Study of the drug-drug interaction between simvastatin and cisapride in man.

OBJECTIVE: The objective of our study was to evaluate in humans the drug-drug interaction occurring during the concomitant administration of cisapride and simvastatin, two well-known substrates of CYP3A4. METHODS: Eleven healthy men aged between 20 years and 35 years gave their written informed consent to participate in the study. Each participant received repeated doses of cisapride and/or simvastatin. At first, subjects received cisapride alone, 10 mg every 8 h, for 3 days. Then, the drug was given at the same regimen during concomitant administration of simvastatin, 20 mg every 12 h for 4 days, starting on the night of day 3. Finally, cisapride was stopped and subjects received simvastatin (20 mg every 12 h) for four additional days. RESULTS: Simvastatin administration caused a 14 +/- 20% increase in the AUC0-8 of cisapride. In contrast, plasma concentrations of simvastatin were unaltered by the coadministration of cisapride, whereas plasma concentrations of simvastatin acid, its active metabolite, were decreased by 33 +/- 24%. CONCLUSION: The concomitant administration of the prokinetic agent cisapride and the 3-hydroxy-3-methylgluaryl CoA reductase inhibitor simvastatin resulted in altered pharmacokinetics of both drugs. Increased plasma concentrations of cisapride suggest that some patients may be at risk of toxicity while receiving both drugs, whereas the decrease in simvastatin acid plasma concentrations suggests that cholesterol lowering effects of simvastatin treatment may be blunted.

Randomized trial of a noninvasive strategy to reduce hospital stay for patients with low-risk myocardial infarction.

OBJECTIVES: This study evaluated the feasibility, pertinence and psychosocial repercussions of a noninvasive reduced hospital stay strategy (three days) for low-risk patients with acute myocardial infarction using simple clinical criteria and predischarge 24-h ambulatory ST-segment ischemic monitoring. BACKGROUND: Previous studies evaluating shorter stays for uncomplicated myocardial infarction have been limited by retrospective or nonrandomized design and overdependence on invasive cardiac procedures. METHODS: One-hundred twenty consecutive patients admitted with an acute myocardial infarction fulfilling low-risk criteria were randomized 2:1 to a short hospital stay (80 patients) or standard stay (40 patients). Short-stay patients with no ischemia on ST-segment monitoring were discharged on day 3, returning for exercise testing a week later. All analyses were on an intention-to-treat basis. RESULTS: Forty-one percent of all screened patients with acute myocardial infarction would have been medically eligible for the short-stay strategy. Seventeen patients (21%) were not discharged early because of ischemia on ST-monitoring or angina. Median initial hospital stay was halved from 6.9 days in the standard stay to 3.5 days in the short-stay group. At six months, median total days hospitalized were 7.5 in the standard stay and 3.6 in the short-stay group (p < 0.0001). Adverse events and readmissions were low and not significantly different, and there were 25% fewer invasive cardiac procedures in the short-stay group. Psychosocial outcomes, risk factor changes and exercise test results were similar in the two groups. CONCLUSIONS: This reduced hospital stay strategy for low-risk patients with acute myocardial infarction is feasible and worthwhile, resulting in a substantial and sustained reduction in days hospitalized. It is without unfavorable psychosocial consequences, appears safe and does not increase the number of invasive cardiac procedures.

Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Ischemia-induced action potential shortening is blunted by d-sotalol in a pig model of reversible myocardial ischemia.

The purpose of this study was to investigate, in an anesthetized pig model of low-flow myocardial ischemia, the electrophysiologic effects of the class III drug d-sotalol during myocardial ischemia. Serial monophasic action potential (MAPD90) recordings and refractory period determinations from the anterior and posterior left ventricular wall were taken in 25 pigs during baseline, after low-flow posterior wall ischemia, after d-sotalol infusion under nonischemic conditions, and after repeated posterior wall ischemia while continuing the drug. Measurements were done at 60 and 150 beats/min after radiofrequency ablation of atrioventricular conduction. At baseline, MAPD90 and refractory periods were comparable in the anterior and posterior wall (323 +/- 15 vs. 318 +/- 10 ms, and 267 +/- 10 vs. 262 +/- 11 ms at 60 beats/min, respectively). In the absence of d-sotalol, low-flow regional ischemia was associated with a significant shortening of MAPD90 in the posterior versus the anterior wall (267 +/- 20 vs. 317 +/- 20 ms at 60 beats/min; p = 0.006). Similarly, ischemia-induced shortening of the refractory periods in the posterior wall was apparent (230 +/- 16 ms in the posterior wall vs. 274 +/- 14 ms in the anterior wall at 60 beats/min). In contrast, ischemia was no longer associated with shortening of MAPD90 (360 +/- 17 ms posterior wall and 360 +/- 20 ms anterior wall at 60 beats/min) and refractory periods (304 +/- 19 ms posterior wall vs. 316 +/- 15 ms anterior wall at 60 beats/min) during combined posterior wall ischemia and d-sotalol infusion. Similar findings were obtained during pacing at 150 beats/min. d-Sotalol attenuates ischemia-induced action potential shortening. This property should decrease dispersion of cardiac repolarization and be antiarrhythmic. On the other hand, longer APD under ischemic conditions may favor calcium overload, which may trigger new arrhythmias.

Comparison of propafenone versus procainamide for the acute treatment of atrial fibrillation after cardiac surgery.

A prospective, randomized, double-blind study to compare the efficacy in terminating postoperative atrial fibrillation of the class Ic drug propafenone versus class Ia drug procainamide was conducted. Intravenous propafenone was superior to procainamide in achieving rapid cardioversion and a better rate control with a lower incidence of symptomatic hypotension.

Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine.

Treatment with second generation histamine H1 receptor antagonists has been associated with lengthening of the Q-T interval and proarrhythmia. Similarly, lengthening of the Q-T interval has been reported in patients after overdosing with diphenhydramine (DPH), a first generation agent. Therefore, our study was designed 1) to assess effects of DPH on cardiac repolarization and 2) to characterize effects of the drug on major voltage-dependent cardiac K+ currents. First, we noticed that oral administration of DPH at usual dosages to healthy volunteers or to patients (prior to angioplasty) was associated with prolongation of the Q-Tc interval. Although this effect was modest in most individuals, Q-Tc was increased more than 20 ms in 7 of 20 patients. Second, we noticed that exposure of isolated guinea pig hearts to DPH 10(-5) M caused a lengthening of monophasic action potential duration. This effect was potentiated by the combined perfusion of other K+ channel blockers such as indapamide. Finally, experiments performed with the patch-clamp technique demonstrated unequivocal block of the rapid component of the delayed rectifier (IKr) by DPH; however, IC50 determined for block of IKr (3 x 10(-5) M) is approximately 40-fold greater than plasma concentrations of the drug measured at usual dosages (7 x 10(-7) M). Consequently, in agreement with the long-term clinical use of the drug, prolongation of cardiac repolarization should be minimal in most patients at usual dosages but may be observed with overdosing. Nevertheless, caution remains since excessive lengthening of cardiac repolarization may occur after administration of DPH with other drugs due to 1) concomitant block of other ionic currents or 2) pharmacokinetic interactions leading to toxic concentrations of DPH.

Incidence, pathophysiology and prognosis of exercise-induced sustained ventricular tachycardia associated with healed myocardial infarction.

Of 150 consecutive patients with sustained monomorphic ventricular tachycardia (VT) (n = 116) or ventricular fibrillation (VF) (n = 34) late after acute myocardial infarction, 17 had reproduction of their sustained monomorphic VT during exercise testing. Data from these patients (group I) were compared with data from patients without exercise-induced VT (group II). No statistical difference was found between groups I and II with relation to age, sex, number of vessels with greater than 70% stenosis, left ventricular ejection fraction, number of previous myocardial infarctions, inducibility during programmed stimulation and total mortality during follow-up. In group I, only 1 patient (6%) developed ST depression during exercise compared with 47 patients (35%) in group II (p less than 0.01). After a 34-month mean follow-up, 6 patients in group I (35%) and 18 patients in group II (13%) died suddenly (p = 0.02). It is concluded that sustained monomorphic VT is reproduced during exercise in only 11% of patients with spontaneous late sustained monomorphic VT or VF. Electrocardiographic findings do not support ischemia as a triggering mechanism of exercise-induced sustained monomorphic VT. Patients with exercise-induced sustained monomorphic VT have a high incidence of sudden death.

Incidence and timing of recurrences of sudden death and ventricular tachycardia during antiarrhythmic drug treatment after myocardial infarction.

Incidence and timing of recurrences of sustained ventricular tachycardia (VT) or sudden death were studied in 206 patients who survived their first episode of ventricular fibrillation (VF; n = 52) or sustained VT (n = 154) after myocardial infarction. All patients were treated with (empirically selected) antiarrhythmic drugs; 49% received amiodarone. After a mean follow-up of 36 months, 64 patients (41%) in the VT group and 10 (19%) in the VF group had nonfatal VT recurrences. Sudden death occurred in 22 (14%) and 9 (17%) patients in the VT and VF groups, respectively. Incidence of sudden death had 2 peaks at approximately 3 and 12 months. Nonfatal VT recurrences were more frequent (most often occurring in first 6 months) in the VT than in the VF group. Sudden death occurred during the following 3 years in only 10% of patients who survived 1 year. There was a much higher incidence of sudden death in patients with left ventricular ejection fraction (LVEF) less than or equal to 40% than in those with LVEF greater than 40% (28 of 65 vs 3 of 141; p less than 0.0001), but no relation between LVEF and nonfatal VT recurrences.