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AIMS: Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice. METHODS: Eleven healthy adult volunteers took part in a single sequence, repeated-measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg-1) with three glasses of 300 ml of grapefruit juice on the same day. RESULTS: Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in all subjects and increased the area-under-the-curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 +/- 14.3 vs 23.9 +/- 11.2 microg ml-1 h, P < 0.005 and Cmax: 3.45 +/- 1.7 vs 1.87 +/- 0.6 microg ml-1, P < 0. 02, respectively) (means +/- s.d.). This inhibition of N-DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals. CONCLUSIONS: Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N-DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.

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To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.

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Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.

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At the present time, there is no satisfactory pharmacological treatment for arrhythmia or conduction disorders induced by or aggravated by vagal hypertonia. The limited duration of action of the atropine derivatives currently available justifies the development of new compounds with expected longer acting duration. The aim of this study was to compare the effects of a single blind intravenous injection of ipratropium bromide to those of atropine sulfate in 22 patients. These patients were studied with continuous Holter recordings for three days. During the second and the third nights (patient sleeping), boluses of atropine (0.03 mg/kg) and of ipratropium bromide (0.03 mg/kg), respectively, were added to a continuous saline intravenous infusion. Accurate ECG analysis allowed determination of maximal heart rate peak, timing of maximal heart rate, variations in sinus cycle length, atrioventricular conduction, and durations of drug action. A nonsuggestive questionnaire was presented to patients to detect possible occurrence of side effects. The mean maximal heart rate rose significantly (p less than 0.001) for atropine (+46.2%) and for ipratropium bromide (+57.4%). The effects obtained with ipratropium bromide on the heart rate lasted nearly twice as long as those obtained with atropine (respectively, 120 +/- 38.4 min and 70 +/- 30 min- for the pharmacological half-life). Common minor muscarinic side effects (dryness of the mouth) were noted with the two drugs. In conclusion, this comparative intraindividual study confirmed the prolonged vagolytic effects of intravenous ipratropium bromide, which may be valuable in the treatment of patients with vagally mediated automaticity and conduction disturbances.

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Nicaïnoprol, a new class 1 antiarrhythmic drug was given intravenously in a dose of 2 mg kg-1 of body weight (two patients) and 3 mg kg-1 of body weight (nine patients), and the clinical, electrocardiographic and electrophysiological effects were studied. Fifteen minutes after the end of drug administration, the PR interval was prolonged by 24.4% (P less than 0.001), and the QTc by 3.9% (P less than 0.01). The prolongation of QRS duration (+6%) was not significant. There was a slight (-3.9%) but non-significant decrease of the heart rate, with no alteration in sinus node function. Alteration of atrial conduction and atrioventricular (AV) conduction were due to an increase in the PA interval (+57.4%, P less than 0.05), the AH interval (+10.9%, NS) and the HV interval (+43.8%, P less than 0.01). The anterograde Wenckebach cycle length increased by 11% (P less than 0.01). The effective and functional atrial refractory periods increased respectively by 4.5% and 11.4% (P less than 0.05), and the effective refractory period of the AV node increased by 11.2% (P less than 0.05). None of the other electrophysiological variables changed significantly. A non-significant drop in blood pressure was noted between the second minute following injection (-9.4%) and the 15th minute (-3.4%), and two patients complained of dizziness; one of these two patients reported a heat flush with an oral burning. In conclusion, nicaïnoprol seems to possess the electrophysiological properties of some other class I antiarrhythmic drugs, and is clinically well tolerated.

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Encainide is a new antiarrhythmic class IC agent. Eleven patients were given 1 mg/kg of encainide i.v. over a 15-min period. Electrophysiological studies were done before and l h after drug administration. Blood levels of encainide and its principle metabolites O-demethyl-encainide, 3 metoxy-O-demetyl-encainide and N-demethyl-encainide were measured serially after drug administration. Heart rate, blood pressure, and conduction intervals were monitored. Sixty minutes after drug administration there was a marked increase of the QRS, PA, AH, and HV intervals of 28.1% (p less than 0.01), 17.2% (p less than 0.01), 22.4% (p less than 0.01), and 32.2% (p less than 0.01), respectively, and a slight increase of the Wenckebach cycle length of 8% (p less than 0.05). BP, RR, QT, CSNRT, ESACT, ERP, and FRP did not vary significantly. The HV interval already was increased significantly 2 min after drug administration, while AH was not increased until 15 min after drug administration. The average blood levels of encainide and ODE 60 min after drug administration were 0.410 +/- 0.12 and 0.176 +/- 0.09 microgram/ml, respectively (mean +/- SE of the mean). There was a positive correlation between the increase of the AH and the blood level of ODE, which points out the importance of prolonged electrophysiological studies when testing drug with possibly active metabolites.

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Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)

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Antiarrhythmic and cardioprotective effects of propranolol and sotalol were examined by studying their action on cellular electrical activity (recorded using standard microelectrode techniques) and creatine-kinase leakage (measured in the effluent from the experimental bath chamber) in the in vitro guinea-pig left ventricular myocardium exposed to conditions mimicking severe or moderate ischemia. Returning the tissue to the normal conditions was considered as equivalent to ischemic-heart reperfusion. Propranolol (2 X 4 mg/kg) was intraperitoneally administered to guinea-pigs, daily for 21 days. It was perfused in vitro (1.10(-6) M) during the whole experiments. Propranolol decreased action potential duration in control conditions (p less than 0,05), precipitated the occurrence of inexcitability during severe ischemia (p less than 0,01) and improved the recovery of cellular excitability during reperfusion. Propranolol did not significantly affect the creatine-kinase leakage during ischemia and reperfusion.

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Acute hemodynamic changes induced by Betaxolol (B.) were studied in 10 patients (7 men, 3 women, mean age: 36 years), with uncomplicated essential hypertension. The brachial artery was cannulated with a short Teflon catheter and Swan-Ganz catheter was introduced into the pulmonary artery. Brachial (BAP) and Pulmonary arterial pressures (PAP), cardiac output (dye dilution) were recorded before (To) and after intravenous infusion of B. (0.2 mg/kg) during 5 minutes (T1), followed by the infusion of B. at a rate of 0.4 mg/kg during 15 minutes (T2). Cardiac index (C.I.), Stroke index (S.I.), Systemic Vascular (SVR) and Pulmonary Vascular Resistances (PVR), Left Ventricular Stroke Work Index (LVSWI) were calculated. C.I. declined significantly. This resulted from a significant decrease of heart rate, since S.I. was unsignificantly changed. BAP (systolic and mean) decreased significantly, since unsignificant changes of PAP were noted. SVR and PVR were significantly increased and LVSWI was significantly decreased. Plasmatic Renin Activity was unsignificantly decreased.

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