METHOD FOR INHIBITING DEVELOPMENT OF LIVER CANCER AND INCREASING SURVIVAL IN CHRONIC HEPADNAVIRUS INFECTION

Abstract: A method of inhibiting the development and growth of hepatocellular carcinoma in a individual chronically infected with Hepatitis B virus involves prolonged administration of a prophylactically effective amount of 3TC to the chronically infected individual. Additionally, the method includes prolonged administration of 3TC in combination with another antiviral agent having activity against Hepatitis B virus.

Description: METHOD FOR INHIBITING DEVELOPMENT OF LIVER CANCER AND INCREASING SURVIVAL IN CHRONIC HEPADNAVIRUS INFECTION This invention was made with government support under grant NOl-AI-35164 awarded by the National Institute of Allergy and Infectious Disease. The government has certain rights in the invention. FIELD OF INVENTION This invention relates to a novel use of a -L(-)- nucleoside analog. More particularly, the present invention relates to the method of using a β-lι ( - ) - nucleoside analog to inhibit the development and growth of hepatocellular carcinomas during Hepatitis B infection. BACKGROUND OF INVENTION Hepatitis B virus (HBV) is a partly double-stranded DNA virus belonging to the family Hepadnaviridae . In the majority of individuals infected with HBV, a self limiting acute infection occurs. However, in some individuals, the viral infection persists and can result in chronic persistent hepatitis or chronic active hepatitis. Chronic viral hepatitis can lead to progressive liver disease (e.g., liver cirrhosis); and is associated with the development of hepatocellular carcinoma (HCC) . HCC is one of the most common cancers in humans. The mechanism(s) by which HBV indirectly or directly causes HCC is not completely understood. It is estimated that more than 300,000 million people worldwide are chronically infected with HBV. Thus, HBV continues to be a major health problem throughout the world. Preventative therapy includes vaccination of those individuals at a particular high risk of HBV infection. Treatment of chronic HBV infection includes the administration of any one of a number of drugs. Interferon α-2b is one of the most widely used drugs for the treatment of chronic HBV infection. While HBV is a DNA virus, its replication involves the use of the enzyme reverse transcriptase . Thus, nucleosides and nucleoside analogs have been evaluated for antiviral activity against HBV. For example, U.S. Patent No. 5,567,688 discloses that 2'- fluoro-5-methyl-jβ-L-arabino-furanosyluracil, known as "L(-)FMAU", and derivatives thereof, have antiviral activity against HBV in cultured human hepatoma cells in vi tro . U.S. Patent No. 5,631,239 discloses that l-(2,3- Dideoxy-beta-L-ribofuranosyl) -5-fluorocytosine (known as /3-L-FddC) and derivatives thereof, have antiviral activity against HBV in cultured human hepatoma cells in vi tro . U.S. Patent No. 5,627,160 discloses that l-(2,3- didehydro-dideoxy-beta-L-ribofuranosyl) -5- fluorocytosine, and derivatives thereof, have antiviral activity against HBV in cultured human hepatoma cells in vi tro . U.S. Patent Nos . 5,486,520 and 5,532,246 disclose certain 1,3 oxathiolane nucleoside analogs as having antiviral activity against HBV in cultured duckling primary hepatocytes infected with duck hepatitis B virus in vi tro . U.S. Patent No. 5,559,100 discloses treating HBV infection with a therapeutic nucleoside comprising 2-aminopurine-9-beta-D-2 ' , 3'- dideoxy-ribofuranoside. U.S. Patent No. 5,444,063 describes certain -D-dioxolanyl nucleoside analogs as having antiviral activity against HBV in cultured cells in vi tro . One jS-L (-) -nucleoside analog which has been described, and is widely used, for its antiviral activity against the human immunodeficiency virus in combination with other antiviral agents (see, e.g., U.S. Patent No. 5,627,186) is commonly known as 3TC. Other names for 3TC include lamivudine, L(-)-SddC, and 2',3'- dideoxy-3 ' -thia-3-L-cytidine. It has been demonstrated that 3TC has antiviral activity against HBV in vi tro (Chang et al . , 1992, J. Biol . Chem . 267:13938-13942). Additionally, short term (e.g., ranging from 4 weeks to 52 weeks) in vivo studies of 3TC treatment in experimental animal models for human HBV infection (HBV- infected ducks and chimpanzees; Tyrrell et al . , 1993, Clin . Invest . 16:B77) and in HBV-infected humans (Nowak et al., 1996, Proc . Natl . Acad. Sci . USA 93:4398-402; Benhamou et al . , 1996, Ann. Intern . Med. 125:705-712; Lai et al . , 1997, Hepatology 25:241-4) have been described. However, it has been reported that, like HIV, HBV develops resistance to 3TC. In particular, one or more amino acid substitutions in the active site of the HBV DNA polymerase contributes to 3TC resistance in HBV isolated from patients following liver transplantation (Tipples et al . , 1996, Hepatology 24:714-717; Ling et al . , 1996, Hepatology 24 : 711-713 ) . These short term in vivo studies do not allow evaluation in HBV-infected individuals of the effects of 3TC in preventing HBV-associated hepatocellular carcinoma (HCC) . One β-L (-) -nucleoside analog, -L (- ) -dioxolane- cytidine or L(-)-OddC, has been suggested as a promising candidate for inhibiting the growth of hepatocellular tumors in HBV-infected individuals because of its in vi tro activity against HepG2 cells. Also, unlike cytosine arabinoside (araC) , L(-)-OddC showed effective in vivo activity against HepG2 tumors in nude mice (Bridges and Cheng, Chapter 9 in Progress in Liver Diseases, 1995, eds . J.L. Boyer and R.K. Ockner, publs. W.B. Saunders Co.) . The property which distinguishes L(-)-0ddC from other jβ-L(-)- nucleosides, and which is also the reason for the potential of L(-)-OddC as an anticancer agent, is that L(-)-0ddC is extremely cytotoxic to cells (CEM cells) in vi tro (Bridges and Cheng, 1995, supra) . Thus, because of the millions of people chronically infected with HBV, and because hepatocellular carcinoma continues to be one of the most common cancers in humans, there remains a need for methods to inhibit the development and growth of hepatocellular carcinomas in HBV-infected individuals. SUMMARY OF INVENTION A method is provided for inhibiting the development and growth of hepatocellular carcinoma in an individual infected with HBV, and particularly a human chronically infected with HBV. The method comprises prolonged administration to the HBV-infected individual of a prophylactically effective amount of 3TC, thereby impairing or inhibiting the development of hepatocellular carcinoma. In one embodiment of the method of the present invention, 3TC alone is administered to the HBV-infected individual. In another embodiment of the method according to the present invention, 3TC is administered in combination with one or more antiviral agents having antiviral activity against HBV. These and further features and advantages of the invention will be better understood from the description of the preferred embodiments when considered in relation to the figures. BRIEF DESCRIPTION OF FIGURES FIG. 1 is a graph illustrating the mean body weight values observed for the placebo group (•) and treatment group (O) . FIG. 2A is a graph illustrating the mean serum ALT (alanine aminotransferase) levels observed for the placebo group (•) and treatment group (O) . FIG. 2B is a graph illustrating the mean serum AST (aspartate aminotransferase) levels observed for the placebo group (•) and treatment group (O) . FIG. 3 is a graph illustrating the mean serum GGT (gamma-glutamyl transpeptidase) levels observed for the placebo group (•) and treatment group (O) . FIG. 4 is a graph illustrating the mean serum amylase levels observed for the placebo group (•) and treatment group (O) . FIG. 5A is a graph illustrating the mean serum viral DNA levels observed for the placebo group (•) and treatment group (O) . FIG. 5B is a graph illustrating the mean genomic equivalents observed for the placebo group (•) and treatment group (O) . FIG. 6 is a graph showing percent free from hepatocellular carcinoma in the treatment group (O) and placebo group (•) during the 136 weeks of the study period. FIG. 7 is a graph showing the survival curve for the treatment group (O) and placebo group (•) during the 136 weeks of the study period. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions The term "3TC" is used herein, for purposes of the specification and claims, to mean L(-)-SddC, 2 ',3'- dideoxy-3 ' -thia-jβ-L-cytidine, or a physiologically acceptable derivative such as 3TC prodrug (see, e.g., Balzarini et al., 1996, Biochem. Biophys . Res . Commun . 225: 363-9) . 3TC can be prepared using methods known to those skilled in the art. The term "prolonged" as related to usage or administration of 3TC, is used herein for purposes of the specification and claims to mean more than 52 weeks of 3TC treatment . The term "antiviral agents" is used herein, for purposes of the specification and claims, to mean drugs having antiviral activity against HBV. These drugs include, but are not limited to, interferon; ddC; D4T (2' ,3' -didehydro-2' , 3 ' -dideoxythymidine) ; L(-)-FTC; L(- )-FddC; L(-)-FMAU; 1- (2 , 3-didehydro-dideoxy-beta-L- ribofuranosyl) -5-fluorocytosine ; 1,3 oxathiolane nucleoside analogs; 2-aminopurine-9-beta-D-2 ' , 3 ' - dideoxy-ribofuranoside; and β-D-dioxolanyl nucleoside analogs . The term "a prophylactically effective amount of 3TC" is used herein, for purposes of the specification and claims, to mean an amount of 3TC effective to impair or inhibit the development of hepatocellular carcinoma in an HBV-infected individual, without causing serious toxic effects in the treated individual . The concentration of 3TC will depend on factors such as the drug's rates of solubility, absorption, excretion, and inactivation (stability) , and drug formulation, and mode of administration; as well as individual factors such as size, age, and weight; and other factors as known to those skilled in the art. Additionally, it is appreciated by those skilled in the art that for any particular individual to be treated with prolonged administration, dosage regimens may need to be adjusted according to the individual need and in the judgment of the health professional supervising dosage administration. 3TC may be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid form, or in solid form. With these considerations in mind, concentrations of 3TC which may be used in the method according to the present invention include 25 mg to 1000 mg daily. Oral daily dosages in humans which have shown antiviral activity against HBV include 25 mg, 100 mg, 300 mg (Lai et al . , 1997, supra; Dienstag et al . , 1995, N. Engl . J. Med. 333:1657-61), and 600 mg (Benhamou et al . , 1996, supra) . A method is provided for inhibiting the development and growth of hepatocellular carcinoma in an individual infected with HBV, and particularly a human infected with HBV. In the following embodiments used to illustrate the invention, it is important to consider the following concepts. The members of the hepadnavirus family are similar in DNA sequence, antigenic structures, morphological appearance, and replicative strategies. In particular, woodchuck hepatitis virus (WHV) and hepatitis B virus (HBV) have a closer phylogenetic relationship, as illustrated by nucleic acid homology and immunological cross-reactivity, than between HBV and the duck hepatitis virus (Rajagopalan et al., 1996, Antimicrob . Agents Chemother . 40:642-45). Additionally, the DNA polymerases of WHV and HBV showing striking similarities in conditions for optimal activity, and susceptibility to inhibition by certain nucleotide triphosphates in vitro. Thus, in addition to the duck hepatitis virus, WHV has been accepted by those skilled in the art as an experimental model for HBV. Woodchucks Marmota monax) have been used by those skilled in the art as an acceptable animal model for HBV infection in humans and for studying the efficacy of antiviral agents against HBV in vivo (Fourel et al . , 1990, Antimicrob . Agents Chemother. 34:473-75; Ikeda et al., 1994, J. Antimicrob. Chemother. 33:83-89). In addition to the similarities between HBV and WHV, and like observed in HBV-infected humans, WHV-infected woodchucks have a high incidence of hepatocellular carcinoma (Rajagopalan et al . , 1996, supra) . Further, the pharmacokinetics of 3TC in woodchucks has been determined; thus, providing a physiological basis for scaling up the therapeutic agents from the woodchuck model to humans (see, e.g., Rajagopalan et al . , 1996, supra) . The following embodiments used to illustrate the invention represent a lifetime study of the effect of 3TC during prolonged treatment of woodchucks chronically infected with WHV, as an in vivo model of chronic HBV infection in humans, including the effects, if any, of prolonged 3TC treatment on: antiviral activity and potential for viral resistance thereto; toxicity associated with drug administration; chronic liver disease; and the prevention or delay in the development of hepatocellular carcinoma. EXAMPLE 1 This example illustrates the development of chronically infected woodchucks . The woodchucks were the offspring of laboratory-raised females and males seronegative for markers of WHV infection at breeding. At 3 days of age, the individual woodchucks were inoculated subcutaneously with 100 μl of a 10 "1 dilution of the WHV7-P-1 pool of woodchuck Hepatitis virus. At three months of age woodchucks were tested and shown positive for the surface antigen of WHV (WHs) ; and at six months of age, persistence of WHs antigenemia was confirmed. As additional indicators of chronic infection, each woodchuck included in the lifetime study tested positive for serum WHV DNA and anti-WHV core antibody at six months of age. Prior to 3TC treatment, baseline serum activity levels of liver enzyme gamma- glutamyl transpeptidase (GGT) were determined to be less than 5 IU/L. According to these criteria, two groups of twenty 7 to 8 month old chronic WHV carrier woodchucks were selected and assigned to a treatment group or a control group. Each group was stratified on the basis of gender and body weight. EXAMPLE 2 This example illustrates the protocols for 3TC administration used to treat chronically infected woodchucks . Initially, 3TC was synthesized by Dr. Raymond F. Schinazi. Subsequently, a commercially available form of 3TC (available from Glaxo Wellcome) was used. 3TC was administered orally in an aqueous solution to each woodchuck in the treatment group. The woodchucks in the control group received water as a placebo. The water or 3TC was added to 2 to 3 ml of a semipurified liquid dietary food to ensure consumption; and was administered via an oral dose syringe. The amount of 3TC or placebo administered was adjusted to reflect changes in body weight each time the woodchucks were weighed during the study. The treatment group received 3TC at a dosage of 5 mg/kg body weight/day orally from the start of the study to week 42 of treatment. After week 42, the treatment group received a dosage of 15 mg/kg/day. EXAMPLE 3 This example illustrates analyses of the effects of 3TC treatment or placebo treatment of chronically infected woodchucks on their body weight and on various parameters measured in sequential blood samples. As shown in FIG. 1, during the first 136 weeks of the study, there were no differences in mean body weight observed between the placebo group (•) and treatment group (O) . Each group demonstrated a gradual increase in body weight until week 40, followed by a slight decrease coincident with normal circannual rhythm. The mean serum ALT (FIG. 2A) and AST (FIG. 2B) activities increased slightly in both the treatment group (O) and the placebo group (•) during the first 64 weeks of the study, but rose more dramatically between week 64 and week 88. Mean AST and ALT activities then decreased at week 96 and week 104 in the control group. In the 3TC recipient group a continued increase was seen in the activity of both enzymes at the week 96. Then the mean serum activities of both ALT and AST fell in the 3TC group at week 104. Mean serum AST and ALT activities subsequently increased in both groups through week 136. Elevations in the levels of these enzymes are usually associated with hepatocellular damage. Thus, the increase seen in both groups are likely due to moderate portal and parenchymal hepatitis. The serum GGT activity of all but 4 animals of the treatment group remained constant; thus, the steady rise observed for the mean serum GGT activity treatment group during the first 72 weeks of the study (O; FIG. 3) , represents the development of HCC (identified by ultrasound) in 4 individuals. The rise in mean serum GGT activity of the placebo group (•; FIG. 3) during the first 50 weeks represents several individuals developing HCC. The reduction after week 50 reflects the loss of a total of 6 individuals with advanced HCC in the placebo group whose elevated GGT activities no longer contribute to the calculation of the mean value. The mean serum GGT activity in the control group subsequently increased between week 72 and week 112 in association with the development of HCC in a further 13 woodchucks. Mean serum GGT activity decreased in the control group at week 120 due to the death of 2 woodchucks with HCC between week 112 and week 120 with substantially elevated GGT activity levels. The mean GGT activity in the control group rose again at weeks 128 and 136 in association with enlarging HCC in all 7 surviving control animals. The mean serum GGT activity in the 3TC group rose gradually during the first 72 weeks of the study, before increasing more rapidly between week 72 and 96 in association with the development of HCC in 10 individuals. The reduction in mean serum GGT in the 3TC group between week 96 and week 104 was due to the loss of four 3TC treated woodchucks with advanced HCC whose elevated GGT activities no longer contributed to the mean value . A steady increase in mean serum GGT activity in the 3TC group was observed between week 104 and week 136 in association with the development of HCC in 5 woodchucks and the continued growth of tumors whose detection predated the week 104 time point in 3 other 3TC treated woodchucks . Mean serum sorbitol dehydrogenase (SDH) and alkaline phosphatase (AP) activity increased in both groups at 80 and 88 weeks. Subsequent reduction in the mean activity in both groups at weeks 96 and 104 were observed in association with either the death of individual animals with HCC or with the return of serum enzyme activity levels to a lower point. There was no significant increase in the mean serum bilirubin in either the 3TC treated or the control groups during the 136 weeks of the study. However, individual serum bilirubin values of greater than 0.8 mg/dl were recorded in association with advanced HCC in two placebo and two 3TC recipients. Treatment with 3TC had no apparent effect on total serum protein, serum albumin, blood urea nitrogen, serum creatinine, serum sodium, serum potassium, serum chloride, serum inorganic phosphorous, serum glucose, or serum cholesterol. As shown in FIG. 4, the mean serum amylase was only slightly elevated during weeks 40 to 60 in the placebo group (•) as compared to the treatment group (O) . The slight increase represents remarkably elevated levels in four individuals in the placebo group associated with the development of HCC. At weeks between 90 and 100, elevated amylase levels were recorded for 8 of the 15 control animals that have died with advanced HCC, and 4 of the 8 3TC treated animals that have died of advanced HCC. There were no changes between the treatment group and the placebo group in mean hematocrit, mean segmented neutrophil counts or mean platelet count. EXAMPLE 4 This example illustrates analyses of the antiviral activity of 3TC during prolonged treatment of chronically infected woodchucks. As shown in Figure 5A, 3TC resulted in a reduction in mean serum WHV DNA (Figure 5A) first noticed at 2 weeks after initiation of treatment. Figure 5B depicts the same data converted to genomic equivalents/ml of serum based upon a calculated weight for one WHV genome of 3.09 x 10 18 g. A continued decrease in serum WHV DNA was observed in the 3TC treatment group until week 12 by which time the mean serum WHV DNA level had fallen from a pretreatment level of 142 ng/ml to 7.22 ng/ml, representing an approximately 1.5 log reduction compared to pretreatment and control levels . No comparable reduction in serum WHV DNA was seen during this time period in the placebo group. However, between week 20 and week 40, the mean serum WHV DNA in the 3TC-treated group rose from to a mean value of 34.5 ng/ml. To investigate this diminished antiviral effect and observed resurgence of WHV DNA in serum, WHV DNA was isolated from serum and analyzed by nucleic acid amplification for the presence of specific mutations known to occur in the Hepatitis viral DNA polymerase gene (e.g. in the portion encoding the polymerase YMDD motif) . These techniques detected only wild-type sequence with no evidence of mutations known to confer resistance to 3TC. Additionally, pharmacokinetic studies were performed on 3TC-treated individuals to rule out diminished intestinal drug uptake or increased hepatic metabolism as possible reasons for the reduction in antiviral effect. However, no significant pharmacokinetic differences were observed between individuals receiving 3TC and untreated control animals . Subsequent to the observation of viral resurgence, at week 42 the dose of 3TC was increased to 15 mg/kg/day in the treatment group. Immediately, the mean WHV DNA levels began to diminish, and reached a mean value of 0.84 ng/ml at week 56. At week 60 and 88, mean serum WHV DNA level varied between 2.2 and 24.1 ng/ml in the 3TC-treated group and between 92 ng/ml and 133 ng/ml in the control group. At week 136, mean serum WHV DNA was 37.3 ng/ml in 3TC-treated group and 88 ng/ml in the placebo treated group. To investigate the diminished antiviral effect and observed resurgence of WHV DNA in the serum of 3TC-treated individuals, WHV DNA was isolated from serum and analyzed by nucleic acid amplification for the presence of specific mutations known to occur in the hepatitis viral DNA polymerase gene. These techniques failed to identify at 46-54 weeks, any mutations known to confer in vivo resistance to 3TC. However, at 80 weeks, four samples from the 3TC treated group contained a mutation at the amino acid position 565 of the WHV DNA polymerase. There were no mutations at this position in any of the placebo group. EXAMPLE 5 This example illustrates an evaluation as to whether prolonged treatment of chronically infected woodchucks with 3TC affects the development of hepatocellular carcinoma in the treated individuals. Transabdominal ultrasound was performed at bimonthly intervals, beginning at week 24, in order to identify and monitor the development of hepatocellular carcinoma in the placebo group and treatment group during the study period. After 72 weeks of treatment, it was observed that 3TC had a significant effect on the course of hepatic disease and the development of hepatocellular carcinoma. A total of 11 animals in the placebo group had developed ultrasonographic lesions consistent with a diagnosis of hepatocellular carcinoma by week 72. Six of the 11 ultrasonographically identified tumors were confirmed at postmortem when the affected woodchucks died or had been euthanized due to fulminant liver failure. Typically, the hepatocellular carcinomas observed in the placebo group were large and multi- lobulated. In contrast, in the treatment group only 4 ultrasonographic lesions consistent with a diagnosis of hepatocellular carcinoma were observed by week 72. Postmortem examination of one of these individuals showed that the hepatoma was significantly less developed when compared to the development of the hepatocellular carcinomas observed in the placebo group. A total of 18 individuals in the control group and 15 in the 3TC treated group developed ultrasonographic mass lesions consistent with a diagnosis of HCC by week 136. At this time point, there were still 2 surviving 3TC treated animals that remained free from HCC based upon ultrasound examination. All surviving placebo animals had ultrasonographically detectable hepatic tumors by week 112. Fourteen of the 18 animals with ultrasonographically identified tumors in the control group died or were euthanized by week 136 and subsequently the diagnosis of HCC was confirmed at post mortem. This compared with the death and confirmation of 8 of the 15 3TC treated animals with hepatic tumors identified by ultrasound. A Kaplan-Meier survival curve plotting percent of animals free of HCC detected by ultrasound versus time for the treatment group (O) and placebo group (•) is shown in FIG. 6. There is a statistically significant difference (p<0.05) between the treatment group and the placebo group with respect to the time to development of HCC as detected by transabdominal ultrasound. That prolonged treatment with 3TC significantly inhibits the development and growth of HCC is an unexpected result for several reasons. First, 3TC lacks the potent cytotoxicity that is characteristic of potential anticancer agents such as L(-)-OddC. For example, and as described in Example 3 herein, the mean values for the assessed hematological parameters appeared normal, e.g., evidence of the lack of toxicity of 3TC. Secondly, and as described in Example 4 herein, viral resurgence occurs during prolonged treatment with 3TC to levels that reflect chronic persistence of the virus despite continued 3TC treatment . Chronic persistent hepatitis is associated with the development of HCC. Yet despite this chronic persistence of the virus during 3TC treatment, there is a statistically significant reduction in the development and growth of HCC in individuals receiving prolonged treatment with 3TC. It is unexpected that 3TC would inhibit the development of HCC in these individuals in view of the persisting viral titers. There were no deaths associated with HCC in the group treated with 3TC during the first 96 weeks of the study. The difference in deaths due to HCC between the 3TC treated individuals and the placebo treated individuals was statistically significant (p<0.01). In other words, there was a highly significant increase in survival of woodchucks chronically infected with WHV due to prolonged 3TC treatment. Illustrated in FIG. 7 are Kaplan-Meier survival curves plotted for the 3TC treated individuals (O) and the placebo treated individuals (•) . The foregoing description of the specific embodiments of the present invention have been described in detail for purposes of illustration. In view of the descriptions and illustrations, others skilled in the art can, by applying, current knowledge, readily modify and/or adapt the present invention for various applications without departing from the basic concept, and therefore such modifications and/or adaptations are intended to be within the meaning and scope of the appended claims .

Claims: What is claimed is: 1. A method of inhibiting the development and growth of hepatocellular carcinoma in a human chronically infected with Hepatitis B virus, said method comprises prolonged administration of a prophylactically effective amount of 3TC to the chronically infected human. 2. The method according to claim 1, wherein the 3TC is administered orally. 3. The method according to claim 1, wherein the amount of 3TC ranges from 25 mg to 1000 mg administered daily. 4. The method according to claim 1, further comprising administering to the individual at least one additional antiviral agent in combination with the 3TC. 5. The method according to claim 2, wherein the amount of 3TC ranges from 25 mg to 1000 mg administered daily. 6. The method according to claim 2, further comprising administering to the individual at least one additional antiviral agent in combination with the 3TC.

Inventors: PEEK SIMON F, TENNANT BUD C, PEEK, SIMON, F., TENNANT, BUD, C.
Applicants: CORNELL RES FOUNDATION INC, PEEK SIMON F, TENNANT BUD C, CORNELL RESEARCH FOUNDATION, INC., PEEK, SIMON, F., TENNANT, BUD, C.
Application year: 1998
Main classification: A61K31
IPC codes: A61K31