Preclinical pharmacology of pirmenol.

Abstract Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology and has a favorable therapeutic index compared with other class I agents. Animal pharmacology studies showed that pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin, chemically, mechanically or electrically induced or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which pirmenol could be used either alone or in combination. Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention or termination of cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of pirmenol, plasma levels and antiarrhythmic efficacy. Administration of pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for pirmenol compared with other class I agents. Analysis of the pharmacokinetic data led to the modeling of a rapid infusion-slow infusion bolus for sustained intravenous administration, thereby optimizing therapeutic utility. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of potassium levels. To test the relevance of the in vitro electrophysiologic results, pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum potassium was either increased or decreased. Studies comparing pirmenol and disopyramide clearly showed a relative lack of serum potassium dependence for pirmenol, suggesting a potential clinical advantage over disopyramide and other antiarrhythmics in variable potassium settings. The clinical relevance of these observations will have to be established in patients with variable potassium levels. Overall, pirmenol compared favorably with other reference agents in efficacy and safety in extensive preclinical investigations.