SUMMARY Pirmenol (CI-845), a new antiarrhythmic drug, was studied for the first time in humans to establish a minimum effective i.v. dose in 10 patients with chronic, stable premature ventricular complexes (PVCs) and to evaluate toxicity and pharmacokinetics. Infusions of 70-150 mg were associated with a 90% or greater reduction in PVCs nine of the 12 times they were administered to six patients. Peak plasma concentrations were 1.0-3.8 Ag/ml at the end of these infusions. At the same time, small but significant increases in diastolic blood pressure (4 mm Hg) and QTc interval (0.01 second) were seen, but both values were within the normal range. Pirmenol was associated with no change in heart rate, systolic blood pressure, PR interval or QRS duration, renal, hepatic or hematologic function, or symptoms. Blood, plasma and free drug concentrations declined biexponentially after cessation of a 150-mg infusion (n = 4), with a terminal half-life of 7-9.4 hours. The therapeutic response, lack of toxicity, and relatively long half-life indicate that pirmenol is a promising antiarrhythmic agent.THERAPY of cardiac arrhythmias is limited by the small number of antiarrhythmic drugs available and in particular by their side effects.1 2 Pirmenol (CI-845, Parke-Davis) is a new antiarrhythmic agent that has not been evaluated previously in man. It is very effective in dogs with experimental ventricular arrhythmias induced by coronary artery ligation and catecholamine infusions. Therapeutic doses in dogs were associated with a plasma half-life of 4-6 hours; minimal effects on cardiac conduction; a lack of pharmacologic tolerance; a good correlation between dose, plasma level and efficacy; distinct separation of therapeutic and toxic plasma levels; a lack of interference with cardioversion after electrically or chemically induced ventricular fibrillation; and lack of adverse interactions with other antiarrhythmic drugs.3 ' These features suggest that pirmenol might be easier to use than currently available antiarrhythmic drugs.In this paper we report the initial experience with pirmenol in man. The study was designed to determine the minimally effective i.v. dose of pirmenol and to evaluate toxicity and pharmacokinetics. Methods PatientsTen males, ages 54 ± 6.4 years, with stable premature ventricular complexes (PVCs), sinus rhythm,

SUMMARYWe report four patients with no preexisting movement disorders who developed oculogyric crises secondary to lamotrigine toxicity and had resolution of these crises after dose reduction. Episode numbers ranged from 1-20 per day and episode duration from 2 s to several hours. Mean plasma concentration of lamotrigine at the time of oculogyric crisis was 15.5 lg/mL, with a mean dose of 16 mg/kg per day.

Patients with congenital QT prolongation have an increased incidence of ventricular arrhythmias and sudden death. Altered sympathetic tone has been suggested as an important contributing factor in this syndrome. Although some patients with an increased QT interval and arrhythmias have an abnormal QT response during exercise, the effect of exercise has not been reported in patients with acquired QT prolongation without clinical manifestations. The purpose of this study was to determine the pattern of QT change with exercise in patients with QT prolongation without exercise-induced arrhythmias in order to: 1) determine the most frequent response in this group; 2) observe the effect of posture on QT changes; and 3) compare the rate of QT change with a control group. Treadmill exercise testing was performed in 10 patients (mean age 52.1 +/- 8.0 years) with a QTc greater than 0.44 s; the results were compared with 14 patients with a normal QTc (mean age 45.8 +/- 12.1 years). Patients with an increased QT interval at rest experienced a significant reduction in QT interval during exercise (0.315 +/- 0.030 s vs 0.394 +/- 0.046 s standing at rest; P less than 0.01), as cycle length was decreased from 0.732 +/- 0.175 s to 0.489 +/- 0.062 s. Patients in the control group had a similar change in QT interval (0.297 +/- 0.015 s vs 0.359 +/- 0.029 s standing at rest (P less than 0.01), with a comparable change in cycle length 0.733 +/- 0.097 s vs 0.511 +/- 0.059 s.(ABSTRACT TRUNCATED AT 250 WORDS)

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