CA2054771A1 - Method of treatment of hepatitis - Google Patents

Abstract

Hepatitis B is treated by administering an effective amount of 2',3'-dideoxyguanosine, 2',3'-dideoxyadenosine, or 2',3'-dideoxyinosine.

Description

WO90/14091 ' 2`0 ~ 4 7 7 1 METHOD OF TREATMENT OF HEPATITIS

FIELD OF THE INVENTION
The present invention relates to a method ~or . treating hepatitis B.
BACKGROUND OF THE INVENTION
Chronic infection with the hepatitis B virus (HBV) affects approximately 5% o the world's population.
Chronic carriers o~ hepatitis B are at an increased risk of morbidity and mortality due to chronic liver disease, and a proportion of the~e will ultimately devQlop cirrhosis and/or hepatocellular carcinoma. At present, there is no therapy of proven benefit for chronic hepatitis B.
Although Y-interferon has shown great promise in a subset of patients treated for prolonged periods of time, the response rates overall have, unfortunately, been disap--pointingly low. ;~
The human hepatitis B virus 1s a m~mber Oe a family o~ virus~s known as h~padnaviru~s. Oth~r viru~
in this ~amily are the woodchu~k hapa~iki~ viru~, tho Z0 ground squlrrel hepatlkis vlru~, and tha duck hopatitls virus. These animal viruses have been invaluable models for characterization of hepadnaviruses and delineation of their unusual replicative cycle. ~hese viruses replicate as~mmetrically through an RNA temp~ate which requires reverse trianscriptase 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, although 2', 3'-dideoxyadenosine (DDA) and ~', 3'-dideaxyguanosine (~DG), and 2', 3'-dideoxyino~ine ~DDI~ are also potent in~ibitors of HIV.

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WO90/14091 ~ 5 4 ~ ~ ~ PCT/US9OtO2686

- 2 -It is an obj~ct of the present invention to overcome the above-mentioned deficiencies in the prior art.
It is another object of the present invention to provide methods for treating hepatitis B.
5It is further object of the present invention to provide compositions for treating hepatitis B.
According to the present invention, hepatitis B
can be treated by administering 2', 3'-dideoxyinosine ~DDI), 2', 3'-dideoxyguanosine (DDG), or 2', 3'-dldeoxyadenosine (DDA) to a pa~ient infected with hepatitis B. The 2', 3'-dideoxyinosine, 2', 3'-dideoxyguanosine, or 2', 3'-dideoxyadenosine, following anabolic phosphorylation, inhibits the reverse transcriptase of the hepatitis B virus.
15While the exact mechanisms o~ the an~iviral activity o~ the compositions ~ccording to th~ pr~nt invention are unknown, it is beli~v~d ~hat th~ mcohan:l~m o~
action ef D~A, ~, or DDX i~ inhibltlon Oe vlr~l pol~merases, in partlcular, rQverCla tran~arlpt~ a~A
DDG and DDI are nuc~eoside an~locJues, 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. Il DDX, 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. 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.
30DDG, DDA and DDI are particularly attractive as antiviral agents because they are absorbed orally and has comparatively minimal side effects under the conditions used.
DETAILED DESCRIPTION OF THE_INVENTION
352', 3'-dideoxyino~ine, 2', 3'-dideox~guanosin~, or 2', 3'-dideoxyaden~ine can be used ~or trqating hepatitis B in patients so infected. The nucleosidqs are well absorbed orally, and are generally well tolqrated.

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Woso/14091 PCT~US90/02686 205~771 ,, - 3 - ; , , ~ vitro ~DA triphosphate, DDG triphosphate, or DDI triphosphate have little effect on DNA polymerase activity of eith~r duck hepatitis B virus or human hepati-tis B virus. Previous researchPrs have used the in vitro assay to asses antiviral activity in hepatitis B cf.
Nordenfelt, et al., Acta Path. Microbiol. Scand. Sect. B
87:75-76, 1979; and Hess, et al., Antimic. Aqents ~emo.
1~:44-50, 1981. However, it has now been discovered that this ass~ssment may b~ unreliable as a means o~ screening antiviral agents. The DNA polym~rase activity measured in serum from humans and ducks in~ected with hepadnaviruses may represent only one o~ the viral enzymes necessary ~or replication, and this activity may be relatively resistant to inhibition.
9~5L~Lh~
Serum DN~ polymera~c ac~ivity was dot~rmincd by measuring 3H~ th~midin~ inaorporation into pur~ d ~ane partlcle3 by th~ m~thod o~ ~aplan, et al., 995~1005, 1973. The ~n ~ Q a~a~ts o~ ~DI, DD~ and ~D~
as a nucleotide analogue~ on D~IBV and HBV were assessed using the DNA pol~merase reaction. A range o~ concentra-tions o~ DDI, DD~ or DDG triphosphate were incubated with puri~ied Dane partic}es ~or one hour ~t 37'C, and the DN~
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 EcoR1 and agarose gel electrophoresis. The DHBV DNA
was radiolabelled with 32p using the random primer method of Feinberg, et al., ibid., to a speci~ic activity o~ 3 x 107 to 1 x 108 cpm/~g.
DHBV DNA was detected in serum and liver tissue by slot blot analysis. For analysis o~ DHBV DNA in serum, 10~1 o~ serum was denatured with 1 ~1 of 1 M NaOH ~or ~ive mlnutes. The mixture wa5 ~hen neutxalized by addiny ~0 ~1 o~ 1 M ammonlum aceta~e. For analysis Oe DH~V DNA in llver biopsy specimens, approximately 100 mg of minced liver was homogenized in 10 ml of iCQ cold 50 mm Tri5, pH 8.5, 10 mM

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WO9~14091 PCT/US90/02686 :5 ~ 4 ~
EDTA and 1% ~Q. The crude liver homogenate was digested with proteinase K t200 ~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. DN~ was precipitated with absolute ethanol and diluted to a con-centration of approximately 2 mg of DNA/ml in TE buffer.
One hundred microliters of the DNA sample pre-pared ~rom serum or liver was spotted onto a nitrocellulose filter premoistened with 1 M ammonium acetate using a slot blot apparatus and vacuum manifold. The membrane was air dried and baked in a vacuum oven at 80-C ~or two hours and hybridized at 40C with the DHBV DNA probe. The hybridized membranes were exposed to X-ray film for 5, 24, and 72 hours, and the resulting autoradiograms were scanned using Zenith Scanning Densitometer. The amount o~ DHBV DNA was ~uanti~ied by comparing the autoradlographlc ~:lgnals ~ox each sample with thosc o~ known amounts oP clolled DH~ DN~
dotted on the ~ame ~ilker dllutad in normal ~orum or normal duck liver DN~.
Liver tissue D~IB~ DN~ was also analyzed by Southern hybridization. Ten micrograms of total cellular DNA was sub~ected to horizontal slab gel electrophoresis in 1~ agarose and transferred to nitrocellulose paper by the method of Southern, J. Mol. Biol. 98:503-517, 1975; as modified by Wahl, et al., Proc. Natl. Acad. Sci. USA 76:
3683-3687, 1979. Hybridization and autoradiography were carried out as described above. ~;
STATISTICAL ANALYSES `
Data were compared using Student's test, the Shapiro-Wilk test for normal distribution, and Spearman's rank correlation coefficient. Mean and standard deviations of serum DNA polymerase levels were calculated a~ter logarithmic trans~ormation of the data. Changes in serum and liver levels o~ these viral makers were expressed as5 percent inhibition o~ the pretreatment level~
I~_Y~Q_~FF~C~Q ~_9~_ON DUCKS
CHRONICALLY ~NFE~e~ 5~ L~ y~ 5~ B VIRUS

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WO90/14091 PCTtUSgO/02686 In contrast to the experience ~a vitro, DDA
exhibited potent antiviral activity when given to ducks chronically infected with duck hepatitis B virus, for six days in doses similar to those used in human antiviral trials, c~. Yarchoan, et al., Lancet l:76_81, 1988. The degrees of inhibition of hoth DNA polymerase activity and duck hepatitis B virus DNA were similar (67% and 69~, respectively) and were comparable to the degrees o~ inhibi-tion o~ these markers reported in studies of other anti-viral agents used in treatment o~ chronic hepatitis B. The antiviral ef~ect was only partial, however, in that no duck became completely negative for duck hepatitis B virus DNA
or DNA polymerase activity, and levels o~ these viral markers ~egan to rise soon aPter the DD~ therapy was stopped. These ~lndings are slmilar to those rcported with other antiviral agcnt~ used in ch~onic hepatlt~ B.
promising ~lnding ~ollowlny DD~ admini~tr~tlon how~v~r, wa~
that some lnhibltlon oP DN~ p~lymara~ ~ctlv~ky and d~tok hepatiti~ ~ viru~ D~ wa~ ~tlll ob~rvad ~or a~ long a~
twelve days a~er therapy wa~ s~opped. This observation is contrary to findings with adenine arabinoside and acyc}o-vir, wherein ~ollowing w~thdrawal of these agents, serum levels o~ duck hepatitis B virus o~ten rebound to 3~
pretreatment levels (Hirota, et al., HePatoloqY 7:24-28, 1987).
IN VIVO EFFECTS OF DDI AND DDG ON DUCXS
CHRONICALLY INFECTED WITH DUCK HEPATITIS B VIRUS
The effect of 2', 3'-dideoxyinosine and 2', 3'-dideoxyguanosine was assessed in eighteen Pekin ducks chronically infected with the duck hepatitis B virus lDHBV). Six ducks were given DDI and six ducks were given DDG at the rate of 0.8 mg/kg per injection by bolus every six hours ~or ~ive days. The antiviral response was assessed by monitoring serum markers o~ viral replication, including DHBV DNA polymera~e. ~he serum levela o~ DUI 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 a~ter bolus injections.
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WO 90/1409l PCr/US90/02686 -- 6 -- t Antivir~l therapy was tolerated well, and all ducks su~rapy and liver biopsy. No duck showed obvious ldence of drug toxicity.
TABLE
5DHBV DNA Polvmerase tcPm/o.2ml) ~ _ _ _ Group tno) Day 1 Pay 5 DaY 18 Control (6) 51Q7 ~ 4009 5182 + 4501 3571 ~ 3070 DDI 2417 e~ 1609 1001 ~ 850 630 ~ 548 DDG 3571 ~ 3Q70 700 + 229 1572 + 412 The TABLE shows that both DDG and DDI caused highly signi~icant inhibition oP DNA polvmerase activity, 83% and 79%, respectively, by day 3 o~ treatment in all treated dUck~ as compared to the control~ ~p~0.01). E~oth 15drug~ caused a E~milar degr~ o~ inhlblt:Lon. ~low~vcr, in ~I DDG trea~ed duck~;, a r~bound in DN7~ polymQra~n act.~vlty was ob~erved in th~ th d~r O.e~ oP traatm~nt~ b~untl .ln DNA polymQrase act:Lvlky ~caurr~à ln c)nly on~ o~ giX e~L)I
treated dUcks, arld inhibition con~inued ~or Up to thirteen 20days aEter stopping treatment and Wa.s significant compared to the control ~pC0.01) groups.
Treatment o~ two ducks With Ara-l~lP yielded results similar to those reported by others, cf. Hirota, et al., oP. cit. DNA polymerase and DHBV DNA levels decreased 25by 7196 and 100% during therapy, but levels of these viral markers rapidly rose to greater than pretreatment values within four days of stopping the intramuscular injections.
The nucleosides for use in the present invention have the ~ollowing formulas:

H Hl~ CH ~ ~Y~c~l;~

~i Hn~,~D~¦ HOCH~O~l ~C~ ,C ~ H

30dideoxyadenosine dideoxyinosine dideoxyguanosine . .. . . . . .

WO90/14091 PCTtUS9OtO2~86 _ 7 _ OS ~ 77 . . , .,~ - , 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 C14 alkoxy); sul~onate esters such as alkyl- or aralkyl-sulfonyl (e.g., methanesul~onyl); and mono-, di-, and triphosphate esters.
The compounds as described above also include pharmaceutically acceptable salts thereof. Unless other-wise speci~ied, 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 pre~erably comprises a ph~nyl group, including a substl-tuted phenyl group.
Examples o~ pharm~cQuticAlly accaptahl~ ~a:Lts and pharmaceutically acceptablQ dcrivativ~ o~ ~h~ compound~
which can bc u~e in treatinc~ h~patltls B ac~ord~ng to thc pre~ent invent~on include base salts such as those derived ~rom a base such as alkali metal ~sodium~ lithium, potas-sium), alkaline earth metal ~magnesium) salts, ammonium and NX4 where X is Cl4 alkyl. Physiologically acceptable salts containing a hydrogen atom or any amino group include salts o~ 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. 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~, NHY4t, and HX4~ (wherein X is C1~4 alkyl and X is halogen).
SpeciPic examples o~ pharmacoutically accQptable derivatives o~ the aompounds that may be used in accordance with the present invention include the monosodium salt and the following 5' esters: monophosphate, disodium monopho-., ' '' ' ` `' `.`. .. .
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WO90/14~91 P~T/US90/02686 i '- 20~771 - 8 - ff~
- sphate, diphosphate, triphosphate, acetate, 3-methyl butyrate, octanoate, palmitate, 3-chloro benzoate, 4-methyl benzoate, hydrogen succinate, pivalate, and methylate.
Also included within the scope of this invention 5 are the pharmaceutically acceptable salts, esters, salts of such esters, nitrile oxides, or any other covalent~y linked or non-linked compound which, upon administration to the recipient, is capable of providing, either directly or indirectly, a nucleoside analogue as described above, or an 10 antivirally active metabolite or residue thereo~. All of these compounds are active and relatively nontoxic at con-centrations of sufficient potency for effective inhibition of viral infectivity and replication.
It is possible for the nucleoside of the present 15 invention to be administered alone in solution. However, the active ingredient may be used or admini~t~r~d in a pharmaaeutical ~ormulation. These ~ormulatlons comprisa the nucleoside or darivativ~ thereor tog~ther wlth ono or mor~ pharmaceutically acc~ptablc c~rr~r~ and/or oth~r 20 therapeutic ~gc~ts. As lncludad wlthin the ~aopa o~ th~
present invention, "acceptable" ls de~ined as being com-patible with other ingredients of the formulation and not injurious to the patient or hos~ cell.
~he administration of DDG, DDA, or DDI to treat 25 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 30 four hours is considered to be a virustatic range in humans. In ordPr 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 requixed 35 in individual patients to ameliorate or inhibit toxic side e~ects.
The pharmaaeu~ical ~armulatlons according to the present invention may conveniently be administered in unit 9 20~477~ 1 dosage form and may be prepared by any metAods known in the pharmaceutical art. Determination of the e~fective 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 ~acilitate processing of the DDA or DDI i*to prepara-tions which can be used pharmaceutically. Pre~erably the preparations, particularly thoee 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 ~uppositories, as well as suitable ~olutions ~or admin-istration by injection or orally, contain ~rom about O.l to 99 percent, and pre~erably ~rom abouk 25-~5 p~raent, by weight, o~ ~DC, togQther with the exclpi~nt.
~ he pharm~aaut:l~a~ preparatLon~ o~ th~ pra~nt invention are manu~actur~d ln fl m~nner which l~ its0l~
known, ~or example, by means o~ conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processe~. Thus, pharmaceutical prepara~ions ~or 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 phasphates, such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste using, ~or example, maize starch, wheat starch, rice starch, potato starch, and the like; gelatin, gum tragacanth, methyl cellulose, hydroxypropylmeth~lcellulo~, sodium aarboxymethylcel-lulose, and/or pol~vinyl pyrrolidone. ~f desired, disin-tegrating agents may be added such as the above-mentione~
starches and carboxymethyl starch, cross-linked polyvinyl .. .. ~ ~ .: . . . ..

W090/14091 PCT~US90~02686 i ., ', ' - 10 -pyrrolidone, agar, alginic acid or a salt thereof such as s ~ ~ nate. 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 yastric juices~ For this purpose, concentra-ted sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethy-lene glycol, titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate or hydroxypropylmethylcellulose phthalate are u~ed. Dyestu~s or pigment~ may be added to the tabl~ts or dragee coatings, ~or example, ~or id~nti~ia~t~on or in order to charaateriz~ di~-~ercnt comblnatlon~ o~ nctivo compound do~e~.
Other pha~na~euti~al preparatlons whi~h c:arl be used orally include pu~h-~it capsules made o~ gelatin, as well as so~t, ~ealed capsules made o~ gelatin and a plas-- ticizer such as glycerol or sorbitol~ The push-~it cap-sules can contain the active compounds in the ~orm of granules which may be mixed with fillers such as lactose, Z5 binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
Possible pharmaceutical preparations which can be used rectally include, for example, suppositories!, which consist of combinations o~ the active ingredient with a suppository base. Suitable suppository bases include natural or synthetic triglycerides, para~ln hydroca~bons, polyethylene glycols or higher alkanols. In addition, it is also possible to use gelatin rectal capsules which consist o~ a combination o~ the active compounds wlth a W~90/1qO91 PCT/US90/02686 ~ 205~71 base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, and paraf~in hydrocar-bons.
Suitable formul~tions for parenteral administra-tion include aqueous solutions of the active compounds asappropriate oil injection suspensions may be administered.
Suitable lypophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, ~or example, ethyl oleate or triglycerides.
A~ueous injection suspen~ions may contain substances which increase the viscosity o~ the suspension such as sodium carboxymethyl cellulose, sorbitol, and/or dextran. Option-ally, the suspension may also contain stabilizers.
In the present invention, the hepatitis B may be treated by direatly delivering the triphosphate dcrivative to the patient. It i8 well known that "un~hield~d" tri-pho~phates cannot be used a~ drugs bccause tripho~phat~
compound~ do not penctrat~ coll mcmbran~ 'hQre~oro, the triphosphate derivatlve~ o~ thi~ in~ention ma~ b~ dolivurod by means o~ liposomes, ~mall particles ~about 2S ~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. Such use of liposomes for drug delivery is well known in the art, and is based upon the ability of a phospholipid to form bilayers spontaneously in aqueous environments.
one method of forming the liposomes is by agitat-ing phospholipids in aqueous suspensions at high frequen~
cies. This results in the formation of closed vesicles characteristic of liposomes. once inside the cells, 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 ~or delivery o~ these drugs~
Formulations suitahle for ~aginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addi-w09~/14091 PCT/US90/02686 205~ 77~ 12 - ~
tion to the active ingredient, such carriers as are known in the art ~o 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 pxior to use.
Extemporaneous injection solutions and suspensions may be prepared ~rom st~rile powders, granules, and tablets o~ the kind previously desaribed.
In treating hepatitis B according to the present invention, the medication is generally administered two to six times a day. In order to improve oral bioavailability, it is often preferable to add a common buffer such as sodium acetate to a solution aontaining a nucleoside according to the present invention.
The ~oregoing description o~ kh~ ~p~ci~ia ~mbodi~
ments will so ~ully reveal th~ gencral natur~ Oe kh~
invention that other~ can, by applyincJ c~lrr~n-t know.lodge, readily modi~y an~/or adapt ~or various applications such æpeci~ic embodim~nts without departing from the generic concept, and there~ore such adaptations and modi~ications are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation.
.

Claims (30)

PCT/US 90/02???

WHAT IS CLAIMED IS:

1. A method for treating hepatitis B comprising administering to a patient infected with hepatitis B an effective amount of a nucleoside selected from the group consisting of 2',3'-dideoxyinosine and 2',3'-dideoxyadenosine, and 2',3'-dideoxyguanosine.

2. The method according to claim 1 wherein the nucleoside is in the form of a triphosphate salt.

3. The method according to claim 1 wherein the nucleoside is in a pharmaceutically acceptable carrier.

4. The method according to claim 3 wherein the carrier is normal saline.

5. The method according to claim 3 wherein the carrier is a liposome.

6. The method according to claim 1 wherein the nucleoside is administered in a dosage range of from about 0.03 to about 0.5 mg/kg administered from two to twelve times daily.

7. The method according to claim 1 wherein the nucleoside is administered orally.

8. The method according to claim 1 wherein the nucleoside is administered intravenously.

9. The method according to claim 1 wherein the nucleoside is administered intramuscularly.

10. The method according to claim 1 wherein the nucleoside is administered rectally.

11. The method according to claim 1 wherein the nucleoside is in the form of a lyophilized powder and is administered intranasally.

12. The method according to claim 1 wherein the nucleoside is 2',3'-dideoxyadenosine.

13. The method according to claim 1 wherein the nucleoside is 2',3'-dideoxyinosine.

14. The method according to claim 1 wherein the nucleoside is 2',3'-dideoxyguanosine.

15. The method according to claim 1 wherein the nucleoside is administered in a dosage range of from about 0.06 to about 2.5 mg/kg per day.

16. The use of a nucleoside selected from the group consisting of 2',3'-dideoxyinosine and 2',3'-dideoxyadenosine, and 2',3'-dideoxyguanosine for the treatment of hepatitis B infection.

17. The use according to claim 16 wherein the nucleoside is in the form of a triphosphate salt.

18. The use according to claim 16 wherein the nucleoside is in a pharmaceutically acceptable carrier.

19. The use according to claim 18 wherein the carrier is normal saline.

20. The use according to claim 18 wherein the carrier is a liposome.

21. The use according to claim 16 wherein the nucleoside is administered in a dosage range of from about 0.03 to about 0.5 mg/kg administered from two to twelve times daily.

22. The use according to claim 16 wherein the nucleoside is administered orally.

23. The use according to claim 16 wherein the nucleoside is administered intravenously.

24, The use according to claim 16 wherein the nucleoside is administered intramuscularly.

25. The use according to claim 16 wherein the nucleoside is administered rectally.

26. The use according to claim 16 wherein the nucleoside is in the form of a lyophilized powder and is administered intranasally.

27. The use according to claim 16 wherein the nucleoside is 2',3'-dideoxyadenosine.

28. The use according to claim 16 wherein the nucleoside is 2',3'-dideoxyinosine.

29. The use according to claim 16 wherein the nucleoside is 2',3'-dideoxyguanosine.

30. The use according to claim 16 wherein the nucleoside is administered in a dosage range of from about 0.06 to about 2.5 mg/kg per day.