WO2003007935A2 - Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt - Google Patents
Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt Download PDFInfo
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- WO2003007935A2 WO2003007935A2 PCT/AT2002/000206 AT0200206W WO03007935A2 WO 2003007935 A2 WO2003007935 A2 WO 2003007935A2 AT 0200206 W AT0200206 W AT 0200206W WO 03007935 A2 WO03007935 A2 WO 03007935A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Definitions
- the invention relates to the use of dithiocarbamate compounds as well as a disinfectant and a method for disinfecting surfaces, media or cell cultures.
- viruses that cause diseases in the respiratory tract of humans and mammals. Although these respiratory pathogenic viruses can be structurally different and belong to different virus families, all these viruses have in common that they are able to enter the body through the respiratory tract, e.g. specific cells of this tract can attack, e.g. the epithelial cell layer in the respiratory tract, alveolar cells, lung cells, ... All have in common the classic symptoms of the flu infection, which is caused by local inflammation and symptoms of the respiratory tract (such as runny nose, hoarseness, coughing, blisters, sore throat) is marked.
- specific cells of this tract can attack, e.g. the epithelial cell layer in the respiratory tract, alveolar cells, lung cells, ... All have in common the classic symptoms of the flu infection, which is caused by local inflammation and symptoms of the respiratory tract (such as runny nose, hoarseness, coughing, blisters, sore throat) is marked.
- NFKB oxidant-specific transcription factor-KB
- Antioxidants can block the activation of NFKB by intercepting the ROIs that would otherwise lead to this activation. Therefore, the use of antioxidants has been proposed, especially in the treatment of latent virus infections; however, it was shown that effective treatment of these latent infections with individual antioxidants alone are not possible, but - if at all - only through a combined therapy using a mixture of different (ie differently acting) antioxidants and other virus-inhibiting agents (US Pat. No. 5,686,436). An inhibition of viral replication or even viral infection by antioxidants has not yet been achieved, especially not for infections with influenza or picornaviruses (Knobil et al. Am. J. Physiol. 274 (1) (1998) (134-142) ,
- L-ascorbic acid and vitamin E serve to protect glutathione; Vitamins K, A and E act as antagonists of peroxynitrite and other strong oxidants in the body.
- Anti-inflammatory steroids, non-glucocorticoids, lazaroids, dithiocarbamates or N-acetyl-L-cysteine have been described as inhibitors of NFKB activation.
- Viruses can be divided into DNA and RNA viruses depending on their carrier of the genetic information, the nucleic acid being single-stranded or double-stranded and surrounded by a protein envelope.
- the single-stranded RNA of these RNA viruses is either a plus strand (RNA) or a minus strand. Furthermore, this genetic information of the virus can also be present in several pieces, for example in the case of the influenza virus.
- the human rhinoviruses which are among the picornaviruses, are the main cause of the common cold that occurs worldwide.
- HRV human rhinoviruses
- the frequent occurrence of HRV the risk of serious secondary infections and the economic influence with regard to medical costs, visits to the doctor, sick leave of employees make HRV important, serious pathogens.
- HRV human rhinoviruses
- the consequences of, for example, a rhinovirus infection are not as serious or even life-threatening, that medication with a high risk of side effects may be accepted. Agents that are to be used against such viruses may therefore have only minor or no side effects.
- the animal picornavirus group includes the Equine Rhinitis A virus (ERAV), which, like the foot-and-mouth disease (FMD) virus, belongs to the genus of the aphtho- viruses.
- EAV Equine Rhinitis A virus
- influenza A and B viruses need 8 RNA segments, while influenza C viruses only need 7.
- Influenza A, B and C viruses can form homotypic reassortants in vivo, but not between types. In theory, 256 reassortants could arise from the 8 segments of two influenza A viruses. However, this random segregation does not take place because at the protein level some proteins need their strain-specific partner.
- influenza Despite wide vaccination programs, influenza remains a cause of morbidity and mortality worldwide and a major cause of illness and death in patients with immunodeficiency or in the elderly.
- the antiviral activity of Amantadine and rimantadine reduce the duration of symptoms of clinical influenza, but important side effects and the appearance of resistant mutants have been described (FIELDS et al., Virology, 3rd Edition (1995) Lippincott-Raven Publ., Philadelphia, Vol.l, p 434-436).
- Zanamivir and Oseltamivir are, for example, inhibitors of influenza A and B virus neuraminidase; however, these drugs only reduce the duration of the symptoms.
- US Pat. No. 5,686,436 describes a method for suppressing the multiplication of retroviruses and latent viruses in humans and animals, such as HIV, for example, wherein a medicament comprising, among other things, antioxidants and NFKB induction inhibitors is administered.
- a medicament comprising, among other things, antioxidants and NFKB induction inhibitors
- the virus must be effectively combated in the acute infection phase; treatment that can only be used at the latent virus level is unsuitable for preventing or treating acute viral infections in the respiratory tract.
- the object of the present invention is achieved by the use of dithiocarbamate compounds of the structural formula R1R2NCS2H, in which R 1 and R 2 independently of one another represent a straight or branched C 1 -C 4 -alkyl or with the nitrogen atom an aliphatic ring with 4 to 6 C atoms form, wherein Ri, R 2 or the aliphatic ring is optionally substituted with one or more substituents selected from OH, N0 2 , NH 2 , COOH, SH, F, Cl, Br, I, methyl or ethyl, and oxidized forms of these compounds , in particular dimers thereof, and pharmaceutically acceptable salts thereof, for the preparation of an agent for the treatment or prevention of infection by RNA viruses which infect the respiratory tract and trigger a disease there.
- R 1 and R 2 independently of one another represent a straight or branched C 1 -C 4 -alkyl or with the nitrogen atom an aliphatic ring with 4 to 6 C atoms form
- the "respiratory tract” includes all organs and areas starting from the body openings (Nose, mouth, eyes (including tear duct) and ears) understood the alveoli.
- the pharmaceutically acceptable salts are in particular Na, K, Ca, Mg, NH 4 and Zn.
- the efficiency of the dithiocarbamate compounds according to the invention against infections with respiratory RNA viruses and the multiplication of these viruses is not solely due to the inhibition of NFKB activation, but it was found that with the dithiocarbamate compounds according to the invention, in the context of the present Registration also includes the oxidized forms, in particular the dimers, which are to be understood as specifically preventing the multiplication of respiratory RNA viruses.
- DE 1963223 A relates to an agent for the treatment of viral infections in the brain, the agent being intended to include an inhibitor for the biosynthesis of the monoamines noradrenaline, dopamine and 5-hydroxy-tryptamine.
- the example given in this document shows the effect of ⁇ -methyltyrosine methyl ester on herpes simplex-infected mice.
- the mechanism described in this document of inhibiting the biosynthesis of special monoamines can therefore only be used for the treatment of DNA virus infections in the brain.
- the inventive treatment of respiratory RNA viruses works on a different principle and is not applicable to viral infections in the brain, as the negative examples for TBE (example 13) and EMC (example 14) show.
- DE 1963223 A thus relates to another area of application and cannot be compared with the inventive application and therefore does not suggest this.
- WO 95/03792 AI relates to the use of thiol compounds for the production of a pharmaceutical composition for the treatment of virus-induced diseases, disulfide bridges present in virus proteins being destroyed by the thiol compound.
- RNA viruses are also mentioned among numerous viruses, including Picornaviridae. Numerous examples of thiol compounds are also given, including generally dithiocarbamate. From these many different possible combinations, only the following examples are shown: as thiol compounds N-acetylcysteine (NAC), cysteine, cysteine hydrochloride and N, S-diacetylcysteine ethyl ester (DACEE), only hepatitis B and vaccinia virus are shown as viral diseases.
- NAC N-acetylcysteine
- DACEE S-diacetylcysteine ethyl ester
- GB 861 043 A relates to compositions which, inter alia, serve as protection against viruses. These compositions include, for example, dithiocarbamates, but specific viruses are not disclosed here.
- DE 2555730 A describes an antimicrobial agent comprising a dimethyldithiocarbamate compound, this compound being an 8-0xyquinolinate-metal-N.N-dimethyldithiocarbamate complex.
- this compound being an 8-0xyquinolinate-metal-N.N-dimethyldithiocarbamate complex.
- fungicidal and antibacterial activity is disclosed in this document.
- WO 99/66918 AI relates to the use of disulfide derivatives of dithiocarbamates for the reduction of nitrogen oxides in a patient or for the inhibition of NFKB.
- a very large number of diseases is specified in this document, the viral diseases not being described in detail.
- Tai D.I. et al., Hepatology, March 2000, 31 (3), pp. 785-787 relates to a study on the inhibition of NFKB activation by PDTC, in which HCV infection is believed to cause anti-apoptosis by activating NFKB could.
- the antiviral activity of the dithiocarbamate compounds according to the invention is also not dependent on a combination of certain substances.
- the dithiocarbamate compounds according to the invention can be used completely on their own, regardless of the other additives, in particular antioxidants, as is absolutely essential for an anti-retrovirus effect of NFKB activation inhibitors according to US Pat. No. 5,686,436, because surprisingly the antiviral Effect relates not only to the control of oxidative stress, but the infection / replication can be inhibited by the dithiocarbamate compounds according to the invention.
- the dithiocarbamate compounds according to the invention induce genes which act as antioxidant-induced transcription factors (Meyer et al., EMBO J. 12, 2005-2015, 1993).
- the heterodimeric transcription factor API can be induced by NAC and the dithiocarbamate compounds according to the invention, which leads to DNA binding and transactivation.
- the activation of API by the dithiocarbamate compounds according to the invention is dependent on protein synthesis and includes the transcription of c-jun and c-fos genes. However, the activation of APl alone is not responsible for the strong inhibition of the viruses according to the invention.
- Pyrrolidine dithiocarbamate is already known as a pro and antioxidant, inhibitor of the activation of the transcription factor NFKB, zinc ionophore and metal chelation agent.
- PDTC Pyrrolidine dithiocarbamate
- NFKB transcription factor
- WO 01/00193 A2 relates to compositions comprising diethyldithiocarbamate in the picomolar and nanomolar range, which have a strong action against apoptosis.
- the dithiocarbamate compounds according to the invention have a strong action against RNA viruses which affect the respiratory tract and trigger a disease there - "respiratory RNA viruses" - both in vitro and in vivo.
- the infection is thus counteracted at a very early stage, before extensive cell damage or even cell death occurs.
- respiratory RNA viruses are understood to mean any viruses of humans and mammals which infect the body via the respiratory tract, that is to say the respiratory tract and lungs, and penetrate into the body, triggering a disease in the respiratory tract.
- the biological processes that occur with this infection are so similar that the effect of the dithiocarbamate compounds according to the invention works efficiently in an analogous manner - despite the biological heterogeneity of this group of viruses.
- other viruses that enter the body via other infection routes and go through other biological cycles e.g. can be integrated into the host genome as a latent virus
- the effect of the dithiocarbamate compounds according to the invention alone is not sufficient to successfully combat a viral infection.
- the dithiocarbamate compounds according to the present invention develop their particular effectiveness especially in an early phase of the viral infection or when it is is taken before infection.
- the dithiocarbamate compounds according to the invention can prevent the outbreak of a virus infection if it is taken prophylactically, for example in areas at times at which there is a risk or even an increased risk of respiratory virus infections, for example in regions with epidemics or from cold waves.
- the dithiocarbamate compounds according to the invention are preferably used to prevent the virus infection.
- the virus inhibition according to the invention is very particularly preferred, however, especially in the early phase of a respiratory RNA virus infection that has already occurred.
- the dithiocarbamate compounds according to the invention are used specifically to inhibit the replication of the viruses, that is to say at a point in time before sustained damage has occurred in the infected individual. This not only prevents the consequences of a progressive virus infection in the individual concerned, but also the spread of other infectious viruses to other individuals; the further risk of infection is minimized, which has a great general health-political effect and importance, especially in the case of the human influenza virus.
- RNA viruses in the context of the present invention: rhinoviruses, coxsackieviruses, echoviruses, coronaviruses, enteroviruses, human orthomyxoviruses (e.g. influenza virus (A, B and C)), paramyxoviruses (e.g. parainfluenza virus and pneumovirus), respiratory virus virus ) and other RNA viruses, as long as they trigger a disease (at least) in the respiratory tract.
- human orthomyxoviruses e.g. influenza virus (A, B and C)
- paramyxoviruses e.g. parainfluenza virus and pneumovirus
- respiratory virus virus e.g. parainfluenza virus and pneumovirus
- Viruses or virus strains which do not cause a disease in the respiratory tract but in another organ, for example in the brain, for example meningitis virus, encephalomyocarditis virus, poliovirus, cardiovirus, etc., are not covered by the present application.
- the respiratory RNA viruses according to the invention have in common the infection of epithelial cells of the upper or lower respiratory tract. Other organs can also be affected.
- the resulting local inflammation in the respiratory tract is considered to be the main cause of the development of the typical symptoms of a flu infection, such as a runny nose, sore throat, hoarseness, coughing, blisters or often fever. Also the frequent occurrence secondary infections in the immunocompromised individual are favored by infection with these respiratory viruses.
- picornaviruses are understood to mean all "real" picornaviruses, according to the currently valid classification of picornaviridae based on King et al. ("Picornaviridae” in "Virus Taxonomy, Seventh Report of the International Committee for the Taxonomy of Viruses” (2000), Eds. Van Regenmortel et al., Academic Press 657-673), insofar as they affect the respiratory tract and there a disease trigger, ie the genera Enterovirus, Rhinovirus, Aphthovirus, Parechovirus, Erbovirus, Kobuvirus and Teschovirus. These viruses of the Picornaviridae family are characterized by a similar genetic structure, protein composition, cultivation properties or resistance to temperature or virucidal agents.
- the present invention is particularly good for combating the human and animal pathogenic representatives of the true respiratory Picornaviridae, in particular from the genera Enterovirus (Enterovirus 70, 71, Coxsackievirus) and Rhinovirus (eg human rhinovirus) and Aphthovirus (eg Maul- and hoof disease virus), whereas for other viruses, including Picornaviruses, which cause latent infections such as HAV, the advantages of the invention could not be proven. This is probably also due to the fact that the group of "real" respiratory picornaviruses is so homogeneous in itself and that the pathophysiological processes which occur in the course of the infections are so similar that the dithiocarbamate compounds according to the invention are analogous come into effect.
- Virus infection in the context of the present application is understood to mean any attack by a respiratory virus on cells, which comprises, for example, one of the following steps: starting with the docking of the virus particle to a cell, and at a later stage the introduction of the genetic information of the Virus into the cell as well as the production of new virus particle parts and the expression of infectious virus particles.
- oxidized forms of these compounds genes, in particular dimers thereof, since, as is known per se, these are rapidly metabolized in the organism in the reduced form.
- such compounds are to be understood as "oxidized forms” whose S radical is oxidized.
- a preferred example of such an oxidized dimeric form is disulfiram, which is also known under the name "Antabus” or “Abstinyl” and is a tetraethylthiuram disulfide (C10H20N2S4).
- disulfiram itself is already known, although it is used in particular for the treatment of alcoholics: disulfiram acts as a mediator in oxidoreduction and inactivates the aldehyde dehydrogenase.
- the intake of ethanol leads to the accumulation of acetaldehyde in the body, which has a markedly negative effect on general well-being:
- disulfiram and alcohol are taken at the same time, anxiety, nausea, vision loss, chest pain, headache etc. occur, with these symptoms Hold for 3-4 days or a week. For this reason, disulfiram is administered to alcoholics as therapy, since any subsequent alcohol consumption should be avoided due to these strong negative effects.
- disulfiram effects of disulfiram are the inhibition of enzymes such as fructose, 1,6-diphosphate dehydrogenase, xanthine oxidase, hexokinase, aldehyde oxidase. and dopamine- ⁇ -hydroxylase.
- enzymes such as fructose, 1,6-diphosphate dehydrogenase, xanthine oxidase, hexokinase, aldehyde oxidase. and dopamine- ⁇ -hydroxylase.
- Disulfiram is also used to treat pediculosis and scabies as well as to treat nickel dermatitis.
- the oxidized form of the dithiocarbamate compounds according to the invention is readily fat-soluble and can be provided, for example, as an agent to be administered orally, the compounds being absorbed in the stomach.
- the connections could special can also be provided as a powder spray.
- the oxidized form of the compounds according to the invention can be provided with hydroxyl groups in order to increase the water solubility in order to make it available in the form of an aerosol. If the dithiocarbamate compounds according to the invention are provided in the form of the oxidized, in particular dimeric product, a depot effect of this agent is achieved, ie the dithiocarbamate compounds according to the invention are gradually released to the body over a certain period of time and absorbed by the latter. For this depot effect, the oxidized dithiocarbamate compounds can also be implanted in the body to be treated, as is known per se.
- a preferred compound according to the invention is characterized in that R 1 and R 2 independently of one another represent a C 3 -C 3 alkyl or form an aliphatic ring with 4 to 6 C atoms with the nitrogen atom. These have proven to be particularly advantageous for the treatment or prevention of a respiratory RNA virus infection.
- the dithiocarbamate compound is preferably selected from pyrrolidine dithiocarbate (PDTC) and N, N-diethyl dithiocarbamate (DDTC). These compounds have an extremely strong activity against respiratory RNA virus infections. on.
- the virus infection is particularly preferably an infection with picornavirus, orthomyxo- or paramyxovirus.
- the dithiocarbamate compounds according to the invention are particularly active against these virus infections.
- the orthomyxovirus is a human influenza virus, especially selected from the group consisting of influenza A, influenza B, influenza C or the paramyxovirus is a parainfluenza virus or pneumovirus.
- the orthomyxovirus is preferably a mammalian influenza A virus and the picornavirus is a rhinovirus, in particular human or equine rhinovirus, an enterovirus, in particular enterovirus 70, 71 or Coxsackie virus, or an aphthovirus, in particular the foot and mouth disease virus or equine rhinitis virus A.
- viruses or virus strains are excluded.
- the Picornaviridae family includes a number of small RNA viruses, including rhinoviruses (e.g. the human rhinovirus), enteroviruses (e.g. Enterovirus 70, 71, Coxsackievirus, which is a causative agent of hand, foot and mouth disease, for example), aphthoviruses (e.g. the foot and mouth disease virus, which causes a disease in the mouth, and equine rhinitis virus A).
- rhinoviruses e.g. the human rhinovirus
- enteroviruses e.g. Enterovirus 70, 71, Coxsackievirus, which is a causative agent of hand, foot and mouth disease, for example
- aphthoviruses e.g. the foot and mouth disease virus, which causes a disease in the mouth
- equine rhinitis virus A equine rhinitis virus A
- Foot-and-mouth disease is particularly interesting to use the compound according to the invention
- Orthomyxo- and Paramyxoviruses are a subdivision of the previous collective name for influenza viruses and other similar viruses. Paramyxoviruses cause measles, mumps, respiratory and neurological diseases in humans. The paramyxoviruses include the parainfluenza virus, mumps virus, Newcastle disease virus, the respiratory syncytial virus (RSV), the measles virus and the bovine plague virus. Orthomyxoviruses include the influenza virus A, B and C, which are the causative agents of the flu in humans.
- Type A influenza viruses are responsible for the majority of the flu epidemics and all pandemics. Influenza A viruses also occur in horses and pigs, and also in birds, for example as causative agents of classic avian influenza, but only the human influenza viruses and the influenza viruses of mammals, e.g. horses, can actually be respiratory viruses Meaning apply, since the biology of the avian influenza virus (AI) is completely different human influenza virus differs. Therefore, the AI virus cannot be regarded as a respiratory virus. In ducks, the AI virus primarily replicates in the intestinal tract, which is not the case in humans. As a consequence, AI viruses can also be isolated from bird faeces. (Hinshaw et al., 1980, Canad. J. Microbiol. 26, 622-9).
- the nucleotide variation rate of AI viruses is lower than that of viruses that can be isolated from mammals.
- the evolution of viral proteins in organisms other than birds typically shows a rapid accumulation of mutations that do not occur in AI viruses. (Gorman et al., 1991, J. Virol. 65: 3704-14; Ludwig et al., 1995, Virology 212: 555-61).
- the receptor specificity varies between different influenza viruses. Most AI viruses prefer to bind to the alpha2-3 galactose sialic acid receptor.
- human influenza viruses primarily bind to the alpha2-6-galactose-sialic acid receptor (Rogers + Paulson, 1983, Virology 127, 361-73; Baum + Paulson, 1990, Acta Histochem. Suppl. 40: 35-8).
- the antiviral activity of the dithiocarbamate compounds according to the invention is particularly important with regard to these viruses. Since the dithiocarbamate compounds according to the invention are extremely effective against these viruses, the dithiocarbamate compounds according to the invention are particularly suitable for the production of a number of agents for the treatment or prevention of these virus infections.
- the dithiocarbamate compounds according to the invention are easy and inexpensive to produce in large quantities and, even in higher concentrations, have hardly any toxic effects on the cells to be treated.
- the dithiocarbamate compounds according to the invention are provided in the agent in a concentration of 0.01 to 5000 mM, preferably 1 to 300 mM, particularly preferably 10 to 100 mM. In these concentrations, the dithiocarbamate compounds according to the invention are particularly effective against respiratory RNA virus infections and have little or no side effects.
- concentration to be used depends on the virus infection to be treated Strength of the virus infection or depending on the organism to be treated, such as whether animal or human or depending on the age.
- the dithiocarbamate compounds according to the invention are provided in the agent in a concentration of 10 mM to 1M.
- the dithiocarbamate compounds according to the invention are in highly concentrated form and the agent can be diluted depending on the desired concentration before the treatment.
- the agent further comprises a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier known to a person skilled in the pharmaceutical field can be used, such as, for example, phosphate-buffered saline (PBS) or other buffered saline solutions or liposome-containing formulations, the carrier again depending on the type of treatment, virus Infection or the organism to be treated is selected.
- PBS phosphate-buffered saline
- the carrier again depending on the type of treatment, virus Infection or the organism to be treated is selected.
- the agent is preferably an agent to be administered orally, intranasally, intravenously, parenterally, rectally or as eye or ear drops, Gurgel solution or aerosol.
- the type of administration depends in particular on the virus infection to be treated. For example, infection in the respiratory tract, e.g. by means to be administered intranasally, e.g. in the form of an aerosol comprising the dithiocarbamate compounds, since the virus infection is treated right at the site of the virus attack.
- the dithiocarbamate compounds are present in a certain concentration or the agent comprises additional substances which are favorable for this administration form. It is of course possible to provide the agent in a dried form, for example, it being diluted with a suitable solvent before treatment.
- the agent comprises further antiviral substances.
- further antiviral substances are, for example, substances which inhibit replication, immune-stimulating substances, neutralizing antibodies, etc., but also, if appropriate, substances which can generally support the immune system.
- the agent preferably comprises a combination of at least two different dithiocarbamates according to the invention, in particular a mixture of PDTC and DDTC.
- the dithiocarbamate compounds according to the invention exercise pro- and anti-oxidative functions in cells. Their anti-oxidative effects include the elimination of hydrogen peroxide, the removal of superoxide radicals, peroxynitrites, hydroxyl radicals and lipid peroxidation products. These eliminations oxidize the dithiocarbamates to thiuram disulfide. Thiuram disulfides are responsible for the pro-oxidative effects of dithiocarbamates, and in some cases the formation of thiurams is dependent on the presence of metals. It has been described that the anti-apoptotic activities of dithiocarbamates may be used in the inactivation of caspases by thiol oxidation.
- the agent according to the invention particularly preferably further comprises substances selected from antibiotics, vaccines, immunosuppressants, stabilizers, immunostimulating substances, blood products or mixtures thereof. If additional antibiotics are used, bacterial infections can also be combated in addition to the respiratory viruses. If the agent comprises additional vaccines, which include both passive and active vaccines, certain other virus infections which can easily infect the weakened organism are prevented at the same time as the treatment or prevention of the virus infection according to the invention. In addition, stabilizers can also be added to increase storage stability and service life. Blood products are e.g. Plasma, blood cells, coagulation factors, etc., depending on what treatment the patient is undergoing.
- the agent is favorably used to inhibit virus replication. In this way it is ensured that a infection that has already occurred does not spread, but on the contrary is treated very quickly.
- the invention also relates to a disinfectant comprising at least one dithiocarbamate compound according to the invention as described above.
- disinfectant is understood to mean any agent that is used outside a human or animal organism for combating viruses, for example on surfaces, in agents, in particular media, or for cell cultures. Such disinfectants can be used in particular if the substance to be treated is sensitive to other more aggressive antiviral substances.
- disinfectants comprising the dithiocarbamate compounds according to the invention are suitable as additives for media or for treating cells or cell cultures which are sensitive to other, more aggressive disinfectants or antiviral substances.
- the dithiocarbamate compounds according to the invention have been shown to be particularly effective in the treatment or prevention of respiratory RNA virus infections of respiratory cells and cell cultures.
- the disinfectant is particularly effective if it comprises the dithiocarbamate compounds according to the invention in a concentration of 10 ⁇ M to 5 M, in particular 30 ⁇ M to 1 M.
- these concentrations are effective against respiratory RNA virus infections
- such a disinfectant is extremely gentle, for example if it is used as an antiviral substance for cell cultures.
- the concentration depends on the type or on the advanced stage of the virus infection or on the substance used for the treatment, for example on the type and sensitivity of the cells.
- the disinfectant preferably comprises further disinfectant, in particular antiviral, substances.
- disinfectant in particular antiviral, substances.
- substances which are known to any person skilled in the field of microbiology are in particular added when other viruses are to be combated at the same time, such as DNA viruses.
- antibacterial substances in particular antibiotics, can also be added.
- a further aspect of the present invention relates to a method for disinfecting surfaces, media or cell cultures, a disinfectant according to the invention being applied to the surface or cell culture as described above or being introduced into the medium.
- a disinfectant according to the invention being applied to the surface or cell culture as described above or being introduced into the medium.
- the disinfectant can act for a longer period of time, the concentration of the disinfectant as described above being able to be varied depending on the purpose.
- the invention relates to the treatment or prevention of a respiratory RNA virus infection with the dithiocarbamate compounds according to the invention.
- An agent comprising the dithiocarbamate compounds according to the invention is administered to the patient or the animal in a suitable form and in a suitable concentration as described above.
- Figure 1 is a graph showing the inhibitory effect of PDTC on HRV replication in cell cultures
- Figure 3 shows the increase in cell viability by PDTC and DDTC
- Figure 4 shows the effect of a PDTC treatment as a function of time
- Figure 5 shows the cleavage of elF4GI
- FIG. 7 shows the effect of other antioxidants on HRV infection
- Figures 8 and 9 show the effect of PDTC on influenza virus replication
- Figures 11A and 11B show the effect of PDTC on mice infected with influenza virus
- Figure 12 shows the effectiveness of PDTC against ERAV
- Figures 13A and 13B show the effectiveness of PDTC against FMD.
- Figure 14 shows the lack of action of PDTC against EMCV.
- Example 1 Reduction of the Production of Infectious Rhinovirus Particles by PDTC
- HeLa cells were infected with HRV serotypes 1A, 2, 14 and 16 with 20 TCID 50 (tissue culture infectious dose 50) per cell.
- TCID 50 tissue culture infectious dose 50
- PDTC tissue culture infectious dose 50
- the supernatants were collected 24 hours (FIG. 1, top) and 48 hours (FIG. 1, bottom) after infection (pI) and the amount of virus progeny was determined by TCID 50 tests.
- the treatment of cells with PDTC reduces the virus titer (vt) by 10 3 after 24 h (FIG. 1, top).
- the supernatants from PDTC-treated cells collected 48 hours after infection also show a significant reduction in virus titer (Fig. 1, below).
- Example 2 PDTC inhibits HRV-induced cytopathic effects and increases the viability of infected cells
- CPE cytopathic effects
- Treatment with PDTC thus leads to a fight against the virus infection at a very early stage, so that further cell damage is prevented.
- Example 3 Increasing the viability of infected cells by PDTC and DDTC
- a cell proliferation assay was performed to test the effect of PDTC or DDTC on cell viability during a viral infection.
- a Cell-Titer 96® Aqlieous Non-radioactive Cell Proliferation Assay (Promega; Madison, Wisconsin, USA) was carried out in accordance with the manufacturer's instructions.
- One day before infection cells were placed in 96 well plates. These cells were infected with various HRV serotypes at 20 TCID 5Q / cell.
- the Le- The viability of the cells was determined by adding a tetrazolium substance, 2 h incubation at 37 ° C. and measuring the absorption at 492 nm.
- Fig. 3 top: DDTC; bottom PDTC
- the viability of the cells is significantly increased even when low concentrations of PDTC or DDTC are added.
- PDTC or DDTC alone has little effect on uninfected cells.
- the concentrations used to inhibit viral infections showed no toxicity ("-" means without).
- Example 4 Effectiveness of PDTC as a function of time
- PDTC In order to test at which stage of the viral life cycle PDTC intervenes, PDTC was added at various times after virus infection with 20 TCID50 per cell and proliferation assays were carried out. It could be shown that the addition of PDTC (125 ⁇ M) within the first six hours after infection (“-” means without) offers the best protection against virus-induced loss of proliferation (FIG. 4A). This effect is also not specific for a single serotype, since HRV serotypes 1A, 2, 14 and 16 were used. Only the PDTC treatment (125 ⁇ M) of cells at a time later than 8 hours after infection reduced the protective effect.
- a characteristic proteolytic activity that occurs in the course of infections with rhino and enteroviruses is the enzymatic cleavage of the cellular translation initiation factors 4GI (eIF4GI) and 4GII with the viral 2A proteinase, so that the host cell protein synthesis ends becomes.
- eIF4G proteins are cleaved at an early stage of infection.
- Another recently described cleavage activity during rhinoviral infection is the cleavage of the intermediate filament protein cytokeratin 8. This cleavage is also dependent on the 2A protease, but occurs at a late stage during the infection.
- a Western blot analysis was carried out to analyze these 2A protease substrates.
- the cells were lysed by adding 100 ⁇ l protein buffer (8% sodium dodecyl sulfate, 20% ⁇ -mercaptoethanol, 20% glycerol, 0.04% bromophenol blue). 20 ⁇ l protein extract were separated per lane using SDS-PAGE and blotted on PVDF membranes. The incubation with antibodies was carried out with 0.1% Tween 20 and 5% skimmed milk powder in TBS. Polyclonal rabbit antibodies against eIF4GI were used for the immunodetection. Anti-rabbit immunoglobulins conjugated with alkaline phosphatase were used as secondary antibodies.
- the staining was carried out by the alkaline phosphatase reaction, and the molecular sizes were determined with the aid of a pre-stained marker SDS-7B (Sigma).
- HRV2-infected HeLa cells 100 TCID50 per cell
- the cleavage of eIF4GI can be detected 4 hours after infection (cp stands for cleavage product), the complete cleavage is reached 8 hours after the infection (FIG. 5) , At these times, no cleavage of the eIF4GI is detectable in infected cells in the presence of PDTC.
- a slight eIF4GI cleavage can also be detected in cells treated with PDTC.
- capsid proteins from HRV2 in protein extracts from HRV2-infected HeLa cells were detected by Western blot analysis (see FIG. 6).
- Western blot analysis was performed as described in Example 5 above using a polyclonal rabbit antiserum against HRV2.
- Significant amounts of the rhinoviral proteins VP1, VP2 and VP3 were detected in untreated cells at 6 hours after infection.
- PDTC treatment prevents expression of these capsid proteins within the first 8 hours after infection.
- the weak expression of VP1, VP2 and VP3 was only detected at a late point in time about 24 hours after infection.
- Example 7 Determination of the dependence of the antiviral effect on the redox potential
- FIG. 7 shows that infection with HRV2 destroys the cell turf, PDTC can prevent this effect, but not NAC.
- the mode of action of vitamin C, Trolox and ⁇ -mercaptoethanol (2-ME) was determined as described in Example 3 (FIG. 7 B, C, D).
- Example 8 Effect of PDTC on Influenza Virus Replication
- 5xl0 5 vero cells were infected with influenza virus A / PR8 / 34 or Vienna / 47/96 with a moi (multiplicity of infection) of 0.01 and incubated for 1 h at room temperature. The inoculum was then removed and infection medium with 5 ⁇ g / ml trypsin and 600 ⁇ M PDTC was added. The supernatant was removed after 48 h and 72 h and the virus titer in the supernatant was measured using a standard plate assay. As shown in Fig. 8, the virus titer of A / PR8 / 34 was reduced by more than 2 log steps in the presence of PDTC compared to the control sample (c).
- TCID50 50% tissue culture infective dose
- TCID50 was calculated according to the Kaerber method at each concentration: 96 well microtiter plates were infected with 2-fold dilution series of the indicated virus, the supernatant was removed after the infection and medium comprising the stated concentrations of PDTC was added. The number of infected wells was determined after 4 days.
- FIG. 9 shows that at a concentration of 300 ⁇ M PDTC the TCID50 was reduced by 76.4% and 82.2% for A / PR8 / 34 and A / Vienna / 47/96, respectively. A Inhibition of over 99.9% was achieved for both viruses at a concentration of 1200 ⁇ M.
- Example 9 Determination of the effective concentration of PDTC
- the effective concentration of PDTC was determined using a CPE (cytopathic effect) reduction assay: Vero cells were cultivated in 96-well microtiter plates and with 5 TCID50 per well and 50 TCID50 per well influenza A / PR8 / 34 and 5 TCID 50 per well influenza A / Vienna / 47/96 infected. 1 h after the infection, the supernatant was removed and medium with 5 ⁇ g / ml trypsin and a 2-fold dilution series of PDTC starting at a concentration of 1200 ⁇ M was added. The plates were examined visually for cytopathic effects over the subsequent 4 days. The occurrence of cytopathic effects in relation to the control sample was calculated for each concentration.
- CPE cytopathic effect
- the complete lysis in all wells means 100% positive. 10 shows that a 50% reduction in positive wells was achieved at concentrations between 50 and 100 ⁇ M PDTC, complete inhibition of the cytopathic effect was achieved at a concentration of 600 ⁇ M PDTC for all viruses.
- Example 10 Determination of the PDTC effect in vivo
- Example 11 Antiviral Activity of PDTC against Equine Rhinitis A Virus (ERAV)
- EAV Equine Rhinitis A Virus
- Fig. 12 shows that the virus titer (vt) in the supernatant decreases compared to untreated cells (-).
- Example 12 Effect of PDTC on the multiplication of foot-and-mouth disease virus (FMD) in cell culture
- IB-RS-2 cells were cultivated in 96-well microtiter plates and infected with FMD virus O-Manisa with 0.1 TCID50 per cell and incubated at 37 ° C. for 1 hour. The inoculum was then removed and infection medium with the indicated concentrations of PDTC (10 ⁇ M to 1200 ⁇ M) was added. The number of infected wells was determined by microscopic observation of the cytopathic effect after 24 hours.
- Fig. 13A it is shown that the number of infected wells (% pos.) After 24 h is dependent on the PDTC concentration. 600 ⁇ M PDTC protect the cells 100% against virus-related cytopathic effects. A 50% reduction in infected wells is achieved in the concentration range between 75 ⁇ M and 150 ⁇ M.
- IB-RS-2 cells in T25cm 2 cell culture bottles were infected with FMD virus O-Manisa with 0.001 TCID50 per cell and incubated for 1 hour at 37 ° C. The inoculum was then removed and infection medium with the specified concentrations PDTC (0 ⁇ M to 200 ⁇ M) added. The supernatants were removed 24 hours after the infection and the viral titer (TCID) was determined in a standard plate assay.
- the virus titer of FMD virus O-Manisa in the presence of PDTC is reduced by more than 2 log levels compared to the control sample (0). No PDTC was added to the control sample.
- Example 13 Effect of PDTC on the proliferation of TBE in cell culture
- TBE viruses are neither picornaviruses nor do they trigger a disease in the respiratory tract.
- Confluent monolayers of BHK-21 cells were infected with 10 pfu / cell FSME virus (Neudörfel) in the presence of the following concentrations of PDTC: 1000 ⁇ M, 500 ⁇ M, 250 ⁇ M, 125 ⁇ M, 62.5 ⁇ M, 31, 25 uM, 15.6 uM, 7.8 uM, 3.9 uM, 1.95 uM, 0.975 uM.
- Virus replication was determined using an enzyme immunoassay. The microscopic analysis shows no evidence of toxic effects of PDTC. A quantification of virus replication shows that PDTC is not able to reduce virus replication in any of the concentrations tested.
- mice were infected intraperitoneally with 10 TCID50 EMC viruses.
- the control group was then treated intraperitoneally once a day with 50 ⁇ l PBS.
- Two other groups were treated with 50 ⁇ l 50 mM PDTC per day, with one group treatment was started at the same time as the infection (PDTC), in the other group only 24 hours after the infection (PDTC 24hpi).
- FIG. 14 shows the change in mouse weight after the start of the infection. It is clearly evident that treated and untreated animals do not differ. On average, death occurs in all groups in 5.5 days in the infected mice.
- PDTC has no effect on an EMC infection, which is a picornavirus but does not cause disease in the respiratory tract but in nerve cells.
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Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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SI200230243T SI1406607T1 (sl) | 2001-07-16 | 2002-07-15 | Uporaba razreda antivirusnih spojin (ditiokarbamatne spojine) za pripravo sredstva za zdravljenje oz. preprecevanje virusne infekcije v resporatornemtraktu |
AT02759851T ATE311181T1 (de) | 2001-07-16 | 2002-07-15 | Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt |
DK02759851T DK1406607T3 (da) | 2001-07-16 | 2002-07-15 | Anvendelse af en klasse antivirale forbindelser til at fremstille et stof til at behandle eller forhindre en virusinfektion i luftvejene |
EP02759851A EP1406607B1 (de) | 2001-07-16 | 2002-07-15 | Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt |
DE50205128T DE50205128D1 (de) | 2001-07-16 | 2002-07-15 | Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt |
CA002454167A CA2454167A1 (en) | 2001-07-16 | 2002-07-15 | Use of a class of antiviral compounds to produce an agent for treating or preventing a virus infection in the respiratory tract |
US10/483,975 US7282599B2 (en) | 2001-07-16 | 2002-07-15 | Dithiocarbamate antiviral agents and methods of using same |
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ATA1102/01 | 2001-07-16 | ||
AT11032001 | 2001-07-16 | ||
ATA1103/01 | 2001-07-16 | ||
AT11022001 | 2001-07-16 | ||
ATA1973/01 | 2001-12-17 | ||
ATA1972/01 | 2001-12-17 | ||
AT19732001A AT411149B (de) | 2001-07-16 | 2001-12-17 | Verwendung von dithiocarbamaten zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen bereich |
AT19722001 | 2001-12-17 |
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PCT/AT2002/000206 WO2003007935A2 (de) | 2001-07-16 | 2002-07-15 | Verwendung einer antiviralen verbindungsklasse (dithiocarbamat-verbindungen) zur herstellung eines mittels zur behandlung bzw. prävention einer virusinfektion im respiratorischen trakt |
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US (1) | US7282599B2 (de) |
EP (1) | EP1406607B1 (de) |
CN (1) | CN1549709A (de) |
AT (1) | ATE311181T1 (de) |
CA (1) | CA2454167A1 (de) |
DE (1) | DE50205128D1 (de) |
DK (1) | DK1406607T3 (de) |
ES (1) | ES2250692T3 (de) |
SI (1) | SI1406607T1 (de) |
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WO2022266330A1 (en) * | 2021-06-16 | 2022-12-22 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Compounds that synergize with copper to kill streptococcus pneumoniae |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51139632A (en) * | 1975-05-26 | 1976-12-02 | Kao Corp | A polycyclic dithiocarbamate antiviral agent for animals |
WO1995003792A1 (de) * | 1993-07-29 | 1995-02-09 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Verwendung von thiolverbindungen zur therapie von viralen erkrankungen |
WO1999008665A2 (de) * | 1997-08-13 | 1999-02-25 | Peter Hofschneider | Verwendung von thiolverbindungen zur inaktivierung von viren |
WO1999064068A1 (en) * | 1998-06-12 | 1999-12-16 | Mount Sinai School Of Medicine Of The City University Of New York | Attenuated negative strand viruses with altered interferon antagonist activity for use as vaccines and pharmaceuticals |
US6093743A (en) * | 1998-06-23 | 2000-07-25 | Medinox Inc. | Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor |
WO2001051046A1 (en) * | 2000-01-14 | 2001-07-19 | University Of Virginia Patent Foundation | Airway alkalinization as therapy for airway diseases |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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NL220927A (de) * | 1956-10-26 | |||
US3786143A (en) | 1968-12-23 | 1974-01-15 | Haessle Ab | Method for treating virus infection affecting the brain |
HU171736B (hu) | 1974-12-11 | 1978-03-28 | Eszakmagyar Vegyimuevek | Fungicid soderzhahhij 8-oksikhinolin v kachestve aktivnogo vehhestva i sposob poluchenija aktivnogo vehhestva |
US5686436A (en) * | 1993-05-13 | 1997-11-11 | Hiv Diagnostics, Inc. | Multi-faceted method to repress reproduction of latent viruses in humans and animals |
-
2002
- 2002-07-15 DK DK02759851T patent/DK1406607T3/da active
- 2002-07-15 DE DE50205128T patent/DE50205128D1/de not_active Expired - Fee Related
- 2002-07-15 ES ES02759851T patent/ES2250692T3/es not_active Expired - Lifetime
- 2002-07-15 CN CNA028171357A patent/CN1549709A/zh active Pending
- 2002-07-15 US US10/483,975 patent/US7282599B2/en not_active Expired - Fee Related
- 2002-07-15 EP EP02759851A patent/EP1406607B1/de not_active Expired - Lifetime
- 2002-07-15 WO PCT/AT2002/000206 patent/WO2003007935A2/de active IP Right Grant
- 2002-07-15 SI SI200230243T patent/SI1406607T1/sl unknown
- 2002-07-15 AT AT02759851T patent/ATE311181T1/de not_active IP Right Cessation
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51139632A (en) * | 1975-05-26 | 1976-12-02 | Kao Corp | A polycyclic dithiocarbamate antiviral agent for animals |
WO1995003792A1 (de) * | 1993-07-29 | 1995-02-09 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Verwendung von thiolverbindungen zur therapie von viralen erkrankungen |
WO1999008665A2 (de) * | 1997-08-13 | 1999-02-25 | Peter Hofschneider | Verwendung von thiolverbindungen zur inaktivierung von viren |
WO1999064068A1 (en) * | 1998-06-12 | 1999-12-16 | Mount Sinai School Of Medicine Of The City University Of New York | Attenuated negative strand viruses with altered interferon antagonist activity for use as vaccines and pharmaceuticals |
US6093743A (en) * | 1998-06-23 | 2000-07-25 | Medinox Inc. | Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor |
WO2001051046A1 (en) * | 2000-01-14 | 2001-07-19 | University Of Virginia Patent Foundation | Airway alkalinization as therapy for airway diseases |
Non-Patent Citations (1)
Title |
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PATENT ABSTRACTS OF JAPAN vol. 001, no. 027 (C-008), 28. März 1977 (1977-03-28) & JP 51 139632 A (KAO CORP), 2. Dezember 1976 (1976-12-02) * |
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ATE311181T1 (de) | 2005-12-15 |
WO2003007935A3 (de) | 2003-09-12 |
EP1406607B1 (de) | 2005-11-30 |
ES2250692T3 (es) | 2006-04-16 |
US20060069153A1 (en) | 2006-03-30 |
US7282599B2 (en) | 2007-10-16 |
DK1406607T3 (da) | 2006-04-10 |
DE50205128D1 (de) | 2006-01-05 |
SI1406607T1 (sl) | 2006-04-30 |
CN1549709A (zh) | 2004-11-24 |
EP1406607A2 (de) | 2004-04-14 |
CA2454167A1 (en) | 2003-01-30 |
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