A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B

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 × 106 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 log10 copies/mL. After 28 days, the median HBV DNA log10 change from baseline was −2.5, −2.7, −3.0, and −2.6 log10. Six months after dosing, median changes from baseline were −1.2, −1.4, −2.7 and −1.7 log10 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. (HEPATOLOGY 2004;40:140–148.

Role of Gα 12-and Gα 13-protein subunit linkage of D \u3csub\u3e3\u3c/sub\u3e dopamine receptors in the natriuretic effect of D \u3csub\u3e3\u3c/sub\u3e dopamine receptor in kidney

The D 3 dopamine receptor is the major D 2-like receptor that regulates sodium transport in the renal proximal tubule (RPT) and helps maintain blood pressure in the normal range. In Wistar-Kyoto (WKY) rats chronically fed high-salt diet, the intrarenal arterial infusion of a D 3 receptor agonist, PD128907, increased absolute and fractional sodium excretion. We have reported that Gα 12 and Gα 13, which participate in the signal transduction of the D 5 receptor, are expressed in RPTs. As the D 3 receptor is also expressed in RPTs, we hypothesized that it may also interact with Gα 12/Gα 13 in RPTs from WKY rats. There were co-localization and co-immunoprecipitation of D 3 receptor and Gα 12/Gα 13 in renal brush border membranes (BBMs) and RPT cells. The intrarenal infusion of PD128907 (1 μg kg -1 min -1) that increased sodium excretion also increased the co-immunoprecipitations of D 3/Gα 12 and D 3/Gα 13 in renal BBMs; their co-immunoprecipitation was confirmed in RPT cells. As Gα 12 and Gα 13 increase sodium pump and transporter activity (for example, Na +-K +-ATPase, NHE3), an increased association of D 3 receptors with Gα 12/Gα 13 receptors after D 3 receptor activation may be a mechanism to prevent Gα 12/Gα 13-mediated stimulation of sodium transport (and thus enhance natriuresis). We conclude that a D 3 receptor interaction with Gα 12/Gα 13 that increases sodium excretion may have a role in the regulation of blood pressure. © 2011 The Japanese Society of Hypertension All rights reserved