Acquired QT interval prolongation and HERG: implications for drug discovery and development

Differentiation, Characterization and Applications of Human Embryonic Stem Cell –Derived Cardiomyocytes

“…Severe reactions, such as syncope, arrhythmia and sudden death, related a special ventricular tachycardia, torsade de pointes (TdP), have led to the refusal of approval or the withdrawal from the market of many pharmaceutical agents (Roden 2004). In the absence of a complete understanding and direct analysis of TdP, the regulatory authorities have adopted the QT prolongation as a marker for the possible development of druginduced TdP even though it is not a perfect marker for arrhythmogenesis (Finlayson, Witchel et al 2004). Prolongation of the QT interval resulting from a delay in ventricular repolarization, whether drug-induced or for instance congenital arising from mutation of genes (to date LQT1-12), can be associated with TdP (Roden 2004;Zareba and Cygankiewicz 2008), though the relationship is complex (Shah and Hondeghem 2005).…”

“…Currently a number of preclinical models and assays have been employed by pharmaceutical companies (Carlsson 2006;Pollard, Valentin et al 2008). These assays include in vivo QT assays, such as ECG telemetry of conscious dogs (Miyazaki, Watanabe et al 2005), and in vitro assays, such as of repolarization assay which detects changes in the action potential delay (APD) of cardiac tissues (isolated animal purkinje fibers, papillary muscles or cardiac myocytes) or the hERG channel assay where hERG current expressed in heterologous cell system (such as CHO-or HEK293-cells) or native IKr is characterized (Finlayson, Witchel et al 2004;Martin, McDermott et al 2004). Current methods are not fully adequate (Redfern, Carlsson et al 2003;Lu, Vlaminckx et al 2008).…”

Inhibitory Effect of Nicardipine on hERG Channel

“…Drug-induced long QT syndrome (LQTS) is known to result from blocking of IKr, which is "delayed rectifier potassium current" (Finlayson et al, 2004). The rapid component of IKr, which is involved in repolarization of cardiac action potential, and can induce polymorphic ventricular tachycardia Torsades de Pointes (TdP) and sudden death, is encoded by human ether-a-go-go-related-gene (hERG) (Roden and Spooner, 1999).…”

“…These cases of drug withdrawals not only caused heavy damage in the pharmaceutical industry, but also unexpected clinical adverse effects, such as sudden death in humans. Recently, testing for drug-induced QT prolongation has been mandatory during drug development in pharmaceutical companies and is required by drug regulatory authorities (Fermini and Fossa, 2003;Picard and Lacroix, 2003;Ajay et al, 2004;Finlayson et al, 2004).…”

Multi-Functional 3,4-Dihydroquinazoline Derivative as T-Type Calcium Channel Blocker: Pharmacokinetics and Anti-Tremor Activity

“…[9][10] These compounds also exhibited the anti-cancer activity in vitro via cellcycle arrest mechanism. [11][12] As a continuous work, three compounds (1-3) with the highest T-channel channel selectivity (No blocking against N-type channel) were selected among the chemical library of 3,4-dihydroquinazoline and evaluated for the blocking effect on the hERG potassium channel, [13][14] which is known for its contribution to the electrical activity of the heart that coordinates the heart's beating: both of % inhibitions at 10 µM concentration and the molar concentrations of compounds needed to produce 50% inhibition of peak currents (IC50) were measured by the whole-cell patch-clamp method. 15 The data were summarized in Table 1 with mibefradil as a positive control for comparison.…”