WO2010009762A1 - Interferon and an agent inducing inhibition of protein phosphatase 2a such as interleukin- 1 and optionally ribavirin for the treatment of hbv or hcv infection - Google Patents

Interferon and an agent inducing inhibition of protein phosphatase 2a such as interleukin- 1 and optionally ribavirin for the treatment of hbv or hcv infection Download PDF

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Publication number
WO2010009762A1
WO2010009762A1 PCT/EP2008/059643 EP2008059643W WO2010009762A1 WO 2010009762 A1 WO2010009762 A1 WO 2010009762A1 EP 2008059643 W EP2008059643 W EP 2008059643W WO 2010009762 A1 WO2010009762 A1 WO 2010009762A1
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Prior art keywords
interleukin
pharmaceutical formulation
interferon
pharmaceutical
pharmaceutical kit
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PCT/EP2008/059643
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French (fr)
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Igor Anatolievich Pomytkin
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United Technologies Ut Ag
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Application filed by United Technologies Ut Ag filed Critical United Technologies Ut Ag
Priority to UAA201102255A priority Critical patent/UA106591C2/en
Priority to EA201100322A priority patent/EA022952B1/en
Priority to PCT/EP2008/059643 priority patent/WO2010009762A1/en
Publication of WO2010009762A1 publication Critical patent/WO2010009762A1/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to pharmaceutical kits containing interferons and agents inducing inhibition protein phosphatase 2A (PP2A) for the treatment of viral diseases.
  • P2A protein phosphatase 2A
  • HCV Hepatitis B
  • HCV Hepatitis B
  • HCV C
  • interferons e.g. pegylated interferons
  • antiviral drug ribavirin for a period of 24 to 48 weeks depending on genotype HCV and average therapeutic efficacy of about 50%.
  • the therapeutic effectiveness of interferons is diminished because of an impaired biological response to0 interferon caused by virus countermeasures to interferon action.
  • PP2A is a ubiquitous serine/threonine phosphatase critical to cell signaling.
  • PP2A could be temporarily inhibited by tyrosine phosphorylation of Tyr307 of the catalytic subunit by numerous receptor and non-receptor tyrosine kinases (e.g. Jak2, pp60 src ) stimulated by insulin, IGF-1 , EGF, growth hormone, some interleukins capable to activate Janus kinase 2 (Jak2) such as IL-1 , IL-2, IL-3, IL-5, IL-6, IL-11 , IL- 12, IL-13, and other protein up-regulators of Jak2 such as EPO, G-CSF, GM-CSF, TPO, CNTF, CT-1 , LIF, and OSM.
  • Jak2 receptor and non-receptor tyrosine kinases
  • kits and methods for treating HCV infection comprising interferon as immunomodulatory agent in combinations with immunogenic polypeptides.
  • US Patent No 6,905,677 discloses kits comprising a nucleoside analogue (e.g. lamivudine, adefovir, or entecavir) in a first container and interferon-alpha in a second container and method of treating a human patient infected with hepatitis B virus.
  • kits and antiviral compositions comprising interferon in combinations with cyclaradine.
  • US Patent No 5,250,296 discloses kits and compositions for immunostimulating mammals comprising interferon as a cytokine in combinations with interleukin-1 and 5'-deoxy-5-flourouridine.
  • US Patent no 5,667,797 discloses kits and antiviral compositions comprising interferon in combinations with milk proteins.
  • US Patent No 5,422,097 discloses kits and compositions for treating common cold comprising interferon as antiviral agent in combination with antiinflammatory compounds specific for inflammatory pathways.
  • US Patent No 6,846,810 discloses method of treatment of hepatitis C by interferon as immune system modulator in combination with antiviral nucleoside derivatives.
  • US Patent No 6,849,254 discloses method for treating hepatitis C by interferon in combination with ribavirin and vitamin C or E.
  • US Patent No 6,387,365 discloses method for treating hepatitis C by interferon in dose below 3 million IU weekly in combination with ribavirin.
  • US Patent 6,177,074 discloses method for treating hepatitis C by pegylated interferon in combination with ribavirin.
  • Interleukin-1 induces inactivation of PP2A in cells. Guv GR, Philp R and Tan YH. Eur. J. Biochem. 1995 229, 503-511.
  • the use of interleukin-1 for monotherapy of hepatitis is disclosed in the art.
  • US Patent No 5,723,117 discloses the method for inhibiting development of hepatitis with the use of interleukin-1 and derivatives thereof.
  • EP0495131 discloses an agent for preventing and treating hepatitis containing interleukin-1 and derivatives thereof.
  • nothing is published or disclosed in the art related to the use interleukin-1 in combination with interferons to increase effectiveness of antiviral interferon therapy.
  • a pharmaceutical kit for treating a viral disease e.g. HCV or HBV
  • a first pharmaceutical formulation containing an interferon e.g. HCV or HBV
  • a second pharmaceutical formulation containing an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells.
  • the pharmaceutical kit further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation and said second pharmaceutical formulation.
  • interferon refers to a protein which exerts virus nonspecific, antiviral activity at least in homologous cells through cellular metabolic processes involving synthesis of both RNA and protein.
  • the term thus includes interferons which are chemically synthesized or expressed using recombinant protein expression systems that use, for example, E-coli or yeast as the host.
  • the present invention is not limited in any way to specific interferon but is applicable to all such interferon now known or subsequently discovered or developed. Nonetheless, a preferred interferon for use in the methods and compositions of this invention is type I interferon, biologically active analogues and derivatives thereof.
  • type I interferon refers to a class interferons including, but are not limiting to, interferon-alpha, interferon- beta, and interferon-omega.
  • analogue of type I interferon refers to an interferon that contains one or more amino acid substitutions, deletions, additions, or rearrangements compared with human interferon at sites such that the interferon analogue still retains the in vivo biological activity of interferon.
  • the term "derivative of type I interferon” refers to naturally occurring type I interferons and interferon analogues that are chemically or enzymatically derivatized at one or more constituent amino acids, including side chain modifications, backbone modifications, and N- and C- terminal modifications, by for example acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and that retain the in vivo biological activity of interferon.
  • An example of the interferon derivative is pegylated interferon.
  • the amount of interferon in the first formulation unit dosage to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein.
  • the first formulation may contain interferon in a dosage range from about 1 to about 3x10 6 IU interferon- alpha, or about 100 to 200 ⁇ g of pegylated interferon per unit dosage form.
  • the first pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems.
  • the first pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the first pharmaceutical formulation is administered parenterally.
  • insulin sensitizer refers to any agent capable to increase biological response to exogenous or endogenous insulin.
  • insulin sensitizers include, but are not limited to, Metformin, Acadesine, thiazolidinediones, and succinic acid or salts thereof.
  • Nonexclusive examples of thiazolidinediones include rosiglitazone and pioglitazone.
  • the second pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems.
  • the second pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the second pharmaceutical formulation is administered parenterally.
  • the amount of inhibitor of PP2A in a unit dosage of the second formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein.
  • the second pharmaceutical formulation comprising interleukin-1 alpha or beta.
  • interleukin-1 refers to proteins having the amino acid sequences and structure of naturally occurring human interleukin-1 alpha or beta, and biologically active analogues and derivatives thereof.
  • the term thus includes interleukin-1 alpha or beta which is chemically synthesized or expressed using recombinant protein expression systems that use, for example, E-coli or yeast as the host.
  • a preferred interleukin-1 alpha is human interleukin-1 alpha expressed using a protein expression system.
  • a preferred interleukin-1 beta is human interleukin-1 beta expressed using a protein expression system.
  • analogue of interleukin-1 refers to an interleukin-1 alpha or beta that contains one or more amino acid substitutions, deletions, additions, or rearrangements compared with human interleukin-1 alpha or beta at sites such that the interleukin-1 analogue still retains the in vivo biological activity of interleukin-1.
  • interleukin-1 alpha analogues examples include Asp36-interleukin-1 alpha and Ser141 -interleukin-1 alpha.
  • interleukin-1 beta analogues examples include OCT-43 (Otsuka Pharmaceutical Co., Ltd., Tokyo,
  • interleukin-1 refers to naturally occurring interleukin-1 alpha or beta and interleukin-1 alpha or beta analogues that are chemically or enzymatically dehvatized at one or more constituent amino acids, including side chain modifications, backbone modifications, and N-and C- terminal modifications, by for example acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and that retain the in vivo biological activity of interleukin-1.
  • An example of an interleukin-1 alpha derivative is N6-myristoyl-l_ys11 -interleukin-1 alpha and HisTag- interleukin-1 alpha.
  • An example of an interleukin-1 beta derivative is myhstoyl-Lys16-interleukin-1 beta and HisTag-interleukin-1 beta.
  • the amount of interleukin-1 in a unit dosage of the second formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein.
  • the second formulation may contain interleukin-1 in a dosage range from about 0.01 to about 1000 ⁇ g per unit dosage form.
  • the interleukin- 1 is administered parenterally. More preferably, the interleukin-1 is administered by injection route, e.g. intramuscular, subcutaneous, or intravenous.
  • the interleukin-1 is administered orally in form of aqueous solution.
  • the pharmaceutical kit of the invention may comprise a third pharmaceutical formulation comprising ribavirin and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical kit further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation, said second pharmaceutical formulation, and said third pharmaceutical formulation.
  • the viral disease is hepatitis B or C.
  • the amount of ribavirin in a unit dosage of the third formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein.
  • the first formulation may contain ribavirin in a dosage range from about 50 to about 300 ⁇ g per unit dosage form.
  • the third pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems.
  • the third pharmaceutical formulation is formulated in form of tablets.
  • the third pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the third pharmaceutical formulation is administered orally.
  • the term "pharmaceutically acceptable carrier or excipient” refers to one or more liquid, semi-solid, or solid filler, diluents, which are safe and non-toxic and are compatible with the active and optional ingredients of the present invention.
  • examples of such carriers include, but are not limited to, water for injections, lactose, and sucrose.
  • Dosage forms of the present invention may further comprise optional ingredients.
  • optional ingredients generally are used individually at levels from about 0.0005% to about 10.0%, preferably from about 0.005% to about 1.0% by weight of the composition.
  • suitable optional ingredients include, but are not limited to, buffers, colorants, flavorants, solvents and co-solvents, coating agents, lubricants, opaquants, sweetening agents, anti-adherents, binders, and capsule diluents, anti-fungal preservatives, antimicrobial preservatives, clarifying agents, emulsifying agents, antioxidants, surfactants, tonicity agents, and viscosity increasing agents.
  • the dosage forms comprise a buffer at a concentration effective to maintain the pH of the composition at between about 4.0 to about 7.5.
  • buffers include, but are not limited to, phosphate buffer, acetate, citrate buffer, and glycine buffer.
  • the dosage forms of the present invention are prepared by well-known procedures. Such procedures include, but are not limited to, mixing the active components with other ingredients of the composition in conventional manner. Guidance for the preparation of cosmetic or dermatological compositions of the invention can be found in " Remington:
  • the present invention provides a method for treating a viral disease which comprises administering to a subject in need thereof the first pharmaceutical formulation and the second pharmaceutical formulation of the present invention.
  • the method further comprising administering to a subject in need thereof the third pharmaceutical formulation of the present invention.
  • the first and second pharmaceutical formulations may be administered stepwise or simultaneously depending on pharmacokinetic and pharmacodynamic properties of formulations and routes of administration.
  • the first and second pharmaceutical formulations are administered to synchronize peaks of blood concentrations of interferon from the first pharmaceutical formulation and the stimulator of PP2A inhibition from the second pharmaceutical formulation.
  • viral disease refers to a condition caused by a virus.
  • the viral disease is hepatitis B or C.
  • the present invention provides the use of an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells, the agent selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1 , epidermal growth factor, tumor necrosis factor, interleukin-1 , interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11 , interleukin-12, interleukin-13, erythropoietin, thrombopoietin, G-CSF, growth hormone, prolactin, leptin, GM-CSF, CNTF, CT-1 , LIF, and OSM for the preparation of a pharmaceutical formulation for the treatment of a viral disease in a combination with a pharmaceutical formulation comprising an interferon.
  • P2A Protein Phosphatase 2A
  • PP2A inhibitory agent e.g. interleukin-1 beta
  • the first formulation preparation Pegylated interferon-alpha2a is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the second formulation preparation Interleukin-1 beta is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the third formulation is a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the third formulation preparation Ribavirin is mixed in conventional manner with carriers and optional ingredients to prepare the tablet.
  • the first, second, and third formulations are packaged in the container.
  • the instruction describing the method of treating a viral disease which comprises administering (1 ) subcutaneously once-a-week to a subject in need thereof the first pharmaceutical formulation, (2) subcutaneously once-a-day to a subject in need thereof the second pharmaceutical formulation, and (3) orally four-times-a-day to a subject in need thereof the third pharmaceutical formulation.
  • the first formulation preparation Pegylated interferon-alpha2a is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the second formulation preparation Acadesine is dissolved in water for injection to the desired volume.
  • the solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the third formulation Acadesine is dissolved in water for injection to the desired volume.
  • the solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the third formulation Acadesine is dissolved in water for injection to the desired volume.
  • the solution is filtered through a sterilizing grade filter (0.2 ⁇ m), and filled into ampoules.
  • the third formulation preparation Ribavirin is mixed in conventional manner with carriers and optional ingredients to prepare the tablet.
  • the first, second, and third formulations are packaged in the container.
  • the instruction describing the method of treating a viral disease which comprises administering (1 ) subcutaneously once-a-week to a subject in need thereof the first pharmaceutical formulation, (2) subcutaneously once-a-day to a subject in need thereof the second pharmaceutical formulation, and (3) orally four-times-a-day to a subject in need thereof the third pharmaceutical formulation.

Abstract

The present invention relates to pharmaceutical kits comprising interferons in first pharmaceutical formulation, agents inducing inhibition of Protein Phosphatase 2A (PP2A) in second pharmaceutical formulation, and further comprising ribavirin in third pharmaceutical formulation, wherein the agents inducing inhibition of PP2A are selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1, epidermal growth factor, tumor necrosis factor, interleukin-1, interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11, interleukin-12, interleukin-13, erythropoietin, thrombopoietin, G-CSF, growth hormone, prolactin, leptin, GM-CSF, CNTF, CT-1, LIF, and OSM.

Description

United Technologies UT AG Wagistrasse 13 CH-8952 Schlieren/ZH Switzerland
INTERFERON AND AN AGENT INDUCING INHIBITION OF PROTEIN PHOSPHATASE 2A SUCH AS INTERLEUKIN-1 AND OPTIONALLY RIBAVIRIN . FOR THE TREATMENT OF HBV OR HCV INFECTION
Field of the Invention 0 [0001] The present invention relates to pharmaceutical kits containing interferons and agents inducing inhibition protein phosphatase 2A (PP2A) for the treatment of viral diseases.
Background of the invention [0002] Hepatitis B (HBV) and C (HCV) are two leading chronic viral5 diseases on worldwide basis. Current treatment of HCV is a combination of interferons, e.g. pegylated interferons, with antiviral drug ribavirin for a period of 24 to 48 weeks depending on genotype HCV and average therapeutic efficacy of about 50%. The therapeutic effectiveness of interferons is diminished because of an impaired biological response to0 interferon caused by virus countermeasures to interferon action. Growing evidence from in vitro and in vivo experiments and clinical data suggest that virus-induced overexpression of protein phosphatase 2A (PP2A) is an important pathogenic factor contributing to interferon resistance in chronic hepatitis caused by HCV and HBV. Heim MH, Moradpour D, Blum HE. J. 5 Virol. 1999, 73(10):8469-75. Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH. Gastroenterology. 2003, 124(5):1465- 75. Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH. Gastroenterology. 2004, 126(1 ):263-77. Christen V, Duong F, Bernsmeier 0 C, Sun D, Nassal M, Heim MH. J. Virol. 2007, 81 (1 ):159-65. Thus, there is the great need in safe and effective inhibitors of PP2A for the use in complex interferon therapy of HCV and HBV to increase the effectiveness of interferon therapy. [0003] PP2A is a ubiquitous serine/threonine phosphatase critical to cell signaling. It is well-documented that PP2A could be temporarily inhibited by tyrosine phosphorylation of Tyr307 of the catalytic subunit by numerous receptor and non-receptor tyrosine kinases (e.g. Jak2, pp60src) stimulated by insulin, IGF-1 , EGF, growth hormone, some interleukins capable to activate Janus kinase 2 (Jak2) such as IL-1 , IL-2, IL-3, IL-5, IL-6, IL-11 , IL- 12, IL-13, and other protein up-regulators of Jak2 such as EPO, G-CSF, GM-CSF, TPO, CNTF, CT-1 , LIF, and OSM. Janssens V, Goris J. Biochem J. 2001 ; 353(Pt 3):417-39. Chen, J., Martin, B. L., and Brautiqan, D. L., Science 257, 1992, 1261-1264. Chen J, Parsons S, Brautiqan DL. J Biol Chem. 1994; 269(11 ):7957-62. Uqi S, lmamura T, Ricketts W, Olefskv JM. MoI Cell Biol. 2002; 22(7):2375-87. Begum N, Raqolia L. Biochem J. 1999; 344 Pt 3:895-901. Fuhrer DK, Yang YC. Biochem Biophvs Res Commun. 1996 16; 224(2):289-96. Guv GR, Philp R, Tan YH. Eur J Biochem. 1995; 229(2):503-11. de Ia Torre P, Diaz-Saniuan T, Garcfa- Ruiz I, Esteban E, Canga F, Muήoz-Yagϋe T, Solfs-Herruzo JA. Cell Signal. 2005; 17(4):427-35. Rane SG, Reddv EP. Oncogene. 2002; 21 (21 ):3334-58. However, nothing is published or disclosed in the art related to the use of such agent inducing inhibition of PP2A in combination with interferons to increase effectiveness of antiviral interferon therapy.
[0004] The use of interferon combinations to increase efficacy of interferons under therapy of viral diseases is well-known from the art. US Patent No 6,682,909 discloses kits and methods for treating HCV infection comprising interferon as immunomodulatory agent in combinations with immunogenic polypeptides. US Patent No 6,905,677 discloses kits comprising a nucleoside analogue (e.g. lamivudine, adefovir, or entecavir) in a first container and interferon-alpha in a second container and method of treating a human patient infected with hepatitis B virus. US Patent No 4,636,383 discloses kits and antiviral compositions comprising interferon in combinations with cyclaradine. US Patent No 5,250,296 discloses kits and compositions for immunostimulating mammals comprising interferon as a cytokine in combinations with interleukin-1 and 5'-deoxy-5-flourouridine. US Patent no 5,667,797 discloses kits and antiviral compositions comprising interferon in combinations with milk proteins. US Patent No 5,422,097 discloses kits and compositions for treating common cold comprising interferon as antiviral agent in combination with antiinflammatory compounds specific for inflammatory pathways. US Patent No 6,846,810 discloses method of treatment of hepatitis C by interferon as immune system modulator in combination with antiviral nucleoside derivatives. US Patent No 6,849,254 discloses method for treating hepatitis C by interferon in combination with ribavirin and vitamin C or E. US Patent No 6,387,365 discloses method for treating hepatitis C by interferon in dose below 3 million IU weekly in combination with ribavirin. US Patent 6,177,074 discloses method for treating hepatitis C by pegylated interferon in combination with ribavirin. However, nothing is published or disclosed in the art related to the interferon combinations with stimulators of inhibition or inhibitors of PP2A.
[0005] Interleukin-1 induces inactivation of PP2A in cells. Guv GR, Philp R and Tan YH. Eur. J. Biochem. 1995 229, 503-511. The use of interleukin-1 for monotherapy of hepatitis is disclosed in the art. US Patent No 5,723,117 discloses the method for inhibiting development of hepatitis with the use of interleukin-1 and derivatives thereof. EP0495131 discloses an agent for preventing and treating hepatitis containing interleukin-1 and derivatives thereof. However, nothing is published or disclosed in the art related to the use interleukin-1 in combination with interferons to increase effectiveness of antiviral interferon therapy.
[0006] It is an object of the present invention to provide a pharmaceutical kit for treating a viral disease, e.g. HCV or HBV, comprising a first pharmaceutical formulation containing an interferon and a second pharmaceutical formulation containing an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells. Detailed Description of the Invention
[0007] The present invention provides a pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising an interferon and a pharmaceutically acceptable carrier or excipient; and (ii) a second pharmaceutical formulation comprising an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells, the agent selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1 , epidermal growth factor, tumor necrosis factor, interleukin-1 , interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11 , interleukin-12, interleukin-13, erythropoietin, thrombopoietin, granulocyte colony- stimulating factor (G-CSF), growth hormone, prolactin, leptin, granulocyte macrophage colony-stimulating factor (GM-CSF), ciliary neurotrophic factor (CNTF), CT-1 , leukemia inhibitory factor (LIF), and oncostatin M (OSM) and a pharmaceutically acceptable carrier or excipient.
[0008] In a preferred embodiment of the present invention, the pharmaceutical kit further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation and said second pharmaceutical formulation.
[0009] As used herein, the term "interferon" refers to a protein which exerts virus nonspecific, antiviral activity at least in homologous cells through cellular metabolic processes involving synthesis of both RNA and protein. The term thus includes interferons which are chemically synthesized or expressed using recombinant protein expression systems that use, for example, E-coli or yeast as the host. The present invention is not limited in any way to specific interferon but is applicable to all such interferon now known or subsequently discovered or developed. Nonetheless, a preferred interferon for use in the methods and compositions of this invention is type I interferon, biologically active analogues and derivatives thereof. [0010] As used herein, the term "type I interferon" refers to a class interferons including, but are not limiting to, interferon-alpha, interferon- beta, and interferon-omega.
[0011] As used herein, the term "analogue of type I interferon" refers to an interferon that contains one or more amino acid substitutions, deletions, additions, or rearrangements compared with human interferon at sites such that the interferon analogue still retains the in vivo biological activity of interferon.
[0012] As used herein, the term "derivative of type I interferon" refers to naturally occurring type I interferons and interferon analogues that are chemically or enzymatically derivatized at one or more constituent amino acids, including side chain modifications, backbone modifications, and N- and C- terminal modifications, by for example acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and that retain the in vivo biological activity of interferon. An example of the interferon derivative is pegylated interferon.
[0013] In a preferred embodiment of the present invention, the amount of interferon in the first formulation unit dosage to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. The first formulation may contain interferon in a dosage range from about 1 to about 3x106 IU interferon- alpha, or about 100 to 200 μg of pegylated interferon per unit dosage form.
[0014] In a preferred embodiment of the present invention, the first pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems. [0015] In a preferred embodiment of the present invention, the first pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the first pharmaceutical formulation is administered parenterally.
[0016] As used herein, the term "insulin sensitizer" refers to any agent capable to increase biological response to exogenous or endogenous insulin. Such insulin sensitizers include, but are not limited to, Metformin, Acadesine, thiazolidinediones, and succinic acid or salts thereof. Nonexclusive examples of thiazolidinediones include rosiglitazone and pioglitazone.
[0017] In a preferred embodiment of the present invention, the second pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems.
[0018] In a preferred embodiment of the present invention, the second pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the second pharmaceutical formulation is administered parenterally.
[0019] In a preferred embodiment of the present invention, the amount of inhibitor of PP2A in a unit dosage of the second formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. [0020] In a preferred embodiment of the present invention, the second pharmaceutical formulation comprising interleukin-1 alpha or beta.
[0021] As used herein, the term "interleukin-1 " refers to proteins having the amino acid sequences and structure of naturally occurring human interleukin-1 alpha or beta, and biologically active analogues and derivatives thereof. The term thus includes interleukin-1 alpha or beta which is chemically synthesized or expressed using recombinant protein expression systems that use, for example, E-coli or yeast as the host. A preferred interleukin-1 alpha is human interleukin-1 alpha expressed using a protein expression system. A preferred interleukin-1 beta is human interleukin-1 beta expressed using a protein expression system.
[0022] As used herein, the term "analogue of interleukin-1 " refers to an interleukin-1 alpha or beta that contains one or more amino acid substitutions, deletions, additions, or rearrangements compared with human interleukin-1 alpha or beta at sites such that the interleukin-1 analogue still retains the in vivo biological activity of interleukin-1.
Examples of interleukin-1 alpha analogues include Asp36-interleukin-1 alpha and Ser141 -interleukin-1 alpha. Examples of interleukin-1 beta analogues include OCT-43 (Otsuka Pharmaceutical Co., Ltd., Tokyo,
Japan), Gly4-interleukin-1 beta, and Ser8-interleukin-1 beta.
[0023] As used herein, the term "derivative of interleukin-1 " refers to naturally occurring interleukin-1 alpha or beta and interleukin-1 alpha or beta analogues that are chemically or enzymatically dehvatized at one or more constituent amino acids, including side chain modifications, backbone modifications, and N-and C- terminal modifications, by for example acetylation, acylation, hydroxylation, methylation, amidation, phosphorylation, pegylation, or glycosylation, and that retain the in vivo biological activity of interleukin-1. An example of an interleukin-1 alpha derivative is N6-myristoyl-l_ys11 -interleukin-1 alpha and HisTag- interleukin-1 alpha. An example of an interleukin-1 beta derivative is myhstoyl-Lys16-interleukin-1 beta and HisTag-interleukin-1 beta.
[0024] In a preferred embodiment of the present invention, the amount of interleukin-1 in a unit dosage of the second formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. The second formulation may contain interleukin-1 in a dosage range from about 0.01 to about 1000 μg per unit dosage form.
[0025] In a preferred embodiment of the present invention, the interleukin- 1 is administered parenterally. More preferably, the interleukin-1 is administered by injection route, e.g. intramuscular, subcutaneous, or intravenous.
[0026] In another preferred embodiment of the present invention, the interleukin-1 is administered orally in form of aqueous solution.
[0027] In a preferred embodiment of the present invention, the pharmaceutical kit of the invention may comprise a third pharmaceutical formulation comprising ribavirin and a pharmaceutically acceptable carrier or excipient.
[0028] In a preferred embodiment of the present invention, the pharmaceutical kit further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation, said second pharmaceutical formulation, and said third pharmaceutical formulation.
[0029] In a preferred embodiment of the present invention, the viral disease is hepatitis B or C. [0030] In a preferred embodiment of the present invention, the amount of ribavirin in a unit dosage of the third formulation to achieve the desired therapeutic effect is within the skill of those who practice in the art having the benefit of the disclosure herein. The first formulation may contain ribavirin in a dosage range from about 50 to about 300 μg per unit dosage form.
[0031] In a preferred embodiment of the present invention, the third pharmaceutical formulation may be formulated with various pharmaceutically acceptable carriers, vehicles, or diluents in the form of solutions, suspensions, emulsions, powders, granulates, tablets, capsules, pills, sprays, aerosols, buccal, sublingual or transdermal delivery systems. Preferably, the third pharmaceutical formulation is formulated in form of tablets.
[0032] In a preferred embodiment of the present invention, the third pharmaceutical formulation may be administered in a variety of routes including parenteral (e.g. subcutaneous, intravenous, or intramuscular injections), oral (e.g. through gastrointestinal tract or oral mucosa), intranasal, topical, rectal, or by inhalation spray. More preferably, the third pharmaceutical formulation is administered orally.
[0033] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to one or more liquid, semi-solid, or solid filler, diluents, which are safe and non-toxic and are compatible with the active and optional ingredients of the present invention. Examples of such carriers include, but are not limited to, water for injections, lactose, and sucrose.
[0034] Dosage forms of the present invention may further comprise optional ingredients. Such optional ingredients generally are used individually at levels from about 0.0005% to about 10.0%, preferably from about 0.005% to about 1.0% by weight of the composition. [0035] Examples of suitable optional ingredients include, but are not limited to, buffers, colorants, flavorants, solvents and co-solvents, coating agents, lubricants, opaquants, sweetening agents, anti-adherents, binders, and capsule diluents, anti-fungal preservatives, antimicrobial preservatives, clarifying agents, emulsifying agents, antioxidants, surfactants, tonicity agents, and viscosity increasing agents.
[0036] In a preferred embodiment of the present invention, the dosage forms comprise a buffer at a concentration effective to maintain the pH of the composition at between about 4.0 to about 7.5. Examples of such buffers include, but are not limited to, phosphate buffer, acetate, citrate buffer, and glycine buffer.
[0037] The dosage forms of the present invention are prepared by well- known procedures. Such procedures include, but are not limited to, mixing the active components with other ingredients of the composition in conventional manner. Guidance for the preparation of cosmetic or dermatological compositions of the invention can be found in " Remington:
The science and practice of pharmacy" 20th ed. Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3 and " Encyclopaedia of Pharmaceutical
Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc.,
New York, 1988 ISBN 0-8247-2800-9 or a newer edition.
[0038] Further, the present invention provides a method for treating a viral disease which comprises administering to a subject in need thereof the first pharmaceutical formulation and the second pharmaceutical formulation of the present invention.
[0039] In a preferred embodiment of the present invention, the method further comprising administering to a subject in need thereof the third pharmaceutical formulation of the present invention. [0040] In practicing the method of the present invention, the first and second pharmaceutical formulations may be administered stepwise or simultaneously depending on pharmacokinetic and pharmacodynamic properties of formulations and routes of administration. Preferably, the first and second pharmaceutical formulations are administered to synchronize peaks of blood concentrations of interferon from the first pharmaceutical formulation and the stimulator of PP2A inhibition from the second pharmaceutical formulation.
[0041] As used herein the term "viral disease" refers to a condition caused by a virus. Preferably, the viral disease is hepatitis B or C.
[0042] Further, the present invention provides the use of an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells, the agent selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1 , epidermal growth factor, tumor necrosis factor, interleukin-1 , interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11 , interleukin-12, interleukin-13, erythropoietin, thrombopoietin, G-CSF, growth hormone, prolactin, leptin, GM-CSF, CNTF, CT-1 , LIF, and OSM for the preparation of a pharmaceutical formulation for the treatment of a viral disease in a combination with a pharmaceutical formulation comprising an interferon.
[0043] The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example 1
[0044] This example demonstrates the inhibition of PP2A in the presence of interferon.
Inhibitory effects of substances of the present invention on PP2A activity were assessed in human hepatoma HepG2 cells with using the commercially available assay (R&D Systems, Inc., DYC3309). Briefly, HepG2 cells (1x107 cells/ml) were exposed to a combination of commercially available pegylated interferon 10 ng/ml and PP2A inhibitory agent (e.g. interleukin-1 beta) for 15 min, cells lysates were prepared and activity of PP2A in lysates was assayed as described by manufacturer. Results are presented in Table 1 as a mean ± SEM (n=8) of percentage of PP2A activity of control.
Table 1
Figure imgf000013_0001
*Differs significantly of Control (P<0.05)
Example 2
[0045] This example demonstrates the pharmaceutical kit and method for the use thereof.
The first formulation:
Figure imgf000013_0002
The first formulation preparation: Pegylated interferon-alpha2a is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
The second formulation:
Figure imgf000013_0003
The second formulation preparation: Interleukin-1 beta is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules. The third formulation:
Figure imgf000014_0001
The third formulation preparation: Ribavirin is mixed in conventional manner with carriers and optional ingredients to prepare the tablet.
The first, second, and third formulations are packaged in the container. The instruction describing the method of treating a viral disease which comprises administering (1 ) subcutaneously once-a-week to a subject in need thereof the first pharmaceutical formulation, (2) subcutaneously once-a-day to a subject in need thereof the second pharmaceutical formulation, and (3) orally four-times-a-day to a subject in need thereof the third pharmaceutical formulation.
Example 3
[0046] This example demonstrates the pharmaceutical kit and method for the use thereof.
The first formulation:
Figure imgf000014_0002
The first formulation preparation: Pegylated interferon-alpha2a is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules.
The second formulation:
Figure imgf000014_0003
The second formulation preparation: Acadesine is dissolved in water for injection to the desired volume. The solution is filtered through a sterilizing grade filter (0.2 μm), and filled into ampoules. The third formulation:
Figure imgf000015_0001
The third formulation preparation: Ribavirin is mixed in conventional manner with carriers and optional ingredients to prepare the tablet. The first, second, and third formulations are packaged in the container. The instruction describing the method of treating a viral disease which comprises administering (1 ) subcutaneously once-a-week to a subject in need thereof the first pharmaceutical formulation, (2) subcutaneously once-a-day to a subject in need thereof the second pharmaceutical formulation, and (3) orally four-times-a-day to a subject in need thereof the third pharmaceutical formulation.

Claims

Claims
1. A pharmaceutical kit comprising (i) a first pharmaceutical formulation comprising an interferon and a pharmaceutically acceptable carrier or excipient; and (ii) a second pharmaceutical formulation comprising an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells, the agent selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1 , epidermal growth factor, tumor necrosis factor, interleukin-1 , interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11 , interleukin-12, interleukin-
13, erythropoietin, thrombopoietin, G-CSF, growth hormone, prolactin, leptin, GM-CSF, CNTF, CT-1 , LIF, and OSM and a pharmaceutically acceptable carrier or excipient.
2. The pharmaceutical kit of claim 1 , further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation and said second pharmaceutical formulation.
3. The pharmaceutical kit of claim 1 , wherein the interferon is selected from the group of interferon-alpha, interferon-beta, interferon-omega, and pegylated interferons.
4. The pharmaceutical kit of claim 1 , which comprises the interferon in a dosage range from about 1 to about 3x106 IU interferon-alpha, or about 100 to 200 μg of pegylated interferon per unit dosage form.
5. The pharmaceutical kit of claim 1 , wherein the first pharmaceutical formulation is in the form of a solution, suspension, emulsion, powder, granulate, tablet, capsule, pill, spray, aerosol, buccal, sublingual or transdermal delivery system. 2
6. The pharmaceutical kit of claim 1 , wherein the first pharmaceutical formulation is administered parenterally to a subject in need thereof.
7. The pharmaceutical kit of claim 1 , wherein the insulin sensitizer is selected from the group consisting of Metformin, Acadesine, thiazolidinediones, and succinic acid or salts thereof.
8. The pharmaceutical kit of claim 1 , wherein the second pharmaceutical formulation is in the form of a solution, suspension, emulsion, powder, granulate, tablet, capsule, pill, spray, aerosol, buccal, sublingual or transdermal delivery system.
9. The pharmaceutical kit of claim 1 , wherein the second pharmaceutical formulation is administered orally or parenterally to a subject in need thereof.
10. The pharmaceutical kit of claim 1 , wherein interleukin-1 is interleukin- 1 alpha.
11. The pharmaceutical kit of claim 1 , wherein interleukin-1 is interleukin- 1 beta.
12. The pharmaceutical kit of claim 1 , which comprises interleukin-1 in a dosage range from about 0.01 to about 1000 μg per unit dosage form.
13. The pharmaceutical kit of claim 1 , wherein interleukin-1 is administered orally or parenterally.
14. The pharmaceutical kit of claim 1 , further comprising a third pharmaceutical formulation comprising ribavirin and a pharmaceutically acceptable carrier or excipient. 3
15. The pharmaceutical kit of claim 1 , further comprising an instruction describing the method of treating a viral disease which comprises administering to a subject in need thereof said first pharmaceutical formulation, said second pharmaceutical formulation, and said third pharmaceutical formulation.
16. The pharmaceutical kit of claim 15, wherein the viral disease is hepatitis B or C.
17. The pharmaceutical kit of claim 14, which comprises ribavirin in a dosage range from about 50 to about 300 mg per unit dosage form.
18. The pharmaceutical kit of claim 1 , wherein ribavirin is administered orally.
19. A method for treating a viral disease which comprises administering to a subject in need thereof the first pharmaceutical formulation and the second pharmaceutical formulation as claimed in claim 1.
20. The method of claim 19, further comprising administering to a subject in need thereof the third pharmaceutical formulation as claimed in claim 14.
21. The method of claim 19, wherein the viral disease is hepatitis B or C.
22. The use of an agent inducing inhibition of Protein Phosphatase 2A (PP2A) in cells, the agent selected from the group consisting of insulin, insulin sensitizers, insulin-like growth factor-1 , epidermal growth factor, tumor necrosis factor, interleukin-1 , interleukin-2, interleukin-3, interleukin-5, interleukin-6, interleukin-11 , interleukin-12, interleukin-13, erythropoietin, thrombopoietin, G-CSF, growth hormone, prolactin, leptin, GM-CSF, CNTF, CT-1 , LIF, and OSM for the preparation of a pharmaceutical formulation for the treatment of a 4 viral disease in a combination with a pharmaceutical formulation comprising an interferon.
23. The use of claim 22, wherein the viral disease is hepatitis B or C.
PCT/EP2008/059643 2008-07-23 2008-07-23 Interferon and an agent inducing inhibition of protein phosphatase 2a such as interleukin- 1 and optionally ribavirin for the treatment of hbv or hcv infection WO2010009762A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2468815C1 (en) * 2011-08-08 2012-12-10 Федеральное государственное бюджетное учреждение "Научный центр здоровья детей" Российской академии медицинских наук Method for providing higher effectiveness of interferon therapy of chronic hepatitis c in children
WO2013062959A2 (en) * 2011-10-26 2013-05-02 Medtronic, Inc. Continuous subcutaneous administration of interferon-alpha to hepatitis b infected patients
WO2022133494A1 (en) * 2020-12-17 2022-06-23 The Regents Of The University Of California Antiviral compounds and applications thereof
US11479530B2 (en) 2015-09-24 2022-10-25 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016204A1 (en) * 1995-11-02 1997-05-09 Schering Corporation Continuous low-dose cytokine infusion therapy
US5928636A (en) * 1996-05-13 1999-07-27 Hoffmann-La Roche Inc. Use of IL-12 and IFNα for the treatment of infectious diseases
WO2003026686A1 (en) * 2001-09-27 2003-04-03 Pomytkin Igor A Potentiating the therapeutic effects of interferons
WO2005071101A1 (en) * 2004-01-23 2005-08-04 University Hospital Of Basel Treatment of hepatitis c infection by increasing stat1 methylation
WO2006032711A1 (en) * 2004-08-18 2006-03-30 Instituto Científico Y Tecnológico De Navarra S.A. Use of insulin-like growth factor type i and interferon alpha in the treatment of a chronic hepatic disease, kit and compositions comprising same
EP1905447A2 (en) * 2005-06-16 2008-04-02 Proyecto de Biomedicina Cima, S.L. Use of a cytokine from the interleukin-6 family in the preparation of a composition for combined administration with interferon-alpha

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997016204A1 (en) * 1995-11-02 1997-05-09 Schering Corporation Continuous low-dose cytokine infusion therapy
US5928636A (en) * 1996-05-13 1999-07-27 Hoffmann-La Roche Inc. Use of IL-12 and IFNα for the treatment of infectious diseases
WO2003026686A1 (en) * 2001-09-27 2003-04-03 Pomytkin Igor A Potentiating the therapeutic effects of interferons
WO2005071101A1 (en) * 2004-01-23 2005-08-04 University Hospital Of Basel Treatment of hepatitis c infection by increasing stat1 methylation
WO2006032711A1 (en) * 2004-08-18 2006-03-30 Instituto Científico Y Tecnológico De Navarra S.A. Use of insulin-like growth factor type i and interferon alpha in the treatment of a chronic hepatic disease, kit and compositions comprising same
EP1905447A2 (en) * 2005-06-16 2008-04-02 Proyecto de Biomedicina Cima, S.L. Use of a cytokine from the interleukin-6 family in the preparation of a composition for combined administration with interferon-alpha

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "NCT00015652", 8 December 2005 (2005-12-08), pages 1 - 4, XP002543597, Retrieved from the Internet <URL:http://clinicaltrials.gov/archive/NCT00015652/2005_12_08> [retrieved on 20090831] *
BERNSMEIER C ET AL: "Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C", JOURNAL OF HEPATOLOGY, MUNKSGAARD INTERNATIONAL PUBLISHERS, COPENHAGEN, DK, vol. 49, no. 3, 30 April 2008 (2008-04-30), pages 429 - 440, XP024527070, ISSN: 0168-8278, [retrieved on 20080430] *
CHAN H L -Y ET AL: "Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese", ALIMENTARY PHARMACOLOGY & THERAPEUTICS, vol. 23, no. 12, June 2006 (2006-06-01), pages 1703 - 1711, XP002543601, ISSN: 0269-2813 *
CHRISTEN VERENA ET AL: "Inhibition of alpha interferon signaling by hepatitis B virus", JOURNAL OF VIROLOGY, vol. 81, no. 1, January 2007 (2007-01-01), pages 159 - 165, XP002543604, ISSN: 0022-538X *
DE LA TORRE P ET AL: "Interleukin-6 increases rat metalloproteinase-13 gene expression through Janus kinase-2-mediated inhibition of serine/threonine phosphatase-2A", CELLULAR SIGNALLING, ELSEVIER SCIENCE LTD, GB, vol. 17, no. 4, 1 April 2005 (2005-04-01), pages 427 - 435, XP025337461, ISSN: 0898-6568, [retrieved on 20050401] *
DUONG ET AL: "Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A", GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 126, no. 1, 1 January 2004 (2004-01-01), pages 263 - 277, XP005313325, ISSN: 0016-5085 *
DUONG FRANCOIS ET AL: "S-adenosamethionine and betaine improve interferon alpha signaling in cells expressing HCV proteins and potentiate its suppressive effects on HCV replicons", HEPATOLOGY, vol. 42, no. 4, Suppl. 1, October 2005 (2005-10-01), & 56TH ANNUAL MEETING OF THE AMERICAN-ASSOCIATION-FOR-THE-STUDY-OF-LIVE R-DISEASES; SAN FRANCISCO, CA, USA; NOVEMBER 11 -15, 2005, pages 554A - 555A, XP002543603, ISSN: 0270-9139 *
GUIDOTTI LUCA G ET AL: "Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and independent pathways", JOURNAL OF VIROLOGY, vol. 68, no. 3, 1994, pages 1265 - 1270, XP002543602, ISSN: 0022-538X *
GUY GRAEME ROY ET AL: "Activation of protein kinases and the inactivation of protein phosphatase 2A in tumour necrosis factor and interleukin-1 signal-transduction pathways", EUROPEAN JOURNAL OF BIOCHEMISTRY, vol. 229, no. 2, 1995, pages 503 - 511, XP002543606, ISSN: 0014-2956 *
HAMASAKI K ET AL: "Interaction of interferon-alpha with interleukin-1beta or tumor necrosis factor-alpha on hepatitis B virus enhancer activity", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 183, no. 2, 16 March 1992 (1992-03-16), pages 904 - 909, XP024840161, ISSN: 0006-291X, [retrieved on 19920316] *
JANSSENS V ET AL: "Protein phosphatase 2A: A highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling", BIOCHEMICAL JOURNAL, THE BIOCHEMICAL SOCIETY, LONDON, GB, vol. 353, no. 3, 1 January 2001 (2001-01-01), pages 417 - 439, XP002222450, ISSN: 0264-6021 *
LOEHR H F ET AL: "Reduced virus specific T helper cell induction by autologous dendritic cells in patients with chronic hepatitis B: Restoration by exogenous interleukin-12", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 130, no. 1, October 2002 (2002-10-01), pages 107 - 114, XP002543599, ISSN: 0009-9104 *
TOGASHI HITOSHI ET AL: "Interferon-gamma, tumor necrosis factor-alpha, and interleukin 1-beta suppress the replication of hepatitis B virus through oxidative stress", RESEARCH COMMUNICATIONS IN MOLECULAR PATHOLOGY AND PHARMACOLOGY, vol. 107, no. 5-6, 2000, pages 407 - 417, XP009122074, ISSN: 1078-0297 *
UGI SATOSHI ET AL: "Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling", MOLECULAR AND CELLULAR BIOLOGY, vol. 22, no. 7, April 2002 (2002-04-01), pages 2375 - 2387, XP002543605, ISSN: 0270-7306 *
ZHU HAIZHEN ET AL: "Interleukin-1 inhibits hepatitis C virus subgenomic RNA replication by activation of extracellular regulated kinase pathway.", JOURNAL OF VIROLOGY, vol. 77, no. 9, May 2003 (2003-05-01), pages 5493 - 5498, XP002543598, ISSN: 0022-538X *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2468815C1 (en) * 2011-08-08 2012-12-10 Федеральное государственное бюджетное учреждение "Научный центр здоровья детей" Российской академии медицинских наук Method for providing higher effectiveness of interferon therapy of chronic hepatitis c in children
WO2013062959A2 (en) * 2011-10-26 2013-05-02 Medtronic, Inc. Continuous subcutaneous administration of interferon-alpha to hepatitis b infected patients
WO2013062959A3 (en) * 2011-10-26 2013-07-11 Medtronic, Inc. Continuous subcutaneous administration of interferon-alpha to hepatitis b infected patients
US11479530B2 (en) 2015-09-24 2022-10-25 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
WO2022133494A1 (en) * 2020-12-17 2022-06-23 The Regents Of The University Of California Antiviral compounds and applications thereof

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