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EP0258412A1 - Composition et procede de traitement du sida et de certaines maladies s'y rapportant - Google Patents

Composition et procede de traitement du sida et de certaines maladies s'y rapportant

Info

Publication number
EP0258412A1
EP0258412A1 EP19870901944 EP87901944A EP0258412A1 EP 0258412 A1 EP0258412 A1 EP 0258412A1 EP 19870901944 EP19870901944 EP 19870901944 EP 87901944 A EP87901944 A EP 87901944A EP 0258412 A1 EP0258412 A1 EP 0258412A1
Authority
EP
European Patent Office
Prior art keywords
deoxycytidine
composition
compound
methyl
dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19870901944
Other languages
German (de)
English (en)
Inventor
Sheldon B. Greer
Wade P. Parks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0258412A1 publication Critical patent/EP0258412A1/fr
Withdrawn legal-status Critical Current

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the present invention relates to pharmaceutical compositions containing 5-methyl-2'-deoxycytidine, 5--chloro-2'- deoxycytidine, 5-fluoro-2'-deoxycytidine or 5-trifluoromethyl-2'-deoxycytidine, preferably with inhibitors of their deamination, and to a method for inhibiting the spread of the carrier state of Acquired Immune Deficiency Syndrome (AIDS) and as a cure for the AIDS diseased state.
  • AIDS Acquired Immune Deficiency Syndrome
  • the compositions may have utility in the treatment of related disease states, such as multiple sclerosis and leukemia.
  • Herpes viruses Diseases caused by Herpes and Herpes-like viruses are particularly widespread in man.
  • Herpes viruses are Herpes simplex virus (HSV) Types 1 (HSV-1) and 2 (HSV-2) and Herpes varicella-zoster virus (VZV) that causes chicken pox in children and shingles in adults.
  • Herpes-like viruses are Epstein-Barr virus, Pseudorabies virus, Cytomegalo virus, Marek's disease virus of chickens, equine abortion virus (EAV) and Lucke-frog virus.
  • Herpes simplex viruses are strongly implicated in many pathological systems and include ocular (Keratitis), cutaneous (including genital and oral), and systemic disseminated infections.
  • HSV-1 Herpes simplex virus Type 1
  • HSV-2 One disease caused by the Herpes simplex virus Type 1 (HSV-1) is a particularly virulent form of encephalitis which, if not treated effectively, is usually fatal.
  • Recurrent and persistent genital infections occur with HSV-2 that are widespread in the population and defy management so that these patients suffer great physical discomfort and psychological distress.
  • HSV-1 causes substantial discomfort to a large segment of the population. There is at this time no known way to manage recurrent infections or to combat this virus in its latent stage.
  • Varicella-zoster is often the cause of morbidity in immunosuppressed patients such as kidney transplant recipients. Cytomegalo virus causes embryological abnormalities, perinatal neurological disease and great problems in the neonate; like zoster, it is a neurotropic virus.
  • IdU is effective against Herpes Keratitis it is less effective than F 3 dT and is not as effective in systemic infections or in the treatment of Herpes genitalis.
  • these two compounds suffer from two major disadvantages. The first is that the compounds undergo rapid catabolism in the body which results in significant reduction of antiviral effectiveness of the compound.
  • the second disadvantage is that the compounds exhibit toxicity towards uninfected cells which, in turn, results in the generation of unpleasant and harmful side effects.
  • IdU has been abandoned for the treatment of Herpes encephalitis because of its toxicity and its ineffectiveness, and F 3 dT has not been considered for the treatment of systemic infections.
  • Adenine arabinoside has been shown to decrease the incidence of death due to human encephalitis.
  • the number of individuals with neurological sequelae was discouraging. That is, the drug decreased the mortality but increased the morbidity.
  • ara-A or ara-AMP is neither effective against recurrent genital Herpes nor does it decrease the incidence of latent virus infection.
  • Phosphonacetic acid is effective in animal systems; however it must be administered in most cases very soon after infection, and is usually ineffective if the onset of treatment is delayed to coincide with realistic intervals for consideration for use in humans. Another disadvantage is that it is accumulated in bone.
  • a drawback of the 5-halo-2'-deoxycytidine compounds is their tendency to undergo deamination in the presence of deaminating enzymes, such as cytidine deaminase.
  • deaminating enzymes such as cytidine deaminase.
  • Such enzymes are usually present in the blood and catalyze the deamination of the 5-halo-2'-deoxycytidine compound to the corresponding 5-halo-2'-deoxyuridine compound.
  • uridine compounds are formed which do not display selectivity and which exhibit toxicity towards uninfected cells and generate unpleasant and harmful side effects.
  • deoxyuridine analogs are further degraded to metabolites that do not display antiviral activity.
  • HSV anti-viral
  • 4-N alkyl derivatives methyl, ethyl, isopropyl
  • IdC The anti-viral activities of 4-N alkyl derivatives (methyl, ethyl, isopropyl) of IdC have been studied, Fox, Doberson and Greer, Antimicrobal Agents and Chemotherapy, Vol. 23, 465-476, 1983, and appears to be incorporated into viral DNA without deamination; that is, it is not necessary to coadminister dH 4 U or H 4 U.
  • Greer U.S. patent 4,210,638 discloses the use of 5-trifluoromethyl-2'-deoxycytidine, together with a cytidine deaminase inhibitor, to treat patients suffering from a disease caused by a Herpes or a Herpes-like virus. Further work has also suggested that 5-trifluoromethyl-2'-deoxycytidine can be used to treat solid tumors, and again the com dine can be used to treat solid tumors, and again the compound (also called F 3 methyl dC or CF 3 dC) would be administered in connection with a cytidine deamination inhibitor such as tetrahydrouridine or 2'-deoxytetrahydrouridine.
  • a cytidine deamination inhibitor such as tetrahydrouridine or 2'-deoxytetrahydrouridine.
  • 5-methyl-2'-deoxycytidine is not incorporated as such in mammalian cells, even when co-administred with dH 4 U, whereas 5-bromo-2'-deoxycytidine and 5-iodo-2'-deoxycytidine are incorporated into DNA.
  • These studies utilize cells transfected with the gene encoding the pyrimidine nucleoside kinease of HSV-1 or HSV-2 so that the analogs would be phosphorylated to the nucleostide level.
  • 5-fluoro-2'-deoxycytidine is incorporated to only a very limited extent in normal cells, but is incorporated to a greater extent in tumor cells.
  • the coadministration of dH 4 U increases the incorporation of 5FdC 25-fold.
  • the effects of co-administering high levels of dH 4 U with FdC in two mouse tumor models has been studied.
  • vherein X is fluoro, chloro, CH 3 or CF 3 , together with an inhibitor of cytidine deaminase and dCMP deami ⁇ nase, s ⁇ ch as 2'-daoxytetrahyrouridine, as well as theuse of such compositions in the treatment or prevention of retroviral associated diseases, such as AIDS.
  • Preferred compounds of the above formula are 5-methyl2'-deoxycytidine (CH 3 dC), 5-chloro-2'-deoxycytidine (CldC), and 5-fluoro-2'deoxycytidine (FdC), with the most preferred compound being CH 3 dC.
  • 5-methyl-2'-deoxycytidine and 2'-deoxytetrahydrouridine should result in the incorporation of 5-methyl-2'-deoxycytidine as such into the DNA of cells utilizing the RNA of HTLV-III as a template, and reverse transcriptase as the DNA polymerase.
  • This enzyme, the RNA dependent polymerase possesses a very low fidelity of DNA replication in contrast to the DNA dependent DNA polymerase utilized by T-helper cells that do not possess HTLV-III.
  • ribavirin is a somewhat effective agent against HTLVIII, 5-methyl dC may also be substantially phosphorylated in the target cells.
  • the enzyme responsible for the activation (phosphorylation) of ribavirin is adenosine kinase; however, deoxyguanosine-deoxycytidine kinase may also be involved in the activation of ribavirin.
  • 5-fluorodeoxycytidine when coadministered with 2'-deoxytetrahydrouridine, may also result in effective selective inhibition of HTLV-III infected cells in view of the finding that 5-fluouro-deoxycytidine is incorporated to only the extent of 0.2% into the DNA, utilizing the DNA dependent DNA polymerase of uninfected mammalian cells.
  • 5-CH 3 dC An advantage of the use of 5-CH 3 dC is that it should display very little toxicity to the patient. If it is deaminated, thymidine will be formed which is a normal metabolite--although it can be inhibitory at extremely high concentrations (as dTTP). There is an internal control which makes it unlikely that generally toxic levels of TTP will be formed, for dCMP deaminase is not only inhibited by 2'deoxytetrahydrouridine, it is also regulated by TTP. TTP also end product inhibits nucleoside diphosphate reductase and thymidine kinase.
  • TTP which may be formed from 5-CH 3 dC
  • dCMP deaminase CTP synthetase
  • nucleoside diphosphate reductase any thymidine formed may, as TTP, inhibit dCMP deaminase, CTP synthetase, and nucleoside diphosphate reductase. Inhibition of CTP synthetase and the reductase would result in lowering pools of dCTP, which possess the potential to compete with the incorporation of the 5-suSstituted analogs of deoxycytidine.
  • a distinct advantage of the use of 5-methyl-2'-deoxycytidirie and 5-chloro-2'-deoxycytidine is that they will not be catabolized by enzymes of pyrimidine catabolism (the nucleoside phosphorylases) when their deamination is prevented. This catabolism is a problem encounted with thymidine and uridine analogs.
  • the problems that this invention may solve will be to provide a cure for a morbid disease which is usually fatal.
  • the present invention should interfere with the dissemination of infection of this highly infectious disease, AIDS.
  • This invention should not only be effective against HTLV-III, but against other retrovirus related disease states such as leukemia and multiple sclerosis, if indeed it is found that HTLV-I is a causative agent of multiple sclerosis, as a recent publication suggests.
  • Another possible advantage of the present invention is that many leukemic states, such as certain T-cell leukemias, have elevated levels of dCMP deaminase; therefore, the addition of 2'-dH,U may interfere with the unique and possibly essential metabolic event in these cells--thereby attacking the disease state at an entirely different target end point.
  • the present invention may offer a cure where none exists.
  • the shortcomings of imminological approaches are that the virus is highly mutable and may change antigenic properties so that an antibody directed against a specific isolate may not be generally effective.
  • the present invention exploits rather than is endangered by the infidelity of viral DNA replication.
  • the infidelity of retrovirus replication is due, in part, to the fact that the viral RNA dependent DNA polymerase lacks a 3' to 5' proof-reading exonuclease which is active in DNA-directed DNA synthesis (i.e., active in uninfected cells).
  • RNA nucleic acid
  • DNA helical double strand
  • compositions for intravaneous, subcutaneous, intramuscular, oral or intraperitoneal administration are included in the present invention. These pharmaceutical compositions will contain viral inhibitory amounts jaf 5-CH 3 dC, FdC, CldC or 5-F 3 methyl dC, and dH 4 U or other deamination inhibitor, together with a pharmaceutically acceptable carrier or diluent. While the components of the composition may be administered to a patient separately, with the dH 4 U administered up to a half hour before or fifteen minutes after the 5-substituted deoxyouridine compound, it is preferred to coadminister the active ingredients as a mixture.
  • the concentration of each of the active ingredients may vary from about 0.01 to about 15% by weight, depending upon the route of administration, the frequency of administration, the severity of the condition, the age, weight and general physical condition of the patient being treated.
  • a more concentrated solution could be used, e.g., 35 grams/100 ml, or a slow I.V. infusion of 0.1 to 257o (or higher) concentration could be used.
  • the concentration of the active components (the 5-substituted deoxycytidine compound and the dH 4 U) will each vary from about 0.05 to about 5%, w/v, preferably about 0.1 to 0.5% w/v.
  • aqueous solution of 5CH 3 dC, CldC, FdC, or F 3 methyl dC and dH 4 U having a concentration generally varying from about 0.5 to 5% w/v, and preferably from 1% w/v, for each compound can be utilized.
  • intraperitoneal mode of administration such as, for instance, intraperitoneal administration for animal studies
  • aqueous solution of 5CH 3 dC, CldC, FdC, or F 3 methyl dC and dH 4 U having a concentration generally varying from about 0.5 to 5% w/v, and preferably from 1% w/v, for each compound can be utilized.
  • intramuscular injection the same conditions as described above for the intraperitoneal mode of administration will be utilized.
  • the concentration of the active ingredients will generally be from 0.05 to 10 weight percent each, preferably about 0.5 to 5 weight percent each, and more preferably each will be present in an amount of about 1 to 2 weight percent.
  • Suppositories may be used for sustained release purposes, and slowrelease surgical implants are also envisaged.
  • the pharmaceutically acceptable carriers or diluents employed in the compositions of the present invention may be any compatible non-toxic material suited for mixing with the active compounds.
  • the carrier which preferably is an aqueous vehicle, may also contain other conventional additives, such as a suspending agent, for example, methyl cellulose or polyvinylpyrrolidone (PVP), and a conventional surfactant.
  • a suspending agent for example, methyl cellulose or polyvinylpyrrolidone (PVP)
  • PVP polyvinylpyrrolidone
  • compositions can be formulated as aqueous solutions, suspensions, capsules, or tablets, suitably containing appropriate carriers or diluents, for example, lactose, starch and/or magnesium stearate for flavoring agents, syrups, sweeteners, and/or coloring materials as customarily used in such preparations.
  • appropriate carriers or diluents for example, lactose, starch and/or magnesium stearate for flavoring agents, syrups, sweeteners, and/or coloring materials as customarily used in such preparations.
  • a preferred pharmaceutical composition provides the patient with a total i.v. dosage of from 3 to 5 ml (cc) per dosage calculated on 70 kg body weight of the patient.
  • the inhibitor which is coadministered with the 5-substituted deoxycytidine compound must inhibit both cytidine deaminase and dCMP deaminase under most conditions. This is so that the inhibitor can prevent deamination of the nucleoside and the corresponding nucleotide. For certain situations, such as, for example, if the dCMP deaminase is at a low level, it may be in order to administer tetrahydrouridine in place of some or all of the 2'-deoxytetrahydrouridine.
  • the patient will preferably be given drugs i.v. or i.m. or in an oral or suppository form or in a slow release form.
  • drugs i.v. or i.m. or in an oral or suppository form or in a slow release form may be particularly advantageous.
  • Different routes may be used for individual drugs in one treatment protocol.
  • additions would preferably be in the form of pretreatments and could include PALA to inhibit aspartyl transcarbamylase, and/or deazauridine to inhibit CTP synthetase (this is also an inhibitor of nucleoside deaminases) and/or the glutamyl transferase inhibitors azaserine or DON, which also inhibit CTP synthetase and/or hydroxyurea or 2'-chloro-deoxyadenosine, which inhibit nucleoside diphosphate reductase, and/or high doses of thymidine, or, more preferably, in view of catabolism, 5-CH 3 dC + tetrahydrouridine, as a source of high doses of thymidine.
  • PALA in 10 ml ampules containing PALA disodium (1.0 gram) with Edetate disodium (1 mg) and NaOH to adjust pH to 6.5 to 7.5 will be given to an AIDS, leukemia, or MS patient at a range of 2 mg to 150 mg/kg per dose, preferably 5 to 20 mg/kg per dose and, more likely, 10 mg/kg per dose. Twelve to thirty-six hours later, preferably 18 to 26 and, most likely, 24 hours later, deazauridine, at a dose of 5-80 mg/kg per dose, preferably 10 to 40, more likely 30 mg/kg, would be administered.
  • 5-CH 3 dC at a dose of 100 mg to 1000 mg/kg
  • tetrahydrouridine at a dose range from 5 to 500 mg/kg, preferably 50 to 300 mg/kg and, more likely, 80 mg/kg.
  • the ratio of H 4 U to CH 3 dC will range from 2:1 to 0.2:1, preferably 1:1 to 0.5:1 and, more likely, 0.75:1.
  • the dose of 5-substituted deoxycytidine analogs will range from 50 to 1000 mg/kg per dose, preferably 75 to 500 mg/kg, more likely 150 mg/kg.
  • the dose of dH 4 U will be similar to that of H 4 U given with CH 3 dC in the pretreatment described above, except when FdC is utilized.
  • the ratios are, however, different; namely, the ratio of dH 4 U to CH 3 dC, CldC or F 3 inethyl dC will range from 1:10 to 1:1, more usually, 1:5 to 1:1.5, and, more likely, 1:2.
  • the dose When FdC is administered, the dose will be in the range of 5 to 80 mg/kg, preferably 10 to 20 mg/kg and, more likely, 12 to 15 mg/kg.
  • the dose of dH 4 U or H 4 U would be 15 to 100 mg/kg, preferably 20 to 30 mg/kg, more likely 25 mg/kg.
  • This dose will be repeated at 6 to 18 hour intervals, more usually 8 to 12, preferably 10 hour intervals.
  • the period of repeated administration of 5-substituted analogs of deoxycytidine + dH 4 U or other deamination inhibitor will be 20 to 60 hours, more usually 30 to 50 hours, more likely 34 to 48 hours.
  • the 5-substituted analogs of deoxycytidine + dH 4 U will be administered in 3 to 4 doses, 8 to 12 hours apart, before initiating another cycle of treatment (including the pretreatment to inhibit the de novo pathway).
  • the interval between PALA/deazauridine/hydroxyurea/-5CH 3 dC + H 4 U pretreatment therapy and the administration of 5-substituted analogs of deoxycytidine, the frequency of administration, the choice between continuous infusion vs. bolus doses and the length of the interval between each cycle of treatment is determined by skilled estimation, drawing upon previous experiences, and observations using this regimen of therapy.
  • CH 3 dC + H 4 U or thymidine or deoxycytidine +H 4 U or dH 4 U may be administered 6 to 12 hours after cessation of the cycle of treatment. Less desireable would be the administration of these rescue antagonists during the treatment cycle, although adding them towards the end of the cycle would be more preferable than if added in the middle of the treatment schedule.
  • Thymidine or CH 3 dC would be added at a dose of 50 to 500 mg/kg, more likely 100 to 400 mg/kg, preferably 150 mg/kg.
  • Deoxycytidine would be added at a dose of 25 to 200 mg/kg, preferably 50 to 100 mg/kg.
  • CH 3 dC or dC When CH 3 dC or dC is utilized, it will be coadministered with tetrahydrouridine at a ratio of tetrahydrouridine to pyrimidine deoxyribonucleoside of 1:05 to 1:5.
  • Deoxycytidine may also be coadministered with deoxytetrahydrouridine for the purpose of antagonism or rescue. This rescue protocol would be repeated 2 to 5 times at 6 to 18 hour intervals.
  • the Table set forth below sets forth in general terms the dosage, in milligrams per killogram, which will normally be utilized in the pretreatment step, the treatment step and the rescue step.
  • This example relates to how the present invention could be used to treat a patient suffering from AIDS.
  • the patient would first be subjected to a pretreatment, involving the i.v. administration of PALA at a level of 10 mg/kg per dose, with the PALA in 10 ml ampoles containing PALA disodium (1.0 gm) with Edetate disodium (1 mg) and NaOH to adjust pH to 6.5 to 7.5.
  • deazauridine would be i.v. administered at a level 30 mg/kg per dose.
  • the deazauridine administration would be immediately followed by the i.v. administration of 5-CH 3 dC in an amount of 150 mg/kg/dose plus tetrahydrouridine in an amount of 150 mg/kg/dose.
  • CH 3 dC would be coadministered in an amount of 150 mg/kg/dose, together with 75 mg/kg/cose of dH 4 U, by i.v. administration.
  • the dose will be repeated at 10 hour intervals for a total administration time of 40 hours.
  • the patient would be subjected to a rescue regime involving the i.v. administration of a mixture of deoxycytidine and 2'-deoxytetrahydrouridine, in an amount of 75 mg/kg/dose of the deoxycytidine and 25 mg/kg/dose of the 2'-deoxytetrahydrouridine.
  • This rescue would begin 10 hours after cessation of the cycle of treatment with the composition of the present invention, and the rescue protocol would be repeated three times at 12 hour intervals. All of the i.v. administration mentioned above would involve the intravenous administration of sterile saline solutions of the indicated compounds.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de traitement de maladies provoquées par des rétrovirus, tel que le SIDA, consistant à administrer au patient une quantité thérapeutiquement efficace d'un composé de 2'-désoxycytidine substitué, tel que par exemple de la 5-méthyl-2'-désoxycytidine, en combinaison avec un inhibiteur de désamination du composé de disoxycytidine. Sont également décrites des compositions permettant l'application du procédé.
EP19870901944 1986-02-20 1987-02-20 Composition et procede de traitement du sida et de certaines maladies s'y rapportant Withdrawn EP0258412A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83127886A 1986-02-20 1986-02-20
US831278 1986-02-20

Publications (1)

Publication Number Publication Date
EP0258412A1 true EP0258412A1 (fr) 1988-03-09

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EP (1) EP0258412A1 (fr)
AU (1) AU7120987A (fr)
WO (1) WO1987004929A1 (fr)

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SE8602981D0 (sv) 1986-07-04 1986-07-04 Astra Laekemedel Ab Novel medicinal use
KR960001372B1 (ko) * 1986-09-24 1996-01-26 예일 유니버시티 레트로비루스로 감염된 환자의 치료에 사용되는 2',3'-디디옥시사이티딘-2'-엔(2',3'-디디옥시-2',3'-디디하이드로사이티딘)의 항생물질
SE8605503D0 (sv) * 1986-12-19 1986-12-19 Astra Laekemedel Ab Novel medicinal use
CA2072083A1 (fr) * 1990-10-23 1992-04-24 Steven S. Smith Methode de production d'inhibiteur de l'adn methyl-transferase
WO1998031375A1 (fr) * 1997-01-21 1998-07-23 The United States Of America As Represented By Thesecretary Of The Department Of Health And Human Sevices Isolation en tranchee pour dispositifs micromecamiques
JP4110347B2 (ja) * 1999-11-05 2008-07-02 大鵬薬品工業株式会社 抗ｈｉｖ剤
BR112023019182A2 (pt) * 2021-03-26 2023-11-28 Cleveland Clinic Found Uso de um inibidor de citidina desaminase na preparação de um medicamento, sistema, kit ou artigo de manufatura e composição

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US4210638A (en) * 1978-03-17 1980-07-01 Pcr, Inc. Antiviral composition and method of treating virus diseases
US4230698A (en) * 1978-05-12 1980-10-28 Research Corporation 2-Substituted arabinofuranosyl nucleosides and nucleotides

Non-Patent Citations (1)

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Title
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WO1987004929A1 (fr) 1987-08-27
AU7120987A (en) 1987-09-09

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