Classifications

• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • 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]
  • A61K38/212—IFN-alpha
• • 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
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the invention relates to methods of treating viral diseases caused by viruses of the family
• Flavlviridae or by a virus which targets the mammalian liver as a main repository for viral replication.
• the methods of this invention involve the use of mycophenolic acid or its derivatives, particularly mycophenolate mofetil alone, or in combination with other anti-viral agents.
• the methods of this invention are particularly useful in treating hepatitis B virus, hepatitis C virus, and dengue virus viral infections.
• HCV infection causes about 10,000 deaths per year. It is estimated that at least 4 million Americans are infected with HCV — 2 percent of the population. Presently there is no cure for the disease and treatments have just begun to be available.
• Hepatitis B virus is an example of a prevalent viral disease which targets the liver. Although a vaccine is currently available, it is of questionable utility in individuals who are chronically infected with HBV.
• Dengue is an example of a virus of the family Flavlviridae . Dengue is not as prevalent as HBV or HCV, but is known to break out in large epidemics in warmer climates. Dengue fever is an acute infectious disease caused by the flavivirus (a small RNA virus related to yellow fever, tick-borne encephalitis, St Louis encephalitis, and Japanese encephalitis) which is transmitted by infected mosquitoes. The disease causes headache, fever, muscle pain and rash, but is rarely fatal.
• flavivirus a small RNA virus related to yellow fever, tick-borne encephalitis, St Louis encephalitis, and Japanese encephalitis
• dengue hemorrhagic fever causes severe symptoms including fever, shock, hemorrhaging from the nose and mouth, respiratory distress and death.
• dengue hemorrhagic fever causes severe symptoms including fever, shock, hemorrhaging from the nose and mouth, respiratory distress and death.
• MMF mycophenolate mofetil
• MPA, MMF and its derivatives may be useful an anti-viral agents
• the viral targets mentioned fall into either the retroviral or the Herpes virus class.
• MPA, MMF and their derivatives would be useful in treating diseases that target the mammalian liver, in particular hepatitis B virus, hepatitis C virus, and dengue virus.
• Viral diseases that target the mammalian liver are often widespread and severe. This, coupled with the lack of effective treatment for a subset of these diseases, places a great need on developing new avenues for treatment.
• Figure 1 depicts the effect of varying concentrations of MPA on the amount of virion-associated hepatitis B virus DNA present in HepG2-2.2.15 cells and on cell death.
• MPA, MMF and their derivatives are surprisingly and unexpectedly useful in treating flavivirus infections and infections caused by virus that use the mammalian liver as their main site for replication.
• the use of these well-known compounds alone, or in conjunction with one or more other anti-viral agents, such as interferons, ribavirin, or inhibitors of viral life cycles (such as protease inhibitors, nucleoside analogs, inhibitors of other viral enzymes necessary for viral replication and infection) provides a method for treating such viral diseases.
• the present invention provides a method of treating a mammal suffering from a viral disease caused by a member of the family Flavlviridae or a viral disease of the liver, wherein said method comprises the step of administering to said mammal an amount of a compound selected from mycophenolic acid, mycophenolate mofetil, or a derivative of either of these compounds effective to lessen the severity of said viral disease, wherein said compound is in a pharmaceutically acceptable composition.
• Mycophenolic acid has the structure:
• Mycophenolate mofetil has the structure:
• viral diseases of the liver means a disease whose causative agent is a virus, wherein the virus targets the mammalian liver as its primary site of replication.
• viruses include, but are not limited to, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus.
• virus from the family Flavlviridae may be treated according to this invention are dengue and hepatitis C virus.
• the methods of this invention are used to treat a hepatitis C virus infection.
• the efficacy of the methods of this invention may be measured by observing how the treatment lessens the severity of the viral infection. This may be measured by various means. For example, a reduction in the viral titer in the blood is considered to be a lessening of the severity of infection. Similarly, a decrease in the amount of an enzymatic activity associated with the virus (e.g., viral protease activity; viral helicase activity; viral polymerase activity) or a reduction in the presence of viral proteins may be taken as a measure of efficacy.
• an enzymatic activity associated with the virus e.g., viral protease activity; viral helicase activity; viral polymerase activity
• a reduction in the presence of viral proteins may be taken as a measure of efficacy.
• Another parameter is a sustained improvement in the patients health and well-being. This may be measured by a reduction or elimination of symptoms associated with the viral infection.
• One specific measure that may be used is the concentration of liver transaminases, particularly ALT and AST, found in the patient's plasma. It may also be measured, in a human being, by interviewing the patient.
• a pharmaceutically acceptable composition according to this invention is one in which the compound is formulated together with a pharmaceutically acceptable carrier for administration to a mammal.
• Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers , polyethylene glycol and wool fat.
• compositions of this invention are formulated for pharmaceutical administration to a human being.
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• carriers which are commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried corn starch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• compositions of this invention may be administered in the form of suppositories for rectal administration.
• suppositories for rectal administration.
• suppositories can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
• suitable non- irritating excipient include cocoa butter, beeswax and polyethylene glycols.
• compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
• Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
• the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
• the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
• compositions of this invention may also be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
• the MPA, MMF or a derivative thereof is administered together with at least one other anti-viral agent.
• anti-viral agents useful in this embodiment include, but are not limited to, - interferons, ⁇ -interferons, ⁇ -interferons, viral protease inhibitors, ribavirin, viral helicase inhibitors, viral polymerase inhibitors, antibodies to viral surface proteins, and antibodies to viral core proteins.
• the other anti-viral agent used in the methods of this invention is an -interferon, which is optionally modified by conjugating with polyethylene glycol ("pegylation" ) .
• the other anti-viral agent may be administered as part of a single dosage combination with MPA, MMF or a derivative thereof. Alternatively, the other anti-viral agent may be administered as a separate dosage form. When used as a separate dosage form the other anti-viral agent may be administered prior to, simultaneously with, or following administration of MPA, MMF or a derivative thereof.
• Daily dosages of MPA, MMF or derivatives thereof utilized in the methods of this invention should be between about 0.01 to 100.0 mg/kg body weight, preferably between about 0.1 to 70 mg/kg of body weight. If other anti-viral agents are present, they should be administered at daily dosages of between about 70 to 100% of the dosage normally administered when that agent is used in a monotherapy.
• the amount of active compound administered will, of course, be dependent upon a number of factors, including the sex of the mammal, the nature and severity of the viral infection, the route and schedule of the administration and the judgment of the prescribing physician.
• HepG2-2.2.15 cells were plated in 96-well microtiter plates at an initial density of 2.5 x 10 3 cells/100 ⁇ l in DMEM medium supplemented with 10% fetal bovine serum. To promote cell adherence, the 96-well plates were pre-coated with collagen prior to cell plating. After incubation at 37°C in a humidified, 5% C0 2 environment for 16-24 hours, the confluent monolayer of HepG2-2.2.15 cells was washed, and the medium was replaced with complete medium containing various concentrations of MPA (0 to 31 ⁇ M) . On day three, the culture medium was replaced with fresh medium containing the same amount of MPA.
• Virion-associated HBV DNA present in the tissue culture supernatant was PCR amplified using primers derived from HBV strain ayw.
• PCR-amplified HBV DNA was detected in real-time (i.e., at each PCR thermocycle step) by monitoring increases in fluorescence signals that result from exonucleolytic degradation of a quenched fluorescent probe molecule following hybridization of the probe to the amplified HBV DNA.
• the TaqMan probe molecule designed with the aid of Primer ExpressTM (PE- Applied Biosystems) software, is complementary to DNA sequences present in the HBV DNA region.
• Figure 1 demonstrates that there is a linear decrease in the amount of HBV DNA detected with increasing amounts of MPA administered up to 0.488 ⁇ M. Above 0.488 ⁇ M, the cells begin to die and therefore the further linear decrease in HBV DNA is difficult to interpret.
• MPA is effective in reducing hepatitis B viral titer in infected cells. Infections caused by other virus of the Flavlviridae family and other virus that target the liver of a mammal as the major site of replication will also be reduced in severity by treatment with MPA.

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• 1999
  • 1999-09-14 WO PCT/US1999/021003 patent/WO2000015210A2/en not_active Application Discontinuation
  • 1999-09-14 JP JP2000569794A patent/JP2002524502A/ja active Pending
  • 1999-09-14 AU AU60374/99A patent/AU6037499A/en not_active Abandoned
  • 1999-09-14 EP EP99969023A patent/EP1113794A2/de not_active Withdrawn

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