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WO1989009055A1 - Composition anti-virale contenant des diones polycycliques aromatiques et analogues de nucleoside, et procede de traitement d'infections retrovirales - Google Patents

Composition anti-virale contenant des diones polycycliques aromatiques et analogues de nucleoside, et procede de traitement d'infections retrovirales Download PDF

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Publication number
WO1989009055A1
WO1989009055A1 PCT/US1989/001035 US8901035W WO8909055A1 WO 1989009055 A1 WO1989009055 A1 WO 1989009055A1 US 8901035 W US8901035 W US 8901035W WO 8909055 A1 WO8909055 A1 WO 8909055A1
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hypericin
pharmaceutical formulation
dione compound
virus
polycyclic
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Daniel Meruelo
Gad Lavie
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New York University NYU
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New York University NYU
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention is related to pharmaceutical formula tions for treating retroviral infections in mammals comprisin antiviral effective amounts of aromatic polycyclic dion compounds in combination with azidothymidine, dideoxycytidin or related nucleoside analogs and methods for use thereof.
  • retroviruses ranges from th slowly progressive encephalitic lentiviruses, to retroviruse causing oncogenic transformations which elicit a wide variet of leukemias, sarcomas, and carcinomas to infections by the recently identifier, human immunodeficiency virus (HIV) .
  • HIV human immunodeficiency virus
  • Limited therapeutic agents exist which can be used to combat retroviral infections in mammals (especially HIV) and are confined to reagents which can interfere with the different stages of the viral replication cycle.
  • the inability of the host immune system to deal effectively with many retroviruses is due to the inherent properties of the infectious retroviruses, such as their capacity to spread directly by cell-to-cell contact, their high recombinational activity, and their ability to integrate in the host genome and remain latent for extended periods of time.
  • HIV causes i munosuppression characterized by a depletion of CD4+ T cells in infected individuals.
  • HIV-l and HIV-2 Two related but distinct viruses cause AIDS, designated HIV-l and HIV-2.
  • the genomes of HIV-1 and HIV-2 are only about 50% homologous at the nucleotide level but the two viruses contain the same complement of genes and appear to attack and kill the same human cells by much the same mechanisms.
  • HIV will be used to refer to these viruses in a generic sense.
  • the most effective antiretroviral agents to date are the nucleoside analogs 2 ' , 3' dideoxycytidine and 3'-azido-3'- deoxythy idine (AZT) , which become phosphorylated in the cell and are incorporated into viral DNA by the viral reverse transcriptase, leading to premature complementary DNA (cDNA) chain termination.
  • cDNA premature complementary DNA
  • AZT is currently used to treat certain patients suffering from Acquired Immunodeficiency Syndrome (AIDS) caused by HIV.
  • AIDS Acquired Immunodeficiency Syndrome
  • AZT has been shown to improve immunologic functions, to reverse, at least partially, HIV-induced neurological disfunction in some patients, and to improve certain other clinical abnormalities associated with AIDS.
  • a dose-dependent suppression of bone marrow, resulting in anemia and leukopenia an abnormally low number of leukocytes in the circulating blood
  • This has limited the effectiveness of AZT for the treatment of AIDS.
  • AZT is the only drug available for the treatment of AIDS patients.
  • Dideoxycytidine has also been tested in patients with AIDS but has proven even more toxic than AZT.
  • compositions for treating infections caused by retroviruses, especially HIV utilizing nucleoside analogs whereby such compositions will enable a significant reduction in the dose of the nucleoside analog to levels which do not cause any measurable toxicity in the afflicted individuals and/or provide an increased antiviral effect.
  • compositions and methods for the treatment of retroviral infections in mammals It is an object of the present invention to provide compositions and methods for the treatment of retroviral infections in mammals.
  • An ⁇ ther object of the present invention is to provid compositions and methods for treating retroviral infections i mammals employing nucleoside analogs such as AZT whereby th toxic effects of the nucleoside analog are minimized.
  • tha nucleoside analogs such as AZT
  • the polycyclic dion compounds hypericin and pseudohypericin interact synergistical ly and provide a more effective anti-retroviral inhibitor effect. Therefore, such a combination of antiviral drugs ma provide an increased benefit to those individuals afflicte with AIDS or with other retroviral infections sensitive t these drugs. This is a most important finding since AZT is th only drug currently in use which has been proven effective fo the treatment of AIDS patients.
  • the present invention provides a method for treating retroviral infections in mammals comprising administering to mammals in need of such treatment an anti- retroviral-effective amount of a nucleoside analog and a compound selected from the group consisting of hypericin, pseudohypericin, salts and mixtures thereof and physiologically acceptable salts and diluents.
  • the present invention provides a composition for treating mammals suffering from retroviral infections comprising an anti-retroviral-effective amount of a nucleoside analog and a compound selected from the group consisting of hypericin, pseudohypericin, salts and mixtures thereof and physiologically acceptable salts and diluents.
  • Figure 1 is a graph showing the survival of mice infected with Friend Leukemia Virus treated with various conce.- ' :-rations of pseudohypericin.
  • Figure 2 is a graph showing the survival of mice infected with Friend Leukemia Virus treated with various concentrations of hypericin.
  • Figure 3 is a graph showing the survival of mice infected with Friend Leukemia Virus treated with various concentrations of AZT plus either hypericin or pseudohypericin.
  • Figure 4 is a graph showing the survival of mice infected with Friend Leukemia Virus treated with various doses of hypericin and pseudohypericin.
  • nucleoside analogs typified by AZT
  • aromatic polycyclic dione compounds hypericin and pseudohypericin interact synergistically so that antiretroviral-effective nucleoside analog treatments (utilizing drugs such as AZT) can be employed at concentrations which are non-toxic for the treated mammals and in which the nucleoside analog alone is ineffective.
  • antiretroviral-effective nucleoside analog treatments utilizing drugs such as AZT
  • concentrations which are non-toxic for the treated mammals and in which the nucleoside analog alone is ineffective This is a most important finding because AZT treatment cannot be tolerated by some patients with AIDS and others must stop treatment when the toxic effects of AZT are manifested.
  • the use of the two drug antiviral therapy for treatment of patients with retrovirus infections such as AIDS may lead to an increased antiviral effect in such patients.
  • the nucleoside analogs and the polycyclic dione compounds inhibit retroviral replication via different mechan ⁇ isms of action.
  • AZT and related nucleo- sides analogs work by causing premature chain termination of growing viral cDNA.
  • the polycyclic diones of the present invention may inhibit late stages of viral replication such . as the shedding or assembly of viral particles from infected cells or may directly inactivate the virus particles.
  • the polycyclic dione compounds did not effect the levels of total viral mRNA or the expression of viral antigens within the cultures of mouse cells infected with Friend Leukemia virus in vitro at dosages which inhibited viral replication (data not shown) .
  • retrovirus refers to viruses containing an RNA genome and RNA-dependent DNA polymerase (reverse transcriptase) enzymatic activity. All retroviruses have common morphological, biochemical and physical properties that justify their inclusion into a single virus family. These parameters are summarized in Table I below.
  • gag Internal structural proteins
  • pol reverse transcriptase
  • env envelope proteins
  • Lipid about 35% by weight; derived from cell membrane
  • Carbohydrate about 4% by weight; associated with envelope proteins
  • HIV encodes at least 5 other proteins, designated TAT, ART/TRS, 3'-ORF, SOR and R whereas HTLV I contains the pX gene which may encode up to four proteins.
  • retroviruses have similar overall chemical composi ⁇ tions. In general, they comprise about 60-70% protein, 30-40% lipid, 2-4% carbohydrate, and about 1% RNA.
  • the envelope of retroviral particles is derived from the cell-surface membrane, and most, if not all, of the lipids in viral particles are located in the unit-membrane envelope of the virion.
  • Non- limiting examples of retroviruses include Friend Leukemia Virus (FV) , Radiation Leukemia Virus (RadLV) , Feline Leukemia virus, Avian Myeoblastosis Virus, and the human T-cell lymphotropic virus family (HTLV I, II, III and IV; HTLV III is also known as Human Immunodeficiency Virus or HIV) .
  • HTLV I has been shown to cause adult T cell leukemia and HTLV II hairy cell leukemia.
  • HTLV IV is related to simian immunodeficiency virus and has been found in African natives suffering from AIDS; its re ⁇ lationship to HTLV III is currently under investigation.
  • composition of the present invention comprising the aromatic, polycyclic diones and nucleoside analogs can be utilized for the treatment of mammals suffering from diseases caused by retroviruses such as HIV. Due to the fact that nucleoside analogs can be employed at sub-toxic concentrations, and that the polycyclic diones lack cellular toxicity at the doses administered, the compositions of the present invention may be particularly useful as specific antiretroviral therapeutic agents for these disorders.
  • the effectiveness of the composition of the present invention in treating retroviral infections is shown in Example 2 below wherein 100% of Friend Leukemia Virus-infected mice survived 65 days post-infection when treated with a composition comprising non-toxic concentra ⁇ tions of AZT and HY.
  • Friend Leuke is Virus infection is shown in Figure 4, where single treatments with nanogram amounts of either of the polycyclic dione compounds inhibited virally-induced splenomegaly when administered intraperitoneally 24 hours after infection. About 1 nanogram of PS or 100 nanograms of HY inhibited FV-induced splenomegaly 50% in infected Balb/c mice. These low doses of HY and PS are surprisingly effective in inhibiting an aggressive retrovirus when administered as a single intraperitoneal dose 24 hours post-infection.
  • Hypericin (HY) and pseudohypericin (PS) are aromatic polycyclic dione compounds which are present in plants of the family Hypericum (St. John's Wort).
  • U.S. Patent Application Serial No. 084,000 of D. Lavie et al. filed August 10, 1987 (incorporated by reference herein) discloses that HY and PS are potent inhibitors of retroviral replication in vivo and in vitro.
  • HY and PS may be obtained by extraction from the St. John's Wort plant, as detailed below in Example 1, or alterna- tively may be chemically synthesized using the methods of Brockmann, H. et al, U.S. Patent No. 2,707,704, issued May 3, 1955 and of Brockmann, H., Tetrahedron Letters 23: 1991-1994, 1974, both incorporated herein by reference. Due to the wide distribution and availability of the St. John's Wort plant throughout the world and the relatively convenient and inexpen ⁇ sive procedure for the extraction and purification of HY and PS (as detailed in Example 1 below) , the " extraction procedure is preferred when small amounts (i.e. grams) are desired. However, for the production of large scale amounts (kilograms or greater) , chemical synthesis is preferred.
  • composition of the present invention further includes salts or other derivatives of hypericin and pseudo ⁇ hypericin which retain their antiviral activity. Salts in which the base of the alkaline or amine type are particularly comprehended within the scope of the present application.
  • Nucleoside analogs envisioned for use in the present invention include but are not limited to 2', 3' dideoxycyti ⁇ dine, 2', 3' dideoxythy idine, 2', 3' dideoxyadenosine, 2', 3' dideoxyinosine and preferably AZT.
  • AZT for practicing the present invention is commercially available from Burroughs Welcome (Research Triangle Park, NC)
  • 2', 3' dideoxycytidine and 2', 3' dideoxyadensine are commercially available from Calbiochem-Behring (San Diego, CA)
  • 2', 3' dideoxythymidine is available from Pharmacia Fine Chemicals (Piscataway, NJ) .
  • the present invention also provides a method for treating mammals suffering from infections caused by retroviruses comprising administering to mammals in need of such treatment an antiretroviral effective amount of a nucleoside analog plus an aromatic polycyclic dione selected from the group consisting of hypericin, pseudohypericin, salts and mixtures thereof.
  • the determination of the most effective type and mixture of the nucleoside analog plus polycyclic dione compound for treatment of the particular retrovirus responsible for the infection can be ascertained by routine experimentation using suitable systems, such as that described in Example 4 for HIV in vitro or in Example 2 for Friend Leukemia Virus in experimental animals.
  • suitable systems such as that described in Example 4 for HIV in vitro or in Example 2 for Friend Leukemia Virus in experimental animals.
  • viremia i.e.
  • the composition of the present invention may be administered orally, topically or preferably parenterally, and most preferably by intravenous administrations of dosages broadly ranging between about 200 micrograms and about 100,000 micrograms per kilogram (kg) of body weight per treatment of the polycyclic diones and between about 1,000 micrograms and about 50,000-micrograms per kilogram of body weight per treatment of the nucleoside analog, and preferably between about 1,000 and about 50,000 micrograms per kg body weight per treatment of the polycyclic diones and between about 1,000 and 50,000 micrograms per kg body weight per treatment of the nucleoside analog.
  • a typical treatment regimen may comprise in ⁇ travenous administration of from about 1,000 to about 10,000 micrograms per kg ⁇ f body weight of the polycyclic diones and between S_?0Ut 2,000 an ⁇ abou l ⁇ OOO micrograms per kilogram of
  • the total dose required for each treatment may be administered in divided doses or in a single dosage.
  • the antiviral treatment may be administered daily, one or two times a week, ⁇ r as determined by the patient's condition and the stage of the patient's disease. It should be noted that when the polycyclic dione compounds are administered orally, 5-10 fold higher concentration may be required than those administered parenterally and when the nucleoside analogs are administered orally, 5-10 fold higher concentrations are also required.
  • the composition of the present invention can be incorporated in conventional, solid and liquid pharmaceutical formulations (e.g. tablets, capsules, caplets, injectable and orally administrable solutions) for use in treating mammals that are afflicted with retroviral infections.
  • the phar- maceutical formulations of the invention comprise an effective antiviral amount of PS or HY or salts or mixtures thereof plus the nucleoside analog (as disclosed above) as the active ingredients.
  • the quantity of effective dose applied by each capsule, tablet or injection is relatively unimportant since the total dosage can be reached by administration of one or a plurality of capsules, tablets, injections or a combination thereof.
  • such formulation may comprise inert constituents including pharmaceutically-acceptable carriers, diluents, fillers, salts, and other materials well-known in the art depending upon the dosage form utilized.
  • the capsules employed may be comprised ⁇ f any pharmaceutically acceptable material, such as gelatin or cellulose derivatives.
  • the tablets may be formulated in accordance with conventional procedures employing solid carriers well known in the art.
  • solid carriers include, starch, sugar, bentonite, and other commonly used carriers.
  • a preferred parenteral dosage form may comprise a sterile isotonic saline solution, containing between about 500 micrograms and about 50,000 micrograms of PS, HY or mixtures thereof and between about 1,000 and about 50,000 micrograms of the nucleoside analog.
  • Propylene glycol, benzyl alcohol, ethanol or other biologically acceptable organic solvents may be used as diluents, carriers or solvents in the preparation of solid and liquid pharmaceutical formulations containing the an- tiretroviral compositions of the present invention.
  • the polycyclic diones may be administered separately, or combined (mixed) with the nucleoside analog in a single dosage form, or co-administered separately at the same time. Selection of the particular agent to be employed will be determined by ascer ⁇ taining the antiviral composition that works best for a particular patient.
  • Hypericin (C ⁇ oH ⁇ gOg, molecular weight 504.43, referred to herein as HY)
  • pseudohypericin f ⁇ Q H ⁇ Og molecular weight 520.43 referred to herein as PS
  • the herb of the whole St. John's Wort plant was harvested at its flowering time, (July through October in the Eastern hemisphere), dried at 55*C, cut and milled, and then extracted with acetone (about 5-10 liters per kg) .
  • One kilogram of the material was placed in a soxhlet (Kimax, available from Fisher Scientific, New Brunswick-, NJ) and extracted until the extracting solvent was colorless (about five to ten hours) .
  • the solution containing the aromatic polycyclic diones had a red fluorescent color with absorption and fluorescence spectra as described in Scheibe Schenta ⁇ . Ber. 25: 2019, 1942, Brockmann, M. , Nature Stamms 2£: 47, 1951, both incorporated herein by reference.
  • the solvent (containing the aromatic polycyclic diones) was evaporated under reduced pressure to complete dryness of the residue, yielding 95 grams.
  • This residue was then further fractionated on a chromatographic column, packed with silica gel 60 (0o06-0. 0mm, Malinckrodt, American Scientific Products, McGaw Park, IL) .
  • a dry chromatographic procedure was utilized whereby 25 grams of the above obtained residue was dissolved in about 500 ml acetone, added to an equal amount of silica gel 60, and evaporated on a rotavapor (Buchi, American Scientific Products) with swirling until the mixture was homogeneous and dry.
  • hypericin (HY) Rf 0.45
  • PS pseudohypericin
  • Rf 0.35 Rf 0.35
  • the NMR spectrum analysis of the two components were the same as those previously reported (Brockmann, H, et al, Tetrahedron Letters 1:37, 1975, incor ⁇ porated by reference) .
  • the compounds were stored in the dark, dry or at 4'C in absolute ethanol, until use.
  • Friend Leukemia Virus is an aggressive retrovirus which induces an acute erythroleukemia in sensitive strains of mice such as BALB/c and NIH Swiss mice as described in Friend, C.J. Exp_. Mild- i__5: 307-324, 1957; Friend, C. et al Proc. Natl. Acad. Sci. U.S.A. 68: 378-383, 1971; Friend, C. et al. Nat. Cancer Inst. Mono ⁇ r. ___: 505-522, 1966, (all incorporated by reference herein) .
  • the malignant transformation is the result of the combined activities of the spleen focus forming virus
  • the acute erythroleukemia is characterized by hepatosplenomegaly (a marked increase in the size of the spleen and liver) and a severe anemia.
  • Friend Leukemia Virus was prepared by homogenizing the enlarged spleen of a mouse previously infected with FV, ten days after intravenous virus injection. The spleen was homogenized in phosphate buffered saline in a volume equal to ten times the weight of the isolated spleen. The effects of HY and PS or mixtures thereof plus AZT on the increase in spleen size (splenomegaly) of BALB/c mice (Jackson Labs, Bar Harbor, ME) was examined.
  • the virus (10 6 focus forming units-FFU) was inoculated intravenously and the indicated doses of the antiretroviral composition of the present invention was administered to the BALB/c mice in ⁇ traperitoneally 24 hours later. The animals were then sacrificed 10 days later and their spleens weighed.
  • mice treated with 10 micrograms of PS As shown in Figure 1 and Table II, while all FV- infected mice were dead by 30 days after virus inoculation, 40% of mice treated with 10 micrograms of PS, 80% of mice treated with 50 micrograms per mouse of PS and 100% of mice treated with 150 micrograms of PS were alive by day 65. In addition as shown in Figure 2 and Table II, 100% of the mice treated with 150 micrograms of HY and 80% of those treated with 10 or 50 micrograms of HY were alive at day 65. By contrast, AZT at doses ranging from 0.2 to 20 micrograms per mouse increased overall survival of FV inoculated mice only minimally. Combinations of AZT and HY or PS were synergistic (Figure 3 and Table II), even at the lowest doses of AZT used.
  • mice when used at a concentration of 0.2 micrograms AZT per mouse, 100% of FV inoculated mice were dead by day 30, and at 50 micrograms per mouse of PS, 20% of mice are dead by day 30, but 100% of mice treated with 0.2 micrograms of AZT plus 50 micrograms of PS were alive at day 65 after FV inoculation. It should be noted that as of day 65 following FV inoculation, no mouse receiving a combination of any dose of AZT with any dose of PS or HY had died.
  • HUT-78 cells infected with HIV and contrasted with those of AZT. Infection was monitored by indirect immunofluorescence using antisera to the entire HIV (inactivated sera from HIV positive individuals and AIDS patients) , or to purified virus components prepared in rabbits.
  • pseudohypericin on the infection of cells by HIV was monitored by simultaneously mixing various dilutions of the compound with the virus and with uninfected cells and incubating the cultures in medium RPMI-1640 (GIBCO, Grand Island, NY) supplemented with 10% heat inactivated fetal calf serum for 24, 48, 72 and 144 hours. The cells are then washed, fixed and incubated with the anti-HIV antibody followed by the fluorescein labeled anti-immunoglobulin and the percentage of infected cells was determined.
  • HIV- infected, OKT4+ lymphoblastoid cells such as clone H9 (described in Popovic, M. , et al, Science 22J_:497-500, 1984, incorporated by reference) or HUT 78 cells (Gazdar, AF et al.
  • the antiviral activity of the composition of the present invention is determined by monitoring the reverse transcriptase activity and the expression of HIV proteins p24 and pl7, as described in Sarin, P.S. et al, £. Nat. Cancer Inst. 28:663-665, 1987, incorporated herein by reference and is described below. EXPRESSION OF HIV GAG PROTEINS P24 AND P17.
  • HUT-78, Molt-4 or H9 cells (2X10 5 ) are continuously exposed to various concentra ⁇ tions of PS, HY and mixtures thereof at concentrations between 5 and 100 micrograms per ml plus 2', 3'-dideoxycytidine or AZT at 0.2 to 20 micrograms per ml for 4 days.
  • the percentage of cells expressing p24 and pl7 gag proteins of HIV is determined by indirect immunofluorescence microscopy with the use of mouse monoclonal antibodies to HIV pl7 and p24 (available in numerous commercial sources such as those in HIV serum antigen detection kits from Abbott Labs, North Chicago, IL, and from DuPont, Wilmington, DE) .
  • the positive cells are visualized by treat ⁇ ment with fluorescein-labeled goat anti-mouse IgG (Cappell Laboratories, Cochranville, PA) .
  • the experiments are performed in duplicate and repeated at least three times.
  • DETERMINATION OF REVERSE TRANSCRIPTASE ACTIVITY H9, HUT-78 or MOLT-4 cells infected with HIV (500 virus particles/cell) are exposed to various concentrations of PS, HY, and mixtures thereof plus AZT or 2', 3'-dideoxycytidine as above.
  • supernatants of the cultures are collected and virus particles are precipitated with polyethylene glycol and obtained by centrifugation as described above in Example 2 for FV.
  • the virus pellet is suspended in 300 microliters of buffer containing 50 mM Tris-HCl (pH 7.5), 5mM dithiothreitol,
  • Triton X-100 Reverse transcriptase activity in these samples is analyzed in a 50 microliter reaction mixture containing 50 mM Tris-HCl (pH 7.5), 5mM dithiothreitol, 100 mM KC1, 0.01% Triton X-100, 10 microliters dT 15 rA n as template primer, 10 mM MgCl 2 , 15 icromolar [ 3 H]dTTP
  • yeast tRNA Sigma Chemical, St. Louis, MO
  • EXAMPLE 5 THE EFFECT OF THE COMPOSITION OF THE PRESENT INVENTION ON THE REPLICATION OF FELINE LEUKEMIA VIRUS .
  • Additional cats will be treated with a combination therapy consisting of a single dose of PS/HY and 4-40 doses administrations of AZT or 2', 3'-dideoxycytidine (lmg/kg) , twice a day for various intervals of time. Serum levels of FeLV will then be followed and treatment will be resumed at the same regimens or adjusted with respect to the levels of viremia suppression obtained. (A control group of cats will receive the deoxynucleoside analog alone at identical concentrations) . The length of follow up will be determined by experimental considerations. A minimum of six months follow-up will be undertaken.

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Abstract

Un procédé de traitement d'infections rétrovirales chez des mammifères consiste à administrer des quantités effectives anti-rétrovirales d'un analogue de nucléoside et une dione polycyclique aromatique sélectionnée dans le groupe incluant l'hypericine, la pseudohypericine, leurs sels et leurs mélanges. Sont également décrites des compositions permettant de traiter des infections rétrovirales chez des mammifères, ces compositions contenant des quantités effectives anti-rétrovirales d'un analogue de nucléoside et d'une dione polycyclique aromatique sélectionnée dans le groupe incluant l'hypericine, la pseudohypericine, des sels et des mélanges de celles-ci.
PCT/US1989/001035 1988-03-23 1989-03-15 Composition anti-virale contenant des diones polycycliques aromatiques et analogues de nucleoside, et procede de traitement d'infections retrovirales Ceased WO1989009055A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426785A4 (en) * 1989-03-16 1991-11-13 New York University Compositions and methods for treating viral infections
DE19547317A1 (de) * 1995-12-18 1998-12-24 Dreluso Pharm Dr Elten & Sohn Antivirales Medikament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3817982A (en) * 1971-12-29 1974-06-18 Syntex Inc 2{40 ,3{40 -unsaturated nucleosides and method of making
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
EP0256452A2 (fr) * 1986-08-08 1988-02-24 Yeda Research And Development Company Limited Compositions pharmaceutiques antivirales contenant de l'hypericine ou du pseudohypericine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3817982A (en) * 1971-12-29 1974-06-18 Syntex Inc 2{40 ,3{40 -unsaturated nucleosides and method of making
US4724232A (en) * 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
EP0256452A2 (fr) * 1986-08-08 1988-02-24 Yeda Research And Development Company Limited Compositions pharmaceutiques antivirales contenant de l'hypericine ou du pseudohypericine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
H. MITSUYA: "Rapid In Vitro systems for Ass-of Agents Against HTLV-III/LAV", published 1987, by Marcel Dekker Inc. (New York), see pages 303-333, especially pages 320-325. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426785A4 (en) * 1989-03-16 1991-11-13 New York University Compositions and methods for treating viral infections
DE19547317A1 (de) * 1995-12-18 1998-12-24 Dreluso Pharm Dr Elten & Sohn Antivirales Medikament

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AU3294289A (en) 1989-10-16
ZA892216B (en) 1990-03-28

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