Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 x 10(6) copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log(10) copies/mL. After 28 days, the median HBV DNA log(10) change from baseline was -2.5, -2.7, -3.0, and -2.6 log(10). Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log(10) in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.
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PMID:A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. 1523 97

L-nucleoside analogs are a new class of antiviral and anticancer agents, several of which are currently used in the clinic. The phosphorylation of these agents to the triphosphate form is thought to be important for exertion of their pharmacological activities. 1-(2'-deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU; Clevudine) is a thymidine analog that is currently under phase III clinical trials as an anti-human hepatitis B virus agent. We examined the behavior of its monophosphate metabolite with human recombinant thymidylate kinase (TMPK) and showed that L-FMAU monophosphate (L-FMAUMP) is a poorer substrate than its D-configuration anomer (D-FMAUMP). The phosphorylation efficiency of l-FMAUMP is similar to that of the monophosphate of 2',3'-didehydro-2',3'-dideoxythymidine (d4T), an anti-human immunodeficiency virus analog, both of which are approximately 1% TMP. To clarify the role of human TMPK in the phosphorylation of L-FMAUMP to the diphosphate metabolite in cells, a Tet-On inducible human TMPK cell line system was established. In this system, the expression of TMPK is closely regulated in response to various concentrations of doxycycline. When the cells were treated with L-FMAU or d4T, the amounts of the diphosphate and triphosphate metabolites of these analogs were increased, in accordance with an increase in human TMPK activity in cells. In conclusion, this is the first demonstration of the behavior of TMPK toward L-FMAUMP. This study indicates that human TMPK can phosphorylate L-FMAUMP and play a critical role in L-FMAU metabolism in cells.
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PMID:Behavior of thymidylate kinase toward monophosphate metabolites and its role in the metabolism of 1-(2'-deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (Clevudine) and 2',3'-didehydro-2',3'-dideoxythymidine in cells. 1585 30