HERG

preclinical studies suggested that hydroxyzine could block the human cardiac ether-a-go-go-related gene (hERG) potassium ion channel, which is responsible for rapid cardiac repolarization, and could produce a prolongation of the QT interval in a dose-dependent manner (Wang et al, 1998; Taglialatela et al, 2000). However, in the first study of Wang the smallest dose tested, which caused a 10.9% increase in the QT interval, was 1µM, higher than the therapeutic free plasma concentration of the drug (Wang et al, 1998), while the second study of Taglialatela, investigated the blockade in vitro of hERG channel with a heterologous expression in the Xenopus oocytes. The concentration producing a 50% decrease (IC50) in the current generated on activation of the patched cell was 10.7µM (Taglialatela et al, 2000). In this context, different studies indicated that this technique in Xenopus oocytes might not be reliable to determine the intensity of the hERG blockade (Madeja et al, 1997; Weerapura et al, 2002). The properties of hydroxyzine to block the hERG channel had been supported by a case report published in 2008 by Sakaguchi and colleagues, where an event of long QT syndrome was induced by hydroxyzine in a patient with a mutated hERG channel and then by an in-vitro study of Lee and colleagues in 2011 where it was demonstrated a direct inhibitory effect of hydroxyzine on the hERG channel resulting in a prolongation of the cardiac action potential of the isolated guinea pig…

Daklinza is a substrate for CYP3A and the dosage modification is required when taken with CYP3A inhibitors. With strong CYP3A inhibitors and moderate CYP3A inducers, the dose of Daklinza should be 30 mg and 90 mg respectively.3 A total of 17 individuals were recruited to determine the EC50 and IC50 values.3 Hybrid replicons of HCV genotype 3a derived NS5A sequences were synthesized. Replicons which did not contain drug resistance associated polymorphism at NS5A sequences, were found to have…