Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis.

PURPOSE: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated. METHODS: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein. RESULTS: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group. CONCLUSION: In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.

Male to male sex is associated with a high prevalence of exposure to GB virus C.

Co-infection with GB virus C (GBV-C) and human immunodeficiency virus (HIV) appears to reduce mortality for HIV/AIDS. Epidemiological and demographic factors for GBV-C were examined prospectively in 167 subjects at risk for co-infection. We attempted to establish a hierarchical exposure risk for GBV-C. Overall exposure to GBV-C was 45.5%. In univariate analysis, GBV-C was associated with male to male sex (P<0.0001), HIV infection (P=0.0005) and hepatitis B infection (P=0.006). Injecting drug use approached statistical significance (P=0.08) while being a female sex worker was not associated with GBV-C exposure/infection (P=0.85). Exposure to GBV-C in 192 healthy blood donors was found to be 9.4%. In conclusion, the data suggest that male to male sex is a more effective mode of transmission of GBV-C and that GBV-C is associated with HIV co-infection. As male to male sex is also a risk factor for HIV transmission our data suggest that many may benefit from the potential protective effect GBV-C exerts on HIV-infected persons.

Hepatic failure due to fibrosing cholestatic hepatitis in a patient with pre-surface mutant hepatitis B virus and mixed connective tissue disease treated with prednisolone and chloroquine.

Fibrosing cholestatic hepatitis (FCH) is a severe variant of hepatitis B infection that has until recently been described almost exclusively in the setting of organ transplantation and HIV infection. This case report describes a patient with pre-surface (pre-S) mutant hepatitis B virus (HBV) infection who developed a fatal form of FCH after high dose prednisolone for mixed connective tissue disease (MCTD). The role of corticosteroids and pre-S viral mutation in the pathogenesis of the disease is discussed, and the importance of early diagnosis is emphasised. This report alerts the physician to the need for close monitoring of LFTs and HBV DNA of hepatitis B carriers during immunosuppressive therapy regardless of the indication. As in the transplantation setting, viral DNA levels should be kept to undetectable if viral replication or recurrence is to be prevented.