Antiarrhythmic — clamikalant sodium
Alterations to the normal rhythm of the heartbeat can lead to a variety of problems, from palpitations and breathlessness to a cardiac arrest and death. If the arrhythmia is a result of myocardial ischaemia, then a heart attack is likely. The opening of ATP-sensitive potassium, or KATP, channels is implicated in this, as this mechanism is not normally in operation — they are opened only during myocardial ischaemia. Hence, blocking the KATP channels should have no effect in normal circumstances, but could prevent potentially fatal arrhythmias developing should myocardial ischaemia occur.
It was discovered some time ago that the sulphonylurea drug glibenclamide can have the desired effect on arrhythmias, but it is too unselective to be of practical use for this indication. Aventis has found a more selective sulphonylurea analogue that looks particularly promising — clamikalant sodium, which was previously known as HMR-10981.
Animal studies proved that, in conditions similar to those experienced during ischaemia, the drug did indeed have the effect of shortening the action potential duration (APD) which, if it transferred to human subjects, would reduce the likelihood of severe arrhythmias developing.
In a Phase I clinical trial in healthy volunteers, candidates were given single oral doses of 50–900mg or single i.v. doses of 37.5–400mg, and also multiple oral doses for up to five days. The drug's oral bioavailability was found to be dependent on both food intake and the precise formulation of the dose. Doses of 600mg gave peak plasma levels of at least 0.5µl/ml, which is thought to be the minimum level for effective prevention of ventricular fibrillation induced by ischaemia2.
In a placebo-controlled study looking at the drug's safety in patients undergoing coronary angioplasty, no worrisome side-effects were seen. Although still in the early stages of development, clamikalant shows promise as a potential selective treatment for cardiac arrhythmias.