Electrophysiological safety of sertindole in dogs with normal and remodeled hearts.

Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents.

HTS techniques to investigate the potential effects of compounds on cardiac ion channels at early-stages of drug discovery.

Within the past few years, the high-throughput screening (HTS) of compounds targeting cardiac ion channels has been primarily focused on the testing of the HERG channel, which is involved in the termination of cardiac action potential. Interaction of drugs with this channel may induce QT interval prolongation and cardiac arrhythmia. These undesirable side effects have forced several pharmaceutical companies to terminate drug discovery and development projects.

Local anaesthetics block hyperpolarization-activated inward current in rat small dorsal root ganglion neurones.

(1) Hyperpolarizing voltage steps evoke slowly activating inward currents in a variety of neurones and in cardiac cells. This hyperpolarization-activated inward current (I(h)) is thought to play a significant role in cell excitability, firing frequency, or in setting of the resting membrane potential in these cells. We studied the effects of lidocaine, mepivacaine, QX-314 and bupivacaine as well as its enantiomers on I(h) in the membrane of dorsal root ganglion neurones (DRG).

Screening lead compounds for QT interval prolongation.

The late detection of cardiotoxic side effects, such as QT prolongation, induced by compounds of pharmacological interest can dramatically impede drug discovery and development projects, and consequently increase their cost. The launch of new drugs with undetected cardiotoxic side effects could have hazardous consequences and could trigger lethal cardiac dysrhythmias in patients. It is desirable, therefore, to test for the potential cardiotoxic side effects of compounds at an early stage of drug development.

Solution structure of hpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel.

HpTX2 is a toxin from the venom of Heteropoda venatoria spider that has been demonstrated to bind on Kv4.2 potassium channel. We have determined the solution structure of recombinant HpTX2 by use of conventional two-dimensional NMR techniques followed by distance-geometry and molecular dynamics.