WO1998043625A1 - Use of amantadine for treatment of hepatitis c - Google Patents
Use of amantadine for treatment of hepatitis c Download PDFInfo
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- WO1998043625A1 WO1998043625A1 PCT/US1998/006302 US9806302W WO9843625A1 WO 1998043625 A1 WO1998043625 A1 WO 1998043625A1 US 9806302 W US9806302 W US 9806302W WO 9843625 A1 WO9843625 A1 WO 9843625A1
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- WO
- WIPO (PCT)
- Prior art keywords
- hepatitis
- patient
- amantadine
- infection
- administration
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Classifications
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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
- A61K31/13—Amines
-
- 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
Definitions
- the present invention pertains to the treatment patients with viral disease utilizing pharmaceutical compositions.
- the present invention pertains to methods for the treatment of Hepatitis C viral infection in humans with amantadine.
- HCV hepatitis C virus
- liver failure due to hepatitis C infection is the most common indication for liver transplantation in many centers [Ascher et al. Hepatology 20 [suppl]:24-27,
- the present invention contemplates the treatment of patients with viral infection utilizing pharmaceutical agents.
- the pharmaceutical agents of the present invention are cyclic amines and preferably cyclic primary amines.
- the pharmaceutical agent is amantadine and the viral infection is
- One embodiment of the present invention contemplates a) providing: i) a patient having symptoms of Hepatitis C infection, and ii) amantadine; and b) administration of a therapeutically effective dose of said amantadine to said patient under conditions such that said symptoms of said infection is reduced.
- the administration is enteral administration.
- said enteral administration is oral administration, and in another embodiment, said enteral administration utilizes polymeric microspheres.
- said administration is parenteral administration.
- said parenteral administration can be topical administration or by a transdermal patch.
- said parenteral administration is subcutaneous admimstration.
- said parenteral administration utilizes an aerosol.
- the present invention is not limited by the nature of the patient.
- said patient is a naive patient (e.g., has not undergone prior treatment for Hepatitis C infection), while in other embodiments said patient is untreatable with interferon (e.g., cannot tolerate interferon or whose condition is unresponsive to interferon).
- said patient is immunocompromised. In one embodiment, said patient is less than eighteen years of age.
- said present invention is also not limited by the method of determining response to treatment.
- said symptoms comprise elevated alanine aminotransferase levels in the blood (e.g., serum) of said patient, while in other embodiments, said symptoms comprise Hepatitis C ribonucleic acid or HCV antibody levels in said patient.
- said symptoms comprise the histology of a liver biopsy that is consistent with hepatitis C infection.
- amantadine is in the form of a salt (e.g., amantadine hydrochloride).
- the present invention is not limited by the type of Hepatitis C infection.
- said Hepatitis C infection is chronic Hepatitis C infection, while in another embodiment, said Hepatitis C infection is acute Hepatitis C infection.
- enteral administration means the introduction of a composition to a patient such that it is absorbed in the intestinal tract of the patient (e.g., pill, tablet, elixir, etc.)
- oral administration means the introduction of a composition to a patient through the oral cavity (i.e., in the mouth).
- parenteral administration means administration of a composition other than enteral (e.g., injection, transdermal, aerosol, etc.).
- topical administration means the introduction of a composition to a patient by application to the surface of the skin.
- subcutaneous administration means introduction of a composition to a patient under the surface of the skin (e.g., injection with a hypodermic needle).
- nonaive patient refers to a patient that has not undergone prior treatment for Hepatitis C infection.
- untreatable with interferon refers to a patient that cannot tolerate the side-effects of interferon or whose viral infection is unresponsive to or has relapsed after interferon treatment.
- immunocompromised refers to a patient whose immune response is inhibited by medical condition such as leukopenia or autoimmune diseases (e.g., AIDS) or by intentional treatment (e.g., cyclosporin for organ transplant recipients).
- medical condition such as leukopenia or autoimmune diseases (e.g., AIDS) or by intentional treatment (e.g., cyclosporin for organ transplant recipients).
- chronic Hepatitis C infection refers to an infection of a patient with the Hepatitis C virus that has lasted for more than six months.
- acute Hepatitis C infection refers to an infection of a patient by the Hepatitis C virus that has lasted for less than six months.
- symptoms of Hepatitis C infection refers to signs and evidence that are associated with Hepatitis C viral infection. Such signs and evidence may be subjective (e.g., fatigue) or objective (e.g., inflammation of the liver, elevated alanine aminotransferase levels in the blood, presence of HCV RNA or HCV antibodies).
- Figure 1 illustrates the reduction of patient mean serum alanine aminotransferase following treatment with amantadine.
- Figure 2 illustrates the change in patient mean serum alanine aminotransferase levels over time with amantadine treatment.
- the present invention contemplates the use of a pharmaceutical agent for the treatment of viral infection.
- the pharmaceutical agent is a cyclic amine and preferably a cyclic primary amine.
- the pharmaceutical agent is amantadine.
- Amantadine a drug developed in the 1960s, has diverse uses ranging from prevention of influenza A infection to the treatment of Parkinson's disease [Aoki and Sitar, Clin Pharm 14:35-51, (1988)]. While an understanding of the precise mechanism is not necessary to carry out the methods of the present invention, it is believed that amantadine blocks events in late viral uncoating or early transcription [Skehel et al., J
- Treatment with amantadine offers several advantages over other treatment schemes (e.g., interferon). Unlike interferon, amantadine is readily absorbed when administered by the oral route, thus potentially improving patient safety and compliance. Amantadine is fairly well tolerated with few side effects, and the cost of amantadine is considerably less than interferon.
- the present invention is not limited by the nature of the prior treatment of the subject, it is contemplated that the present invention be utilized in patients who have not undergone prior treatment for their condition (i.e., naive patients), as well as patients who have not responded to interferon or other treatments.
- patients who have not undergone prior treatment for their condition i.e., naive patients
- patients who have not responded to interferon or other treatments i.e., naive patients
- retreatment or dose escalation with interferon in patients who have failed standard therapy has not been beneficial [ Taliani et al., Arch Virol Suppl 4:294-298, (1992) and Marcellin et al., Gastroenterology 109:156-165, (1995)], in these patients, amantadine is useful.
- the present invention is not limited by the sensitivities of the patient to other treatments, and in one embodiment it is contemplated that the present invention be used with patients who cannot tolerate the side effects of interferon. Additionally, since amantadine does not depress leukocyte counts or significantly augment immunity, in one embodiment the present invention is used in patients with leukopenia, autoimmune diseases, or organ transplants in addition to HCV. Unlike interferon. in one embodiment, the present invention is used in children under eighteen years of age with HCV. 1-Aminoadamantane hydrochloride (amantadine hydrochloride) is available commercially as an antiviral under the name Symmetrel (E. I. du Pont de Nemours and Company, Wilmington, Del.).
- Amantadine hydrochloride may also be prepared as known in the art, e.g., as described in U.S. Pat. No. 3,310,469.
- the present invention also contemplates the use of amantadine derivatives.
- the (1-) position of adamantane has also been substituted with -CH(CH 3 )NH 2 [U.S. Patent No. 5,599,998 to Kraus, herein incorporated by reference].
- the resulting compound is available commercially under the name Rimantadine which is also used in the treatment and prevention of influenza A.
- amantadine non-specifically inhibits viral entry into the cell by altering the pH of the endocytic vesicle. At lower concentration (about 5 microM), it is believed that amantadine exhibits a selective strain- specific inhibition of virus assembly [Hay and Zambon, Dev. Mol. Virol. 4:301-15(1984)].
- the present invention is not limited by the method of administration of amantadine. In one embodiment, it is by conventional means available for use in conjunction with pharmaceuticals; either in combination with one another or in combination with other therapeutic agents.
- Other therapeutic agents include, but are not limited to, antiviral agents, such as interferon or ribavirin. It is contemplated that the methods of the present invention be administered alone or can be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- amantadine is administered orally in solid dosage forms, such as capsules, tablets, or powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; however, it can also be administered parenterally, in sterile liquid dosage forms, or rectally in the form of suppositories.
- the dosage is increased to overcome a non-responsive condition.
- amantadine can be employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral (e.g., topical application) or enteral (e.g., oral) which do not deleteriously react with the active compounds.
- conventional excipients i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral (e.g., topical application) or enteral (e.g., oral) which do not deleteriously react with the active compounds.
- Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose, amylose, or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, merely to name a few.
- the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifier, salts for influencing osmotic pressure, buffers, coloring, flavoring, and/or aromatic substances and the like which do no deleteriously react with the active compounds. They can also be combined where desired with other agents, e.g. vitamins.
- auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifier, salts for influencing osmotic pressure, buffers, coloring, flavoring, and/or aromatic substances and the like which do no deleteriously react with the active compounds.
- auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifier, salts for influencing osmotic pressure, buffers, coloring, flavoring, and/or aromatic substances and the like which do no deleteriously
- compositions can be formulated, e.g., liposomes or those wherein the active compound is protected with differentially degradable coating, e.g., by microencapsulation, multiple coatings, etc.
- the present invention may be introduced into a subject in polymeric microspheres for the controlled release of the compound.
- Methods of producing microspheres from polymer can be found in U.S. Patent No. 5,601,844 to
- injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants including suppositories.
- Nebulizers and inhalation aerosols may also be used.
- Ampules are in convenient unit dosages. It is also possible to freeze-dry the new compounds and use the lypophilizates obtained, for example, for the preparation of products for injection.
- viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water.
- suitable formulations include but are not limited to transdermal patches, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservations, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure, etc.
- sprayable aerosol preparations wherein amantadine, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with pressurized volatile, normally gaseous propellant, e.g., a freon.
- the application of these embodiments can be to the skin or mucous membrane or in the interior of the body and can be oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intervenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, subcutaneous.
- the parenteral preparations are preferably sterile or sterilized products.
- U.S. Patent No. 4,895,727 to Allen herein incorporated by reference, describes a method of inducing a reservoir effect in skin and mucous membranes so as to enhance penetration and retention and reduce transdermal flux of topically applied therapeutic and cosmetic pharmacologically active agents.
- U.S. Patent No. 4,557,934 to Cooper herein incorporated by reference, describes topical pharmaceutical compositions containing a pharmaceutically-active agent and the penetration enhancing agent, l-dodecylazacycloheptan-2-one. This composition provides marked transepidermal and percutaneous delivery of the selected pharmaceutically-active agent.
- Suppositories containing amantadine can be created using a suitable oleaginous or water-soluble base.
- the oleaginous class includes cocoa butter and fats with similar properties: the water-soluble class includes polyethylene glycols.
- Other medicaments containing amantadine can be produced in a known manner, whereby the known and customary pharmaceutical adjuvants as well as other customary carrier and diluting agents can be used.
- Examples include, but are not limited to, gelatins, natural sugars such as sucrose or lactose, lecithin, pectin, starch (for example cornstarch), alginic acid, tylose, talc, lycopodium, silica (for example colloidal silica), glucose, cellulose, cellulose derivatives for example, cellulose ethers in which the cellulose hydroxyl group are partially etherified with lower aliphatic alcohols and/or lower saturated oxyalchohols, for example, methyl hydroxypropyl cellulose, methyl cellulose, cellulose phthalate, stearates, e.g., methylstearate and glyceryl stearate, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially saturated acids (for example, calcium stearate, calcium laurate, magnesium oleate, calcium palmitate, calcium behenate and magnesium stearate), emulsifiers, oils and fats, especially of plant origin
- glyceryl monostearate e.g. glyceryl distearate, glyceryl tristearate, glyceryl trilaurate
- pharmaceutically compatible mono- or polyvalent alcohols and polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, and other polyethylene glycols, as well as derivatives of such alcohols and polyglycols, esters of saturated and unsaturated fatty acids (2 to 22 carbon atoms, especially 10 to 18 carbon atoms), with monohydricaliphatic alcohols (1 to 20 carbon atom alkanols), or polyhydric alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, glyceryl trilaurate
- esters of polyvalent alcohols can in a given case be etherified, benzyl benzoate, dioxolane, glycerine formal, tetrahydrofurfuryl alcohol, polyglycol ethers with 1 to 12 carbon atom alcohols, dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate, ethyl carbonate, silicones (especially middle viscosity dimethyl polysiloxane).
- adjuvants can also be substances which bring about decomposition (so-called explosives) such as: cross-linked polyvinyl pyrrolidone, sodium carboxy methyl starch, sodium carboxy methyl cellulose or microcrystalline cellulose.
- coating agents such as e.g. polyacrylates, cellulose ethers and the like can be used.
- water of physiologically compatible organic solvents as for example, ethanol, 1,2-propylene glycol, polyglycols, e.g., diethylene glycol, triethylene glycol and dipropylene glycol and their derivatives dimethyl sulfoxide, fatty alcohols, e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and oleyl alcohol, triglycerides, e.g.
- glyceryl delate glyceryl stearate, glyceryl palmitate, and glyceryl acetate, partial esters of glycerine, e.g., glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, paraffins, and the like.
- non-toxic parenterally compatible diluting agents or solvents can be used, for example: Water, 1,3 butane diol, ethanol, 1,2-propylene glycol, polyglycols in a mixture with water, Ringer's solution, isotonic solution of sodium chloride or also hardened oils including synthetic mono or diglycerides or fatty acids like oleic acid.
- solution assistants or emulsifiers can be used in the production of the preparations.
- polyoxyethylated means in this context that the substances in question contain polyoxyethylene chains whose polymerization is generally between 2 to 40 and especially between 10 to 20.
- Such polyoxyethylated substances can be obtained, for example, by reacting compounds containing hydroxyl groups (e.g. mono or diglycerides or unsaturated compounds such as, e.g., those containing the oleic acid residues) with ethylene oxide (e.g. 40 moles ethylene oxide per mole glyceride).
- ethylene oxide e.g. 40 moles ethylene oxide per mole glyceride.
- oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cotton seed oil and corn oil.
- preservatives stabilizers for example, calcium hydrogen phosphate, colloidal aluminum hydroxide, taste correctives, antioxidants and complex formers (for example, ethylene diamine tetraacetic acid) and the like.
- the pH is adjusted to about 3 to 7 with physiologically compatible acids or buffers.
- antioxidants there can be used, for example, sodiummeta bisulfite, ascorbic acid, gallic acid, alkyl gallates, e.g., methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihydroguararetic acid, tocopherols as well as tocopherol and synergists (materials which bind heavy metals by complex formation, for example, lecithin, ascorbic acid, phosphoric acid). The addition of synergists increases considerably the antioxidant activity of tocopherol.
- preservatives there can be used, for example, sorbic acid, p-hydroxybenzoic acid esters (for example, lower alkyl esters such as the methyl ester and the ethyl ester) benzoic acid, sodium benzoate. trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride, and formalin derivatives.
- sorbic acid for example, p-hydroxybenzoic acid esters (for example, lower alkyl esters such as the methyl ester and the ethyl ester) benzoic acid, sodium benzoate.
- trichloroisobutyl alcohol phenol, cresol, benzethonium chloride, and formalin derivatives.
- This example establishes the safety and efficacy of amantadine in patients with chronic hepatitis C infection who had previously failed interferon therapy.
- HCV infection was documented by detection of anti-HCV and HCV RNA in serum. The diagnosis was confirmed by percutaneous liver biopsy in all except one patient who had a coagulation defect. Patients were included who had not responded to therapy with interferon alfa-
- the previous dosage of interferon administered ranged from 3 to 10 million units (mean 4.6) three times weekly for 6 months in 15 patients and for 9 to 18 months in the remaining 7 patients.
- Laboratory values (aminotransferases, liver function tests, and complete blood count) were available and summarized from before (23.6 ⁇ 4.5 months), during, and after (12 ⁇ 2.6 months) interferon therapy.
- Exclusion criteria included a prothrombin time greater than 2 seconds over control, a bilirubin greater than 2.0 mg/dl, encephalopathy, ascites, other forms of liver disease (i.e., autoimmune, hepatitis B, alcohol), pregnancy, psychiatric illness, severe medical conditions, or coinfection with HIV virus.
- ALT and HCV RNA values were divided into one of three groups based upon responses in ALT and HCV RNA values: responders (normalization of ALT and loss of HCV RNA), partial responders (greater than 50% reduction in ALT and reduction in HCV RNA compared to the pre-treatment values), or non-responders (either no response or less than 50% reduction in ALT and HCV RNA values compared to pre-treatment levels). Patients were followed for an additional six months after the termination of amantadine to assess durability of response.
- responders normalization of ALT and loss of HCV RNA
- partial responders greater than 50% reduction in ALT and reduction in HCV RNA compared to the pre-treatment values
- non-responders either no response or less than 50% reduction in ALT and HCV RNA values compared to pre-treatment levels
- HCV RNA values fell below this level of detectability, analysis was performed by RT-PCR [Laa et al., Lancet 341 :1501-1509, (1993)] with a sensitivity capable of detecting 100 copies of HCV RNA. All serum samples were aliquoted in several smaller volumes and frozen at -70°C to prevent degradation from thawing and refreezing should retesting be necessary.
- ALT values for each patient were recorded and averaged during each of the four time intervals. All the mean values in each time interval were then averaged for comparison so that equal weight was given to each patient.
- Statistical evaluation was performed utilizing analysis of variance and two-sample t-test, with significance determined at a level of p ⁇ 0.01 to correct for multiple comparisons to control. Two patients who dropped out of the study due to side effects were considered treatment failures and were included in the non-responder group; data available from these patients was analyzed with the others by an intent-to treat basis. Results
- the age range of patients enrolling in the study was 17 to 74 years.
- the suspected source of hepatitis C was blood or blood product transfusions in 11, intravenous drug abuse in 7, and was unknown in 4 patients (Table 1).
- Figure 1 compares patient serum alanine aminotransferase levels with no treatment, during interferon therapy, no treatment following interferon therapy and during amantadine therapy. No statistically significant differences in ALT values occurred between the intervals without therapy or while on interferon. Treatment with amantadine, however, significantly lowered ALT levels compared to both intervals without therapy and compared to ALT values during interferon administration.
- HCV RNA values decreased with amantadine from 27.5 ⁇ 7.7 x 10 5 Eq/ml to undetectable levels in the responder group and from 131 ⁇ 36 to 69 ⁇ 30 x 10 5 Eq/ml in the partial responder group. Patients who responded to amantadine therapy had significantly lower pre-treatment HCV RNA titers than the non-responders (pO.Ol).
- Figure 2 demonstrates the monthly patient serum alanine aminotransferase levels according to amantadine response. In responders, normalization of ALT occurred and partial responders achieved > 50% reduction in ALT levels from baseline during the six month course of amantadine treatment. These ALT levels remained low after discontinuation of therapy.
Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU70991/98A AU7099198A (en) | 1997-03-28 | 1998-03-27 | Use of amantadine for treatment of hepatitis c |
EP98917967A EP0973510A4 (en) | 1997-03-28 | 1998-03-27 | Use of amantadine for treatment of hepatitis c |
CA002285292A CA2285292A1 (en) | 1997-03-28 | 1998-03-27 | Use of amantadine for treatment of hepatitis c |
JP54191798A JP2001521502A (en) | 1997-03-28 | 1998-03-27 | Use of amantadine for the treatment of hepatitis C |
BR9808100-4A BR9808100A (en) | 1997-03-28 | 1998-03-27 | Use of amandantine to treat hepatitis c. |
Applications Claiming Priority (2)
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US08/826,249 | 1997-03-28 | ||
US08/826,249 US5849800A (en) | 1997-03-28 | 1997-03-28 | Use of amantadine for treatment of Hepatitis C |
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WO1998043625A1 true WO1998043625A1 (en) | 1998-10-08 |
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PCT/US1998/006302 WO1998043625A1 (en) | 1997-03-28 | 1998-03-27 | Use of amantadine for treatment of hepatitis c |
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US (1) | US5849800A (en) |
EP (1) | EP0973510A4 (en) |
JP (1) | JP2001521502A (en) |
AU (1) | AU7099198A (en) |
BR (1) | BR9808100A (en) |
CA (1) | CA2285292A1 (en) |
WO (1) | WO1998043625A1 (en) |
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US5573934A (en) * | 1992-04-20 | 1996-11-12 | Board Of Regents, The University Of Texas System | Gels for encapsulation of biological materials |
US5552310A (en) * | 1992-06-12 | 1996-09-03 | Hiroshi Yoshikura | Replication of hepatitis C virus genome and identification of virus having high infectivity |
AU5434094A (en) * | 1992-11-18 | 1994-06-08 | Fujisawa Pharmaceutical Co., Ltd. | Prolonged-action pharmaceutical preparation |
US5514539A (en) * | 1993-06-29 | 1996-05-07 | The United States Of America As Represented By The Department Of Health And Human Services | Nucleotide and deduced amino acid sequences of the envelope 1 gene of 51 isolates of hepatitis C virus and the use of reagents derived from these sequences in diagnostic methods and vaccines |
US5599998A (en) * | 1994-10-24 | 1997-02-04 | Iowa State University Research Foundation, Inc. | Method for the synthesis of adamantane amines |
AU5157998A (en) * | 1996-11-01 | 1998-05-29 | Thomas Najarian | Methods and compositions for treatment of hepatitis c infection |
-
1997
- 1997-03-28 US US08/826,249 patent/US5849800A/en not_active Expired - Fee Related
-
1998
- 1998-03-27 BR BR9808100-4A patent/BR9808100A/en not_active IP Right Cessation
- 1998-03-27 AU AU70991/98A patent/AU7099198A/en not_active Abandoned
- 1998-03-27 WO PCT/US1998/006302 patent/WO1998043625A1/en not_active Application Discontinuation
- 1998-03-27 JP JP54191798A patent/JP2001521502A/en active Pending
- 1998-03-27 EP EP98917967A patent/EP0973510A4/en not_active Withdrawn
- 1998-03-27 CA CA002285292A patent/CA2285292A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5502080A (en) * | 1994-11-01 | 1996-03-26 | Hitzig; Pietr | Combined use of dopamine and serotonin agonists in the treatment of allergic disorders |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999013894A2 (en) * | 1997-09-18 | 1999-03-25 | F. Hoffmann-La Roche Ag | Use of ifn-alpha and amantadine for the treatment of chronic hepatitis c |
WO1999013894A3 (en) * | 1997-09-18 | 1999-06-03 | Hoffmann La Roche | Use of ifn-alpha and amantadine for the treatment of chronic hepatitis c |
Also Published As
Publication number | Publication date |
---|---|
JP2001521502A (en) | 2001-11-06 |
BR9808100A (en) | 2000-03-08 |
US5849800A (en) | 1998-12-15 |
EP0973510A1 (en) | 2000-01-26 |
EP0973510A4 (en) | 2002-05-08 |
AU7099198A (en) | 1998-10-22 |
CA2285292A1 (en) | 1998-10-08 |
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