EP0472663A1 - Procede de traitement de l'hepatite - Google Patents

Procede de traitement de l'hepatite

Info

Publication number
EP0472663A1
EP0472663A1 EP90909416A EP90909416A EP0472663A1 EP 0472663 A1 EP0472663 A1 EP 0472663A1 EP 90909416 A EP90909416 A EP 90909416A EP 90909416 A EP90909416 A EP 90909416A EP 0472663 A1 EP0472663 A1 EP 0472663A1
Authority
EP
European Patent Office
Prior art keywords
nucleoside
administered
hepatitis
use according
dideoxyguanosine
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Withdrawn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
EP90909416A
Other languages
German (de)
English (en)
Other versions
EP0472663A4 (en
Inventor
Hiroaki Mitsuya
Jay H. Hoofnagle
Samuel Broder
Robert Yarchoan
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.)
US Department of Commerce
Original Assignee
US Department of Commerce
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 US Department of Commerce filed Critical US Department of Commerce
Publication of EP0472663A1 publication Critical patent/EP0472663A1/fr
Publication of EP0472663A4 publication Critical patent/EP0472663A4/en
Withdrawn legal-status Critical Current

Links

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a method for treating hepatitis B. BACKGROUND OF THE INVENTION
  • Chronic infection with the hepatitis B virus (HBV) affects approximately 5% of the world's population.
  • Chronic carriers of hepatitis B are at an increased risk of morbidity and mortality due to chronic liver disease, and a proportion of these will ultimately develop cirrhosis and/or hepatocellular carcinoma. At present, there is no therapy of proven benefit for chronic hepatitis B.
  • the human hepatitis B virus is a member of a family of viruses known as hepadnaviruses. Other viruses in this family are the woodchuck hepatitis virus, the ground squirrel hepatitis virus, and the duck hepatitis B virus. These animal viruses have been invaluable models for characterization of hepadnaviruses and delineation of their unusual replicative cycle. These viruses replicate asymmetrically through an RNA template which requires reverse transcriptase activity, cf. Summers, Cell .29.:403- 415, 1982.
  • the 2 » , 3'-dideoxynucleosides are nucleosides which recently have been shown to have potent antiviral activity against the reverse transcriptase activity of the human immunodeficiency virus, HIV, as described by Mitsuya, et al. in Proc. Natl. Acad. Sci. USA 1986; 83:1911-1915.
  • DDA dideoxyadenosine
  • DDG 3'-dideoxyguanosine
  • DI 2', 3'-dideoxyinosine
  • hepatitis B can be treated by administering 2' , 3*-dideoxyinosine (DDI) , 2*, 3 » -dideoxyguanosine (DDG) , or 2 1 , 3'- dideoxyadenosine (DDA) to a patient infected with hepatitis B.
  • DDA, DDG, or DDI are nucleoside analogues, and they appear to prevent the formation of normal phosphodiester linkages once they become incorporated into a growing DNA chain. This process leads to "chain termination.”
  • DDI, and DDA have a high affinity for reverse DDG, transcriptase, and, therefore, may inhibit replication of hepatitis B virus by preventing reverse transcription from the pregenomic RNA template.
  • DDG, DDA and DDI are particularly attractive as antiviral agents because they are absorbed orally and has comparatively minimal side effects under the conditions used.
  • Serum DNA polymerase activity was determined by measuring 3 H- thymidine incorporation into purified Dane particles by the method of Kaplan, et al., . Virol. 12: 995-1005, 1973.
  • the in vitro effects of DDI, DDA and DDG as a nucleotide analogues on DHBV and HBV were assessed using the DNA polymerase reaction.
  • a range of concentra ⁇ tions of DDI, DDA or DDG triphosphate were incubated with purified Dane particles for one hour at 37°C, and the DNA polymerase reaction was then performed.
  • DHBV DNA was analyzed by molecular hybridization using a 3.0 kb, full-length DHBV DNA clone in CACYC184.
  • the DHBV DNA insert was freed from plasmid A49 by digestion with EcoRl and agarose gel electrophoresis.
  • the DHBV DNA was radiolabelled with 32 P using the random primer method of Feinberg, et al., ibid. , to a specific activity of 3 x 10 7 to 1 x 10 8 cpm/ ⁇ g.
  • DHBV DNA was detected in serum and liver tissue by slot blot analysis.
  • lO ⁇ l of serum was denatured with 1 ⁇ l of 1 M NaOH for five minutes. The mixture was then neutralized by adding 90 ⁇ l of 1 M ammonium acetate.
  • DHBV DNA in liver biopsy specimens approximately 100 mg of minced liver was homogenized in 10 ml of ice cold 50 mm Tris, pH 8.5, 10 mM EDTA and 1% SDS. The crude liver homogenate was digested with proteinase K (200 ⁇ g/ml) for two hours at 50°C. Total cellular DNA was prepared by two extractions with a mixture of phenol and chloroform (1:1) in Tris pH 7.5. DNA was precipitated with absolute ethanol and diluted to a con ⁇ centration of approximately 2 mg of DNA/ l in TE buffer.
  • DHBV DNA was quantified by comparing the autoradiographic signals for each sample with those of known amounts of cloned DHBV DNA dotted on the same filter diluted in normal serum or normal duck liver DNA. Liver tissue DHBV DNA was also analyzed by
  • the effect of 2' , 3'-dideoxyinosine and 2' , 3'- dideoxyguanosine was assessed in eighteen Pekin ducks chronically infected with the duck hepatitis B virus (DHBV) .
  • DHBV duck hepatitis B virus
  • Six ducks were given DDI and six ducks were given DDG at the rate of 0.8 g/kg per injection by bolus every six hours for five days.
  • the antiviral response was assessed by monitoring serum markers of viral replication, including DHBV DNA polymerase.
  • the serum levels of DDI and DDG were 386 ng/ml and 772 ng/ml, respectively, at 20 minutes and 120 ng/ml and 50 ng/ml, respectively, at one hour after bolus injections.
  • Antiviral therapy was tolerated well, and all ducks survived therapy and liver biopsy. No duck showed obvious evidence of drug toxicity.
  • nucleosides for use in the present invention have the following formulas:
  • the DDG, DDA, or DDI may be in the form of carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is selected from straight or branched chain alkyl, alkoxyalkyl (e.g. ,methoxymethyl) , aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl) , aryl (e.g., phenyl optionally substituted by halogen, C _,__. 4 alkyl or C_,.
  • alkoxyalkyl e.g. ,methoxymethyl
  • aralkyl e.g., benzyl
  • aryloxyalkyl e.g., phenoxymethyl
  • aryl e.g., phenyl optionally substituted by halogen, C _,__. 4 alkyl or C_,.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms.
  • Any aryl moiety present in such esters preferably comprises a phenyl group, including a substi ⁇ tuted phenyl group.
  • Examples of pharmaceutically acceptable salts and pharmaceutically acceptable derivatives of the compounds which can be use in treating hepatitis B according to the present invention include base salts such as those derived from a base such as alkali metal (sodium, lithium, potas ⁇ sium) , alkaline earth metal (magnesium) salts, ammonium and NX 4 where X is C ⁇ alkyl.
  • base salts such as those derived from a base such as alkali metal (sodium, lithium, potas ⁇ sium) , alkaline earth metal (magnesium) salts, ammonium and NX 4 where X is C ⁇ alkyl.
  • Physiologically acceptable salts containing a hydrogen atom or any amino group include salts of organic carboxylic acids such as acetic, lactic, tar- taric, maleic, isothionic, lactobionic, and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesul- fonic, benzenesulfonic, and p-toluenesulfonic acid, and inorganic acids such as hydrochloric, sulfuric, phosphoric, and sulfamic acids.
  • organic carboxylic acids such as acetic, lactic, tar- taric, maleic, isothionic, lactobionic, and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesul- fonic, benzenesulfonic, and p-toluenesulfonic acid
  • inorganic acids such as hydrochloric, sulfuric, phospho
  • Physiologically acceptable salts of a compound containing any hydroxy group include the anion of said compound in combination with a suitable cation such as Na + , NHY + , and HX 4 + (wherein X is C ⁇ alkyl and X is halogen) .
  • suitable cation such as Na + , NHY + , and HX 4 + (wherein X is C ⁇ alkyl and X is halogen) .
  • Specific examples of pharmaceutically acceptable derivatives of the compounds that may be used in accordance with the present invention include the monosodium salt and the following 5' esters: monophosphate, disodium monopho- sphate, diphosphate, triphosphate, acetate, 3-methyl butyrate, octanoate, palmitate, 3-chloro benzoate, 4-methyl benzoate, hydrogen succinate, pivalate, and methylate.
  • compositions which, upon administration to the recipient, is capable of providing, either directly or indirectly, a nucleoside analogue as described above, or an antivirally active metabolite or residue thereof. All of these compounds are active and relatively nontoxic at con ⁇ centrations of sufficient potency for effective inhibition of viral infectivity and replication.
  • nucleoside of the present invention may be administered alone in solution.
  • active ingredient may be used or administered in a pharmaceutical formulation.
  • formulations comprise the nucleoside or derivative thereof together with one or more pharmaceutically acceptable carriers and/or other therapeutic agents.
  • pharmaceutically acceptable carriers and/or other therapeutic agents included within the scope of the present invention, "acceptable” is defined as being com ⁇ patible with other ingredients of the formulation and not injurious to the patient or host cell.
  • the administration of DDG, DDA, or DDI to treat hepatitis B can be accomplished by a variety of means of administration. Whatever administrative method is chosen should result in circulating levels of the nucleoside within a range of about 0.01 ⁇ M to about 2.0 ⁇ M. A range of approximately 0.05 to about 0.5 mg/kg administered every four hours is considered to be a virustatic range in humans. In order to achieve this, the preliminary dosage range for oral administration may be broader, being, for example, 0.001-0.50 mg/kg administered every four hours. It is recognized that dosage modifications may be required in individual patients to ameliorate or inhibit toxic side effects.
  • the pharmaceutical formulations according to the present invention may conveniently be administered in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Determination of the effective amounts to be included in the dosage forms within the skill of the art.
  • the pharmaceutical compositions according to the present invention may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the DDA or DDI into prepara ⁇ tions which can be used pharmaceutically.
  • the preparations particularly those which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, an capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for admin- istration by injection or orally, contain from about 0.1 to 99 percent, and preferably from about 25-85 percent, by weight, of DDC, together with the excipient.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optically grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste using, for example, maize starch, wheat starch, rice starch, potato starch, and the like; gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcel- lulose, and/or polyvinyl pyrrolidone.
  • fillers such as sugars, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste using, for example, maize starch, wheat starch, rice starch, potato starch, and the like; gelatin, gum
  • disin ⁇ tegrating agents may be added such as the above-mentioned starches and carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
  • Auxiliaries are, for example, flow- regulating agents and lubricants, such as silica, talc, stearic acid or salts thereof such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentra ⁇ ted sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethy- lene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate are used.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize different combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plas- ticizer such as glycerol or sorbitol.
  • the push-fit cap ⁇ sules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of combinations of the active ingredient with a suppository base.
  • Suitable suppository bases include natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocar ⁇ bons.
  • Suitable formulations for parenteral administra- tion include aqueous solutions of the active compounds as appropriate oil injection suspensions may be administered.
  • Suitable lypophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension such as sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the hepatitis B may be treated by directly delivering the triphosphate derivative to the patient.
  • the triphosphate derivatives of this invention may be delivered by means of liposomes, small particles (about 25 ⁇ M to about 1 ⁇ M in diameter) which can serve as an intracellular transport system to deliver normally non-absorbable drugs across the cell membrane.
  • liposomes small particles (about 25 ⁇ M to about 1 ⁇ M in diameter) which can serve as an intracellular transport system to deliver normally non-absorbable drugs across the cell membrane.
  • the liposomes are by agitat ⁇ ing phospholipids in aqueous suspensions at high frequen ⁇ cies. This results in the formation of closed vesicles characteristic of liposomes.
  • the triphosphate derivatives act to eliminate the replication of the hepatitis B virus. Since the triphosphate has been shown to be active inside the cells, and to be the active form therein, the liposome is clearly a method of choice for delivery of these drugs.
  • Formulations suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addi- tion to the active ingredient, such carriers as are known in the art to be appropriate.
  • the formulations according to the present inven ⁇ tion may be in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a lyophil- ized condition requiring only the addition of the sterile liquid carrier for injections immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the medication is generally administered two to six times a day.
  • a common buffer such as sodium acetate
  • a solution containing a nucleoside according to the present.invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Application Of Or Painting With Fluid Materials (AREA)

Abstract

On traite l'hépatite B par l'administration d'une quantité efficace de 2',3'-didésoxyguanosine, 2',3'-didésoxyadénosine, ou 2',3'-didésoxyinosine.
EP19900909416 1989-05-15 1990-05-15 Method of treatment of hepatitis Withdrawn EP0472663A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35150289A 1989-05-15 1989-05-15
US351502 1989-05-15

Publications (2)

Publication Number Publication Date
EP0472663A1 true EP0472663A1 (fr) 1992-03-04
EP0472663A4 EP0472663A4 (en) 1992-07-01

Family

ID=23381196

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900909416 Withdrawn EP0472663A4 (en) 1989-05-15 1990-05-15 Method of treatment of hepatitis

Country Status (5)

Country Link
EP (1) EP0472663A4 (fr)
JP (1) JPH04501857A (fr)
AU (1) AU5832990A (fr)
CA (1) CA2054771A1 (fr)
WO (1) WO1990014091A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5039667A (en) * 1987-08-07 1991-08-13 The Governors Of The University Of Alberta Antiviral therapy for hepatitis B with 2',3'-dideoxypurine nucleosides
IL100502A (en) * 1991-01-03 1995-12-08 Iaf Biochem Int PHARMACEUTICAL PREPARATIONS CONTAINING CIS-4-AMINO-1-) 2-HYDROXIMETHIL-1,3-OXETYOLEN-5-IL (-
GB9110874D0 (en) * 1991-05-20 1991-07-10 Iaf Biochem Int Medicaments
US20030100532A1 (en) 1997-02-14 2003-05-29 Gary S. Jacob Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections
US7122207B2 (en) 1998-05-22 2006-10-17 Bristol-Myers Squibb Company High drug load acid labile pharmaceutical composition
US6174873B1 (en) * 1998-11-04 2001-01-16 Supergen, Inc. Oral administration of adenosine analogs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0216510A2 (fr) * 1985-08-26 1987-04-01 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Inhibition de l'infectivité in vitro et de l'effet cytopathique du HTLV-III/LAV par la 2'3'-didéoxyinosine, la 2'3'-didéoxyguanosine ou par la 2'3'-didéoxyadénosine
EP0307914A2 (fr) * 1987-09-18 1989-03-22 F. Hoffmann-La Roche Ag Composition pharmaceutique contenant un didéoxynucléoside
EP0302760B1 (fr) * 1987-08-07 1992-07-29 The Governors of the University of Alberta Thérapie antivirale contre l'hépatite B employant des 2',3'-didéoxynucléosides

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT82580B (pt) * 1985-05-15 1989-01-17 Wellcome Found Processo para a preparacao de 2',3'- didesoxinucleosidos e de composicoes farmaceuticas que os contem
US4704357A (en) * 1985-09-30 1987-11-03 United States Of America As Represented By The Department Of Health And Human Services Immortalized T-lymphocyte cell line for testing HTLV-III inactivation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0216510A2 (fr) * 1985-08-26 1987-04-01 THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce Inhibition de l'infectivité in vitro et de l'effet cytopathique du HTLV-III/LAV par la 2'3'-didéoxyinosine, la 2'3'-didéoxyguanosine ou par la 2'3'-didéoxyadénosine
EP0302760B1 (fr) * 1987-08-07 1992-07-29 The Governors of the University of Alberta Thérapie antivirale contre l'hépatite B employant des 2',3'-didéoxynucléosides
EP0307914A2 (fr) * 1987-09-18 1989-03-22 F. Hoffmann-La Roche Ag Composition pharmaceutique contenant un didéoxynucléoside

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 33, no. 3, March 1989, pages 336-339, American Society for Microbiology; B. LEE et al.: "In vitro and in vivo comparison of the abilities of purine and pyrimidine 2',3'-dideoxynucleosides to inhibit duck hepadnavirus" *
ANTIVIRAL RESEARCH, vol. 12, nos. 5-6, 1989, pages 301-310, Elsevier Science Publishers B.V. (Biomedical Division); B. L\FGREN et al.: "Inhibition of RNA- and DNA-dependent duck hepatitis B virus DNA polymerase activity by nucleoside and pyrophosphate analogs" *
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 156, no. 3, 15th November 1988, pages 1144-1155, Academic Press, Inc.; S. SUZUKI et al.: "Inhibition of duck hepatitis B virus replication by purine 2',3'-dideoxynucleosides" *
GASTROENTEROLOGY, vol. 96, no. 5, part 2, 13th 19th May 1989, page A628, Washington, DC, US; P. MARTIN et al.: "2',3'-Dideoxyinosine(DD1) and dideoxyguanosine (DD3) are potent inhibitors of hepadnaviruses in vivo" *
HEPATOLOGY, vol. 8, no. 5, 1988, page 1329, abstract no. 444; P. MARTIN et al.: "Effects of 2',3'-dideoxyadenosine on duck hepatitis B virus" *
LAB. INVEST., vol. 60, no. 1, January 1989, page 71A, abstract no. 420; K.L. PAUW et al.: "Histological effects of 2',3'-dideoxypurines in duck hepatitis B virus infection" *
See also references of WO9014091A1 *

Also Published As

Publication number Publication date
JPH04501857A (ja) 1992-04-02
WO1990014091A1 (fr) 1990-11-29
EP0472663A4 (en) 1992-07-01
AU5832990A (en) 1990-12-18
CA2054771A1 (fr) 1990-11-16

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