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WO1990014079A1 - Procede de traitement de l'hepatite - Google Patents

Procede de traitement de l'hepatite Download PDF

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Publication number
WO1990014079A1
WO1990014079A1 PCT/US1990/002685 US9002685W WO9014079A1 WO 1990014079 A1 WO1990014079 A1 WO 1990014079A1 US 9002685 W US9002685 W US 9002685W WO 9014079 A1 WO9014079 A1 WO 9014079A1
Authority
WO
WIPO (PCT)
Prior art keywords
dideoxycytidine
administered
hepatitis
ddc
dna
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.)
Ceased
Application number
PCT/US1990/002685
Other languages
English (en)
Inventor
Jay H. Hoofnagle
Samuel Broder
Hiroaki Mitsuya
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.)
United States Department of Commerce
Original Assignee
United States 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 United States Department of Commerce filed Critical United States Department of Commerce
Priority to CA002055433A priority Critical patent/CA2055433A1/fr
Publication of WO1990014079A1 publication Critical patent/WO1990014079A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
  • HBV HBV
  • Chronic carriers of hepatitis B are at a increased risk of morbidity and mortality due to chronic liver disease r 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. Although o ⁇ -interferon has shown great promise in a subset of patients treated for prolonged period of time, the response rates overall have, unfortunately, been disap ⁇ pointingly low.
  • 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.
  • the most potent of these analogues is 2' , 3'-dideoxycy- tidine, or DDC, which inhibits HIV in cell culture in concentrations as low as 10 nM.
  • hepatitis B can be treated by administering 2' , 3 '-dideoxycytidine to a patient infected with hepatitis B.
  • DDC is a nucleoside analogue, and it appears to prevent the formation of normal phosphodiester linkages once it becomes incorporated into a growing DNA chain. This process leads to "chain termina ⁇ tion.”
  • DDC has a high affinity for reverse transcriptase, and, therefore, may inhibit replication of hepatitis B virus by preventing reverse transcription from the pregeno- mic RNA template. This interference in replication would lead to a decrease in serum levels of virus and a gradual fall in the amounts of hepatitis B virus DNA in the liver.
  • DDC is particularly attractive as antiviral agent because it is absorbed orally and has comparatively minimal side effects under the conditions used.
  • Figure 1 shows the in vitro effects of 2' , 3'- dideoxycytidine triphosphate on the DNA polymerase reaction of the human and duck hepatitis B viruses.
  • Figure 2 shows changes in mean serum DNA polymerase activity among Peking ducks chronically infected with duck hepatitis B virus who received DDC or no treatment.
  • Figure 3 shows changes in mean serum duck hepatitis B virus DNA levels among Peking ducks chronically infected with duck hepatitis B virus who received either DDC or no treatment.
  • Figure 4 shows liver duck hepatitis B virus DNA levels in ducks before and after treatment with DDC.
  • Figure 5 shows autoradiograms of duck hepatitis
  • 2' , 3 '-dideoxycytidine can be used for treating hepatitis B in patients so infected.
  • the DDC is well absorbed orally, and is generally well tolerated. In humans, the dose-limiting toxicity has been a peripheral neuropathy which can be significantly reduced by lowering the dose. In vitro DDC triphosphate had little effect on
  • DNA polymerase activity of either duck hepatitis B virus or human hepatitis B virus was assessed for antiviral activity in hepatitis B, cf. Nordenfelt, et al., Acta Path. Microbiol. Scand. Sect. B 82:75-76, 1979; and Hess, et al., Anti ⁇ tic. Agents Chemo. JL :44-50, 1981.
  • This assessment may be unreliable as a means of screening antiviral agents.
  • the DNA polymerase activity measured in serum from humans and ducks infected with hepadnaviruses may represent only one of the viral enzymes necessary for replication, and this activity may be relatively resistant to inhibition.
  • DHBV DNA which was measured in total cellular DNA extracted from liver biopsies obtained before and on the last day of treatment with DDC, showed an average inhibition of 96% in three ducks treated with DDC, but showed no decrease in the remaining five ducks.
  • Serum DNA polymerase activity was determined by measuring 3 H- thymidine incorporation into purified Dane particles by the method of Feinberg, et al., Analyt. Biochem. 132:6-13, 1983.
  • the in vitro effects of DDC as a nucleotide analogue on DHBV and HBV were assessed using the DNA polymerase reaction.
  • a range of concentrations of DDC 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 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/mk) 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/ml 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 homogenate. Liver tissue DHBV DNA was also analyzed by
  • DDC triphosphate had little effect on the DNA dependent DNA polymerase activity of either HBV or DHBV, as shown in Figure 1. There was no inhibition of either viral DNA polymerase activity at concentrates below 10 ⁇ M and less than 20% inhibition at .100 ⁇ M DDC. At this concentration, cellular DNA polymerase activity is also inhibited by DDC.
  • Serum levels of DHBV DNA polymerase decreased in all nine ducks given DDC, but in none of the controls, as shown in Figure 2.
  • the mean inhibition of DNA polymerase activity measured on the third day of treatment was 64%.
  • the difference between the pretreatment and day 3 value was statistically significant (p ⁇ 0.01).
  • Serum levels of DHBV DNA also decreased in all nine ducks during therapy, but in none of the controls, as shown in the Table.
  • the mean percentage inhibition of DHBV DNA levels was 73% of day 3 of treatment (p ⁇ 0.01) , as shown in Figure 3.
  • successive changes in DNA polymerase levels correlated with successive changes in DNA polymerase levels on days 3, 6, and 10 of treatment.
  • DDC or 2', 3,'- dideoxycytidine
  • 2', 3,'- dideoxycytidine comprises a pyrimidine nucleoside with the ribose moiety of the mole ⁇ cule in the 2', 3'-dideoxy configuration, as illustrated below:
  • the DDC 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., phenoxymethy1) , aryl (e.g., phenyl optionally substituted by halogen, C,_ 4 alkyl or C,_ alkoxy) ; sulfonate esters such as alkyl- or aralkylsulfonyl (e.g., methanesulfonyl) ; and mono-, di-, and triphosphate esters.
  • alkoxyalkyl e.g. ,methoxymethyl
  • aralkyl e.g., benzyl
  • aryloxyalkyl e.g., phenoxyme
  • 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,_ 4 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,_ 4 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 4 + , and HX 4 + (wherein X is C,_ 4 alkyl and X is halo ⁇ gen) .
  • 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.
  • DDC to treat hepatitis B can be accomplished by a variety of means of administra ⁇ tion. Whatever administrative method is chosen should result in circulating levels o the DDC within a range of about 0.01 ⁇ M to about 2.0 ⁇ M. A range of approximately 0.05 to about 0.5 g/kg administered ever four hours is considered to be a virustatic range in humans. In order to achieve this, the preliminary dosage range for oral admin ⁇ istration 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.
  • compositions 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.
  • compositions according to the present invention may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the DDC into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the DDC into preparations which can be used pharmaceutically.
  • the prepa ⁇ rations particularly those which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and 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 as 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 agitating phospholipids in aqueous suspensions at high frequencies. 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 tri ⁇ phosphate 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 lyophi- lized 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 2' , 3 '-dideoxycy ⁇ tidine according to the present invention.

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

Abstract

On a mis au point un procédé de traitement de l'hépatite B, consistant à administrer de la 2',3'-didésoxycytidine à un patient atteint de l'hépatite B. La 2',3'-didésoxycytidine, après la phosphorylation anabolique, inhibe la transcriptase inverse du virus de l'hépatite B.
PCT/US1990/002685 1989-05-15 1990-05-15 Procede de traitement de l'hepatite Ceased WO1990014079A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002055433A CA2055433A1 (fr) 1989-05-15 1990-05-15 Methode de traitement de l'hepatite

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35151989A 1989-05-15 1989-05-15
US351,519 1989-05-15

Publications (1)

Publication Number Publication Date
WO1990014079A1 true WO1990014079A1 (fr) 1990-11-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/002685 Ceased WO1990014079A1 (fr) 1989-05-15 1990-05-15 Procede de traitement de l'hepatite

Country Status (5)

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EP (1) EP0472595A4 (fr)
JP (1) JPH04501854A (fr)
AU (1) AU5659990A (fr)
CA (1) CA2055433A1 (fr)
WO (1) WO1990014079A1 (fr)

Cited By (9)

* 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
EP0507188A1 (fr) * 1991-04-05 1992-10-07 Bayer Ag 2',3'-Didéoxy-5-trifluorométhyluridine substitué, procédé pour leur préparation et leur utilisation comme médicaments
WO1992019246A1 (fr) * 1991-05-02 1992-11-12 The Wellcome Foundation Limited Of Unicorn House Emploi d'un derive d'oxathiolane-1,3 pour le traitement de la contamination par l'hepatite b
EP0515144A1 (fr) * 1991-05-20 1992-11-25 Biochem Pharma Inc. 1,3-Oxathiolanes utiles dans le traitement de l'hépatite
US5234913A (en) * 1991-03-06 1993-08-10 Burroughs Wellcome Co. Antiviral nucleoside combination
US5532246A (en) * 1991-01-03 1996-07-02 Biochem Pharma, Inc. Use of 1,3-oxathiolane nucleoside analogues in the treatment of hepatitis B
US6156737A (en) * 1992-12-24 2000-12-05 Biochem Pharma Inc. Use of dideoxy nucleoside analogues in the treatment of viral infections
JP3479068B2 (ja) 1991-03-06 2003-12-15 エモリー・ユニバーシティ ５−フルオロ−２’−デオキシ−３’−チアシチジンのｂ型肝炎治療への使用
US6812233B1 (en) 1991-03-06 2004-11-02 Emory University Therapeutic nucleosides

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
US4666892A (en) * 1984-03-06 1987-05-19 Sloan-Kettering Memorial Cancer Center Method and composition for hepatitis treatment with pyrimidine nucleoside compounds
US4719235A (en) * 1984-10-16 1988-01-12 Gerald N. Kern Methods and compositions for treating viral infection

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR861255B (en) * 1985-05-15 1986-09-16 Wellcome Found Therapeutic nucleosides
JPS62501777A (ja) * 1985-08-26 1987-07-16 アメリカ合衆国 ２′，３′―ジデオキシシチジンを含有する抗ｈｔｌｖ―３／ｌａｖ剤
CA1327000C (fr) * 1987-08-07 1994-02-15 David L.J. Tyrrell Therapie antivirale pour l'hepatite b
JP2648329B2 (ja) * 1987-09-18 1997-08-27 エフ・ホフマン−ラ ロシュ アーゲー エイズの予防または治療用医薬組成物

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
US4666892A (en) * 1984-03-06 1987-05-19 Sloan-Kettering Memorial Cancer Center Method and composition for hepatitis treatment with pyrimidine nucleoside compounds
US4719235A (en) * 1984-10-16 1988-01-12 Gerald N. Kern Methods and compositions for treating viral infection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0472595A4 *

Cited By (12)

* 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
US5532246A (en) * 1991-01-03 1996-07-02 Biochem Pharma, Inc. Use of 1,3-oxathiolane nucleoside analogues in the treatment of hepatitis B
MD1224C2 (ro) * 1991-01-03 1999-11-30 Biochem Pharma Inc. Utilizare a analogilor nucleozidici cu 1,3-oxatiolan în tratamentul hepatitei B
USRE39155E1 (en) * 1991-01-03 2006-07-04 Shire Biochem Inc. Use of 1,3-oxathiolane nucleoside analogues in the treatment of hepatitis B
US5234913A (en) * 1991-03-06 1993-08-10 Burroughs Wellcome Co. Antiviral nucleoside combination
JP3479068B2 (ja) 1991-03-06 2003-12-15 エモリー・ユニバーシティ ５−フルオロ−２’−デオキシ−３’−チアシチジンのｂ型肝炎治療への使用
US6812233B1 (en) 1991-03-06 2004-11-02 Emory University Therapeutic nucleosides
EP0507188A1 (fr) * 1991-04-05 1992-10-07 Bayer Ag 2',3'-Didéoxy-5-trifluorométhyluridine substitué, procédé pour leur préparation et leur utilisation comme médicaments
WO1992019246A1 (fr) * 1991-05-02 1992-11-12 The Wellcome Foundation Limited Of Unicorn House Emploi d'un derive d'oxathiolane-1,3 pour le traitement de la contamination par l'hepatite b
EP0515144A1 (fr) * 1991-05-20 1992-11-25 Biochem Pharma Inc. 1,3-Oxathiolanes utiles dans le traitement de l'hépatite
US5486520A (en) * 1991-05-20 1996-01-23 Biochempharma, Inc. 1,3-oxathiolanes useful in the treatment of hepatitis
US6156737A (en) * 1992-12-24 2000-12-05 Biochem Pharma Inc. Use of dideoxy nucleoside analogues in the treatment of viral infections

Also Published As

Publication number Publication date
JPH04501854A (ja) 1992-04-02
CA2055433A1 (fr) 1990-11-16
AU5659990A (en) 1990-12-18
EP0472595A4 (en) 1992-07-08
EP0472595A1 (fr) 1992-03-04

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