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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • 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
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • 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
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1816—Erythropoietin [EPO]
• • 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
  • A61K38/41—Porphyrin- or corrin-ring-containing peptides
• • 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
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention is concerned with methods and compositions for treating viral infections such as retroviral infections in mammals, especially humans.
• HIV-l human immunodeficiency virus
• HTLV-III human T-cell lymphotropic virus
• AIDS Acquired Immune Deficiency Syndrome
• ARC AIDS related complex
• AIDS related diseases is a retrovirus.
• feline leukemia virus (Fe. ) of cats is a retrovirus.
• AIDS is almost always fatal within 1 to 2 years of the first clinical manifestations of illness. This disease was initially described and characterized in four high-risk groups (homosexual men, hemophiliacs, Haitians, and intravenous drug abusers) ; however, individuals belonging to no apparent high-risk groups have also developed the disease. AIDS is generally spread by intimate sexual contact or by the administration of infected blood products, and occasionally by the maternal-fetal route. Many patients who develop AIDS are asymptomatic when they transmit their disease to contacts because a 6-month to 5-year (or more) latency interval may exist between infection and clinical manifestations of illness.
• Antiviral therapy for the treatment of AIDS is based on the assumption that continued retroviral replication is involved in both the pathogenesis and progression of the disease. Therefore, RT has been a major target for antiviral therapy in AIDS, and indeed, most of the agents now being investigated, including AZT, act on this enzyme.
• the phosphorylated forms of these compounds inhibit HIV replication by acting as chain terminators. Reverse transcriptase of HIV is much more susceptible to the inhibitory effects of these phosphorylated dideoxynucleotides than mammalian DNA polymerases.
• Administration of AZT has been shown to result in immunologic improvements and to confer a survival advantage in patients with AIDS.
• AZT AZT anti-viral tyre-associated tyreactive protein
• neutropenia neutropenia
• thrombocytopenia AZT suppresses the proliferation of erythroid, granuclocyte, macrophage and primitive hematopoietic stem cells in a dose-related and time- dependent fashion.
• AZT regimens are associated with significant bone marrow toxicity.
• long term treatment with AZT may create a selective pressure which affords replication advantage to viruses of drug-resistant phenotype. Such variants have been isolated from patients suffering from advanced HIV-1 associated disease, sometimes, as early as six months after initiation of treatment.
• Tsutsui and Mueller (1) reported that the virion- associated RT activity of Rauscher murine leukemia virus was inhibited by hemin at a concentration of lOOum. Hemin is the chloride of ferriprotoporphyrin IX (heme) . The inhibition of RT by this large concentration of hemin was reversible and appeared to be directed against the enzyme rather than the template. On the other hand, hemin did not inhibit the activity of RT purified from avian myeloblastosis virus.
• Synthetic hemes include a wide variety of organometallic porphyrins in which the chelated atom is a metal other than iron such as tin, chromium, cobalt, zinc or manganese or analogous compounds in which the porphyrin ring structure is modified as in protoporphyrins or mesoporphyrins.
• Typical synthetic hemes which might be mentioned by way of example are tin protoporphyrin (SnPP) , tin mesoporphyrin (SnMP) , tin diiododeuteroporphyrin (SnI_DP) and the corresponding zinc, chromium, manganese and cobalt compounds all of which are known or can be prepared by known procedures. All are useful in the practice of this invention. Tin protoporphyrin and tin mesoporphyrin are preferied because they are readily available and especially active.
• heme derivatives useful in the practice of the invention include acid addition salts of heme, particularly amino acid salts of heme including L-amino acids such as arginine.
• Heme arginate is especially preferred for use in the invention, although other non- toxic acid addition salts of inorganic and organic acids especially the naturally occurring L-amino acids may also be employed.
• heme products will enhance the activity of antiviral compounds especially antiretroviral compounds such as AZT.
• the invention is particularly useful with therapeutic agents of the nucleoside type such as AZT or dideoxyinosine (DDI) .
• the invention also includes within its scope pharmaceutical compositions containing one or more heme products, an anti-HIV infection drug such as AZT together with erythropoietin (EPO) .
• the invention therefore comprises methods and compositions for the treatment of retroviral infections of mammals especially humans in need of such treatment.
• the invention is especially applicable to controlling AIDS infections of humans.
• Figures 1, 2, 3 4 and 5 illustrate by means of graphs the results of studies described herein utilizing hemin, AZT, and combinations of hemin and AZT, and combinations of these agents with EPO.
• the term "coadministration” means that the therapeutic agents are administered simultaneously or sequentially at time intervals sufficiently close so that the administration of one agent has a beneficial effect on the action of the other. Normally, they will be administered parenterally in one dosage unit although the invention is not so limited.
• the one component of the therapeutic mixture e.g. the nucleoside can be administered orally and the heme product parenterally.
• the invention will be described principally as it relates to heme, AZT and EPO, but as is clear from the foregoing, the invention is not limited to these materials.
• a number of tests were conducted to determine the antiviral efficacy of heme alone or with various concentrations of AZT utilizing an AZT sensitive strain of HIV, an AZT resistant strain of HIV, both isolated from human patients, and AZT sensitive strain HTLV-III B obtained from ERC Bioservices Corporation.
• a total of three strains of HIV-I were utilized. Two strains were isolated (2) from blood obtained from AIDS patients. One isolate was obtained from a patient who had been on AZT therapy for four months; this isolate is defined as AZT-resistant (at luM AZT) , in Table 1. The other isolate was derived from a patient who had never received AZT and is referred to as AZT-sensitive (at luM AZT) in Table 1. The third HIV strain (HTLV-IIIB) was obtained from ERC Bioservices Corporation (Rockville, MD) through the NIAID AIDS Research and Reference Reagent Progra .
• HTLV-IIIB (3, 4) was replicated in the H9 cell line (5, 6) (ERC Bioservices Corp.)
• the AZT-resistant patient-derived HIV was also adapted to the H9 cell line but the AZT-sensitive HIV (Table 1) could not be adapted to these cells.
• the two HIV strains werea passaged in H9 cells in IMDM (Gibco) supplemented with 10% fetal bovine serum (FBS) (Gibco) and subcultured at 3-4 days.
• H9 cells were infected with the two strains of HIV and graded amounts (O-luM) of AZT were added to the two groups of cultures. The cultures were maintained at 37°C in RPMI 1640 supplemented with 10% FBS with replacement of 50% of media containing hemin (1 or lOuM) twice within 7 days.
• the dose-response effect of hemin alone on the replication of HIV in H9 cells of both the AZT-resistant and the AZT-sensitive strains of HIV was also determined. Viral replication of the drug sensitive strain was reduced by 50% at a hemin concentration of ⁇ 0.05uM (Fig. 3); for the drug-resistant strain the comparable inhibitory concentration of hemin was about 15uM.
• compositions of this invention are designed for parenteral ; dministration.
• the antiviral agent or agents will be in isotonic, aqueous, buffered solution, typically, made isotonic by the addition of sodium chloride, glucose or other standard solute.
• the compositions may also contain propylene glycol, sesame oil or other inert excipient.
• AZT and similar agents may be administered separately by the oral route.
• the therapeutic compositions of the invention will contain a heme product and may additionally contain one or more of the compounds useful for the treatment of retroviral infections, especially HIV infections attributable to HIV 1 or HIV 2.
• the heme products and antiretroviral agents will be present in amounts effective usefully to treat a mammal such as a human afflicted with such infections.
• Anti-HIV nucleosides such as AZT and DDI are preferred.
• the compositions may also contain EPO.
• the dosage level when administered with a hemin product of the invention will be from about 5 to 250 mg/kg body weight. Such levels may be conveniently achieved by providing parenteral dosage units containing from about 1 to 80 mg/kg of AZT.
• the dosage range will normally be from 50 to 300 mg/kg body weight. Typically dosage units will contain from about 10 to 100 units/kg of EPO.
• compositions of this invention will be prepared by the usual procedures employed for such purposes utilizing standard readily available components.
• the pH of the buffered compositions will be from about 7 to 8, preferably 7.4 to 7.5.
• HIV Antigen P24, pg/ml (% Inhibition)

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
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• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Oncology (AREA)
• Communicable Diseases (AREA)
• Molecular Biology (AREA)
• Gastroenterology & Hepatology (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
• Tropical Medicine & Parasitology (AREA)
• AIDS & HIV (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 1991
  • 1991-07-25 JP JP3514118A patent/JPH05504774A/ja active Pending
  • 1991-07-25 EP EP19910915068 patent/EP0543902A4/en not_active Withdrawn
  • 1991-07-25 AU AU84104/91A patent/AU645131B2/en not_active Ceased
  • 1991-07-25 CA CA002088593A patent/CA2088593A1/en not_active Abandoned
  • 1991-07-25 WO PCT/US1991/005283 patent/WO1992002242A1/en not_active Ceased

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