Prolongation of the QT interval induced by probucol: demonstration of a method for determining QT interval change induced by a drug

Abstract

Sudden death has occurred in monkeys fed large doses of probucol, a cholesterol-lowering drug, given in combination with an atherogenic diet. These monkeys develop prolonged QT intervals and high serum levels of probucol. We investigated the effect of probucol on QT interval and the incidence of ventricular ectopy during a double-blind placebo-controlled study in 16 patients with less than 600 premature ventricular complexes (PVCs) per day and a corrected QT interval of less than 0.44 second. Seven patients received probucol and nine patients received placebo. Three 24-hour continuous ECG recordings were obtained prior to entry into the study and three additional recordings were obtained after 6 months of drug or placebo therapy. A 15-second ECG tracing was sampled from the continuous ECG recording every 30 minutes and, for the group, 15,000 QT intervals were measured permitting construction of QT versus R-R regression lines for each patient before and during therapy. Comparison of the regression lines revealed that the measured QT interval prolonged 20 +/- 18 msec during the awake state and 24 +/- 20 msec during sleep (mean + standard deviation) at matched heart rates in the seven patients receiving probucol (p less than 0.01). Using Bazett's formula to correct for rate, corrected QT interval prolonged 22 +/- 23 msec in the awake state and 20 +/- 18 msec in the asleep state (p less than 0.01). In probucol treated patients QT interval prolongation was directly related to increasing probucol plasma levels (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)