counter) nose decongestant and mucolytic treatment.In 24 hours, described nonprescription drugs is invalid for treatment influenza related symptoms.
Nonprescription drugs be proved to be invalid after, to the cysteamine hydrochloride of the about 700mg of the Orally administered dosage of this object.In 24 hours, the influenza infection related symptoms disappears.This Object table reveals common health sensation.
Embodiment 2-cysteamine is to the research of the antiviral activity of H5N1 bird flu virus: use phosphoric acid
Research in the Oseltamivir external and body in contrast
According to one embodiment of the invention, cysteamine shows the antiviral activity of anti-H5N1 type bird flu virus.Because to the unpredictable consequence of bird flu virus, theme of the present invention is particularly advantageous.For example, as described below, cysteamine is particularly effective when treatment H5N1 type bird flu virus, even (its adopted name is an oseltamivir phosphate capsule than anti-avian influenza virus registration medicine phosphoric acid Ao Sitawei
(TAMIFLU
)) not bad a lot.
Material and method
Cysteamine (to call " TG21 " in the following text, containing 99% cysteamine) is provided by Omega Bio-Pharma (H.K.) Limited.The Embryo Gallus domesticus ovum (BeiJing, China) from specific pathogen free (SPF) hen is used in this experiment.H5N1 type bird flu virus CV strain separates acquisition from infected chicken.Luo Man chicken (Roman chicken) is available from Hebei, without the avian influenza vaccine immunity.As described here, used oseltamivir phosphate capsule
(Chinese Shanghai, Luo Shi (China) company limited).
Estimate the toxicity of TG21 in the Embryo Gallus domesticus ovum
With the TG21 of 1g be dissolved in 10mL (1: 10) 0.01mol/L pH be among 7.2 the PBS (1: 10,10mg/mL), through 2 times of serial dilutions, be diluted to 1: 5120 then from 1: 10.To dilute the fine hair allantoic cavity that back medicine (test group) or PBS buffer (matched group) are expelled to instar chicken embryo ovum on the 10th, each dilution factor has 5 ovum.Ovum is 37 ℃ of hatchings and monitor twice every day, continues 5 days, observes embryo survival and calculates LD50 (50% fatal dose of virus).
In the Embryo Gallus domesticus ovum, estimate the EID50 of H5N1 type bird flu
The original preservation thing of bird flu virus CV strain uses the PBS of 0.01M pH7.2 from 10
-1To 10
-10Carry out 10 times of serial dilutions.0.2mL dilution back virus (test group) or PBS buffer (matched group) are inoculated in the fine hair allantoic cavity of instar chicken embryo ovum on the 10th 5 ovum of each dilution factor.Hatch ovum down and monitor twice every day at 37 ℃, continue 5 days, observe embryo survival.Calculate EID50 (50% infective dose of ovum) according to the Reed-Muench method.
In the Embryo Gallus domesticus ovum, estimate the antiviral activity of TG21 to bird flu
With the TG21 of 1g be dissolved in 10mL 0.01mol/L pH be among 7.2 the PBS (1: 10,100mg/mL), then through 2 times of serial dilutions, from 1: 10 to 1: 5120.Dilution back TG21 solution was at room temperature together hatched 30,60 and 120 minutes with the H5N1 type bird flu virus CV strain of equal volume 10 or 100 times of EID50 respectively, then 0.2mL virus-medicament mixed solution is inoculated in the fine hair allantoic cavity from the instar chicken embryo ovum on the 10th of SPF chicken.All Embryo Gallus domesticus ovum are 37 ℃ of hatchings and monitor twice every day, continue 5 days, observe embryo survival.Calculate IC50.
As positive control, under 100 times of EID50 conditions, estimate oseltamivir phosphate capsule
Antivirus action to bird flu virus.
In chicken, estimate bird flu virus LD50
The original preservation thing of bird flu virus CV strain uses the PBS of 0.01M pH7.2 from 10
-1To 10
-9Through 10 times of serial dilutions, then by the collunarium infected chicken, 10 of each dilution factors.Every day, twice pair of animal monitored, and continued 7 days, observed survival.Calculate the LD50 of bird flu virus according to animals survived to chicken.
In chicken, estimate the effectiveness of TG21 anti-avian influenza
Use three days TG21 by drinking-water to the Luo Man chicken in 4 to 6 ages in week, dosage is every every day 40,20,10mg TG21, with 2.5,25,250 times of EID50 chicken is carried out counteracting toxic substances by collunarium then, once a day, continues three days.Counteracting toxic substances continuous five days is afterwards handled animal with the TG21 continuation of same dose.Every day, twice pair of chicken monitored, and continued 7 days.The parallel negative control handled do not accepted.Write down animals survived, estimate the effectiveness of TG21 medicine according to following formula: effectiveness=(matched group mortality rate-processed group mortality rate)/(matched group mortality rate) * 100%.
The result
1. toxicity
Behind the TG21 inoculated into chick embryo 120 hours, to the higher dosage scope of 25mg/mL (1: 40), detecting some toxicity from about 100mg/ml (dilution in 1: 10).TG21 is 32.1mg/ml to the LD50 of Embryo Gallus domesticus.When being lower than 12.5mg/ml (1: 80), dosage do not find side effect.
2.H5N1 the EID50 of type bird flu in Embryo Gallus domesticus, and the LD50 in chicken
When the original preservation thing dilution of virus surpasses 10
9(concentration 10 doubly
-9) time Embryo Gallus domesticus survival.According to the Reed-Muench method, calculating the EID50 of H5N1 type bird flu in Embryo Gallus domesticus is 10
-8.17Preserve thing when virus and be diluted to 10
-8Or when following, institute's Test Virus right and wrong are fatal.The LD50 of H5N1 type bird flu in chicken is 10
-5.41/ 0.2mL.
In Embryo Gallus domesticus TG21 to the antivirus action of H5N1 type bird flu virus.
Before the inoculated into chick embryo, handled H5N1 type bird flu virus 30,60 and 120 minutes with different dilution TG21.Under 10 times of EID50 virus counteracting toxic substances dosage, TG21 is respectively 15.6,14.9 and 6.8mg/mL to the IC50 of H5N1 bird flu virus when handling 30,60 and 120 minutes.Virus dosage is under 10 times of EID50, handles virus in the time of 30 and 120 minutes with TG21 before the inoculation, and IC50 is respectively 17.5 and 16.1mg/mL (seeing the following form 1).
Using oseltamivir phosphate capsule
In the positive controls of handling, viral dosage is under 100 times of EID50, when handling 30 and 120 minutes before the inoculation, and oseltamivir phosphate capsule in Embryo Gallus domesticus
The IC50 of H5N1 type bird flu is respectively 25.1 and 19.4mg/mL.In the negative control group (not having drug administration), all chicken embryo deaths.
Table 1---TG21 in Embryo Gallus domesticus to the antivirus action of H5N1 type AIV
Annotate:
aThe drug dose that EID50:50% Embryo Gallus domesticus ovum infects;
bThe response time of medicine-virus before the inoculation;
cThe medicine initial concentration is 100mg/mL;
dSurvival/sum;
eThe drug level that the IC50:50% embryo survival is required.
The effectiveness of TG21 anti-H5N1 type bird flu virus in chicken
With the viral dosage of height (250 * LD50), medium viral dosage (25 * LD50) and low viral dosage (before 2.5 * LD50) the infectious H5N1 type bird flu virus counteracting toxic substances continuous three days and continuous afterwards five days, by drinking-water to 4 to 6 age in week the Luo Man chicken use every every day 10-40mg TG21.The effect of TG21 anti-H5N1 type bird flu virus in chicken is as shown in table 2 below.Under 250 times of LD50 viral infection dosage, all test chickens are dead in 3 days, comprise oseltamivir phosphate capsule
Animals of control group.This may be owing to too high viral infection dosage, so that there is not drug treating (to comprise oseltamivir phosphate capsule
) the effective protective effect to viral infection can be provided.
Every every day 40,20, TG21 protective effect to the H5N1 bird flu virus in chicken of 10mg dosage under 2.5 times of LD50 viral infection dosage, be respectively 100%, 62.5% and 87.5%, under 25 times of LD50 viral infection dosage, be respectively 70%, 80% and 50%.TG21 and negative control (no medicine) infect the significant difference highly significant (X that renders a service
2All p values all＜0.01 in the check).Oseltamivir phosphate capsule under 25 times of LD50 virus attack dosage
The effectiveness of (every every day 5mg) is 50%.Under 25 times of LD50 virus attack dosage, TG21 (every every day 10mg) and oseltamivir phosphate capsule
Do not find significant difference (P＞0.05, table 2) between the IC50 of (every every day 5mg).
Show 2-TG21 antivirus action to H5N1 type bird flu virus in chicken
Annotate:
*P＜0.01 is through X
2Check is compared with matched group; A: survival/sum
Sum up
Use in this research SPF (no-special pathogen) chicken instar chicken embryo ovum on the 10th and 4 to 6 age in week chicken check the antivirus action of TG21 to H5N1 type bird flu virus CV strain.At first measure virus to the LD50 (50% fatal dose) of chicken, virus to the EID50 (50% Embryo Gallus domesticus infective dose) of Embryo Gallus domesticus and TG21 LD50 to Embryo Gallus domesticus.For in vitro study, virus was cultivated 30-120 minute in advance altogether with the TG21 of variable concentrations respectively, was inoculated into then in the Embryo Gallus domesticus to observe the survival of Embryo Gallus domesticus.Calculate the IC50 (drug level that the survival of 50% Embryo Gallus domesticus is required) of TG21.For studying in the body, before virus attack for three days on end and continuous afterwards 5 days, for high, in and the AIV of low dosage, use TG21 by drinking-water to chicken.The record animals survived is also estimated pharmaceutical efficacy.In parallel study, carry out positive control (oseltamivir phosphate capsule
) and negative control (no medicine).The result shows: (1) handled 10 times of EID50 with TG21 before inoculation virus is in the time of 30,60 and 120 minutes, and the IC50 of the anti-H5N1 type of TG21 bird flu virus is respectively 15.6,14.9 and 6.8mg/ml in Embryo Gallus domesticus; When before the inoculation during with the virus 30 of 100 times of EID50 of described drug treating and 120 minutes, described IC50 is respectively 17.5 and 16.1mg/ml.Before inoculation, use oseltamivir phosphate capsule
When handling the virus 30 of 100 times of EID50 and 60 minutes, oseltamivir phosphate capsule in Embryo Gallus domesticus
The IC50 of anti-H5N1 type bird flu virus is respectively 25.1 and 19.4mg/ml; (2) under 2.5 times of LD50 virus attack dosage, it is respectively 100%, 62.5% and 87.5% that the TG21 antagonism H5N1 type bird flu virus of every every day 40,20,10mg dosage is induced the effectiveness of chicken death, under 25 times of LD50 virus attack dosage is respectively 70%, 80% and 50%, and oseltamivir phosphate capsule
The effectiveness of (every every day 5mg) is 50%.These results show that cysteamine has the antiviral activity of strong anti-H5N1 type bird flu virus, with the anti-avian influenza medicine of present registration such as oseltamivir phosphate capsule
Compare, it can provide similar or even the protective effect of better anti-H5N1 type bird flu virus.
The antiviral activity of embodiment 3-cysteamine anti-H5N1 type bird flu virus in mice
Material and method
Cysteamine (to call " TG21 " in the following text, containing 99% cysteamine) is provided by Omega Bio-Pharma (H.K.) Limited.H5N1 type bird flu virus WV strain separates acquisition from infected chicken.As described here, used oseltamivir phosphate capsule
(Chinese Shanghai, Luo Shi (China) company limited).
Estimate 50% fatal dose (mLD50) of H5N1 type bird flu virus in mice
H5N1 type bird flu (WV strain) is preserved solution and is at first diluted by 1: 5 with PBS, obtains 5 dilution factors (1: 5 to 1: 1280) by four times of serial dilutions then.The 1% barbital sodium anesthesia female mice in six to eight ages in week of intramuscular injection 100 μ L is then by giving mouse inoculation (10 mices of each dilution factor of n=) to every mice nasal cavity Dropwise 50 μ L dilution back H5N1 type bird flu virus WV strain.Monitor animal continuous 14 day every day, calculates mLD50 with the Reed-Muench method based on dead mouse.The result points out, the mice survival rate is 0% in 1: 5 viral dilution degree group, survival rate is 10% in 1: 20 viral dilution degree group, survival rate is 25% in 1: 80 viral dilution degree group, survival rate is 80% in 1: 320 viral dilution degree group, and survival rate is 90% in 1: 1280 viral dilution degree group.The mLD50 of H5N1 type bird flu (WV strain) is 10
-2.1509/ 0.05mL or 1: 141.5 dilution factor/0.05mL.
The therapeutical effect of cysteamine in the mice that infects bird flu virus
50 female mices (6-8 age in week) are assigned to 3 treatment groups (T1, T2 and T3), a negative control group (being untreated) and a positive controls (oseltamivir phosphate capsule
), every group of 10 mices wherein.After the anesthesia of intramuscular injection 100 μ L 1% barbital sodium, the H5N1 type bird flu virus of the 10 times mLD50s of all mice intranasal vaccinations in 50 μ L PBS.Within an hour, in T1 to T3 treatment group, handle animal according to continuous 12 days of the TG21 of every mice every day 4.8,2.4,1.2mg dosage through raising by force to use respectively after the infection, in positive controls, use the oseltamivir phosphate capsule of every mice 0.3mg every day
, give isopyknic PBS in the negative control group.
Clinical infection sign and the survival of twice observation continuous 14 day every day mice.Calculate the protective rate of TG21 antagonism H5N1 type bird flu virus, through X
2Check is the significant difference between each group relatively.For example, by following Equation for Calculating protective rate: protective rate (%)=(matched group mortality rate-treatment group mortality rate)/(matched group mortality rate) * 100%.The result shows that the protective rate that TG21 handles in T1 group (every mice 4.8mg every day), T2 group (every mice 2.4mg every day) and the T3 group (every mice 1.2mg every day) is respectively 50%, 70% and 10%; Protective rate is 0% in the negative control group; Positive controls (oseltamivir phosphate capsule
) in protective rate be 60%.Protective rate and the negative control group significant difference of TG21 in T1 group (P＜0.05), T2 group (P＜0.01) and the T3 group (P＜0.05).These results show that TG21 has the antiviral activity of strong anti-H5N1 type bird flu virus, can be used as the ideal medicament of treatment avian influenza.
All patents, patent application and the publication of mentioning herein or quoting incorporated this paper into by reference with its full content (comprising all charts), and wherein they do not contradict with the clearly instruction of this description.
Should be appreciated that embodiment as herein described and embodiment are only presented for purposes of illustration, those skilled in the art can expect multiple variation or improvement based on this, and these changes and improvements are also included within the application's the spirit and scope.
Claims (40)
1. cysteamine or its salt are used for the treatment of purposes in the medicine of influenza infection in the object in preparation.
2. according to the purposes of claim 1, wherein said influenza virus is selected from first type, B-mode and influenza virus C.
3. according to the purposes of claim 2, wherein said influenza A virus is a bird flu virus.
4. according to the purposes of claim 2, wherein said object infects following at least a avian influenza virus subtype: H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7.
5. according to the purposes of claim 1, wherein said medicine is made every day and is used described cysteamine or its salt of 0.1mg at least to described object.
6. according to the purposes of claim 5, wherein said medicine is made and is used 2mg to 3 every day, the described cysteamine of 000mg or its salt.
7. according to the purposes of claim 1, wherein said cysteamine salt is cysteamine hydrochloride or phosphocysteamine.
8. according to the purposes of claim 1, wherein said medicine is made oral or parenteral formulation or use described cysteamine or its salt through suppository.
9. purposes according to Claim 8, wherein said medicine is made intravenous, intramuscular, transdermal, is used described cysteamine or its salt through oral cavity approach or subcutaneous preparations.
10. cysteamine or its salt are used for reducing purposes in the medicine of the order of severity, intensity or persistent period of influenza infection related complication at object in preparation.
11. according to the purposes of claim 10, wherein said influenza virus is selected from first type, B-mode and influenza virus C.
12. according to the purposes of claim 11, wherein said influenza A virus is a bird flu virus.
13. according to the purposes of claim 11, wherein said object infects following at least a avian influenza virus subtype: H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7.
14. according to the purposes of claim 10, wherein said medicine is made every day and is used described cysteamine or its salt of 0.1mg at least to described object.
15. according to the purposes of claim 14, wherein said medicine is made and is used 2mg to 3 every day, the described cysteamine of 000mg or its salt.
16. according to the purposes of claim 10, wherein said cysteamine salt is cysteamine hydrochloride or phosphocysteamine.
17. according to the purposes of claim 10, wherein said medicine is made oral or parenteral formulation or use described cysteamine or its salt through suppository.
18. according to the purposes of claim 17, wherein said medicine is made intravenous, intramuscular, transdermal, is used described cysteamine or its salt through oral cavity approach or subcutaneous preparations.
19. cysteamine or its salt are used for reducing purposes in the related indication medicine of influenza infection at object in preparation.
20. according to the purposes of claim 19, wherein said influenza virus is selected from first type, B-mode and influenza virus C.
21. according to the purposes of claim 20, wherein said influenza A virus is a bird flu virus.
22. according to the purposes of claim 19, wherein said object infects following at least a avian influenza virus subtype: H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7.
23. according to the purposes of claim 19, wherein said medicine is made every day and is used described cysteamine or its salt of 0.1mg at least to described object.
24. according to the purposes of claim 23, wherein said medicine is made and is used 2mg to 3 every day, the described cysteamine of 000mg or its salt.
25. according to the purposes of claim 19, wherein said cysteamine salt is cysteamine hydrochloride or phosphocysteamine.
26. according to the purposes of claim 19, wherein said medicine is made oral or parenteral formulation or use described cysteamine or its salt through suppository.
27. according to the purposes of claim 26, wherein said medicine is made intravenous, intramuscular, transdermal, is used described cysteamine or its salt through oral cavity approach or subcutaneous preparations.
28. cysteamine or its salt are used in object prevention purposes in the medicine of influenza infection related complication taking place in preparation.
29. according to the purposes of claim 28, wherein said influenza virus is selected from first type, B-mode and influenza virus C.
30. according to the purposes of claim 29, wherein said influenza A virus is a bird flu virus.
31. according to the purposes of claim 29, wherein said object infects following at least a avian influenza virus subtype: H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2 and H10N7.
32. according to the purposes of claim 28, wherein said medicine is made every day and is used described cysteamine or its salt of 0.1mg at least to described object.
33. according to the purposes of claim 32, wherein said medicine is made and is used 2mg to 3 every day, the described cysteamine of 000mg or its salt.
34. according to the purposes of claim 28, wherein said cysteamine salt is cysteamine hydrochloride or phosphocysteamine.
35. according to the purposes of claim 28, wherein said medicine is made oral or parenteral formulation or use described cysteamine or its salt through suppository.
36. according to the purposes of claim 35, wherein said medicine is made intravenous, intramuscular, transdermal, is used described cysteamine or its salt through oral cavity approach or subcutaneous preparations.
37. a compositions, it comprises the cysteamine that is used for the flu-prevention viral infection or its salt and the antiviral agents of effective dose.
38. according to the compositions of claim 37, wherein said influenza infection is a bird flu virus, and wherein said antiviral agents is selected from ganciclovir, acyclovir, foscarnet sodium, amantadine, rimantadine and Oseltamivir.
39. a compositions, it comprises the cysteamine that is used for the flu-prevention viral infection or its salt of effective dose and is used for the treatment of the related indication medicinal materials of influenza infection.
40. according to the compositions of claim 39, wherein said influenza infection is a bird flu virus, and wherein said medicinal materials is selected from antitussive, mucolytic, expectorant, antipyretic, analgesic and nose decongestant.
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| PCT/US2006/045652 WO2007062272A1 (en) | 2005-11-28 | 2006-11-28 | Materials and methods for treating viral infections with a cysteamine compound |
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| EP3030566B1 (en) | 2013-09-12 | 2020-07-08 | Janssen BioPharma, Inc. | 7,8-dihydro-3h-pyrazino[1,2-b]pyridazine-3,5(6h)-dione compounds and uses thereof |
| EP3268368A4 (en) | 2015-03-11 | 2018-11-14 | Alios Biopharma, Inc. | Aza-pyridone compounds and uses thereof |
| CN106619592A (en) * | 2016-11-17 | 2017-05-10 | 郑州郑先医药科技有限公司 | Medicine for treating acute pharyngitis |
| WO2021202650A1 (en) * | 2020-04-01 | 2021-10-07 | Thiogenesis Therapeutics, Inc. | Cysteamine precursor compounds for the treatment of betacoronavirus infections |
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| US5554655A (en) * | 1991-09-30 | 1996-09-10 | Jess G. Thoene | Method of treating HIV infection |
| DE19817511A1 (en) * | 1998-04-20 | 1999-10-21 | Werner Slenczka | Treating or preventing skin or mucosal virus infections, e.g. by herpes viruses, using pantothenic acid, dexpanthenol or derivatives |
| CN1624116A (en) * | 2003-12-02 | 2005-06-08 | 中国农业科学院哈尔滨兽医研究所 | Artificial recombined influenza virus and its application |
-
2006
- 2006-11-28 CN CN2006800443056A patent/CN101340902B/en not_active Expired - Fee Related
- 2006-11-28 ZA ZA200805191A patent/ZA200805191B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5554655A (en) * | 1991-09-30 | 1996-09-10 | Jess G. Thoene | Method of treating HIV infection |
| DE19817511A1 (en) * | 1998-04-20 | 1999-10-21 | Werner Slenczka | Treating or preventing skin or mucosal virus infections, e.g. by herpes viruses, using pantothenic acid, dexpanthenol or derivatives |
| CN1624116A (en) * | 2003-12-02 | 2005-06-08 | 中国农业科学院哈尔滨兽医研究所 | Artificial recombined influenza virus and its application |
Non-Patent Citations (4)
| Title |
|---|
| Bergamini A et.al.In vitro inhibition of the thereplicationofhumanimmunodeficiency virus type 1 by beta-mercaptoethylamine(cystramine).The Journal of Infectious Diseases174 1.1996,174(1),214-218. |
| Bergamini A et.al.In vitro inhibition of the thereplicationofhumanimmunodeficiency virus type 1 by beta-mercaptoethylamine(cystramine).The Journal of Infectious Diseases174 1.1996,174(1),214-218. * |
| Robert A. Anderson et al..Characterization of Cysteamine asaPotentialContraceptiveAnti-HIV Agent.Journal of Andrology19 1.1998,19(1),37-49. |
| Robert A. Anderson et al..Characterization of Cysteamine asaPotentialContraceptiveAnti-HIV Agent.Journal of Andrology19 1.1998,19(1),37-49. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101340902A (en) | 2009-01-07 |
| ZA200805191B (en) | 2009-08-26 |
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