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At least 199 records · Page 11Linked to original sources
PubMed1985

[Effects of antiarrhythmic drugs on rat erythrocytes, isolated hepatocytes and dipalmitoyl phosphatidyl choline (DPPC)-liposomes].

The effects of antiarrhythmic drugs, aprindine, mexiletine and lidocaine, on rat erythrocytes, isolated rat hepatocytes and DPPC-liposomes were studied at various concentrations. Maximal inhibition of aprindine on the hypotonic hemolysis was observed at a concentration of 2 X 10(-4) M. In isolated rat hepatocytes, aprindine caused an increase in GOT leakage above 4 X 10(-4) M. Mexiletine and lidocaine caused a slight decrease in GOT. Only aprindine caused an increase in LDH leakage above 2 X 10(-4) M. In the relationship between the surface tension and pH conditions (pH 5.7, 7.4 and 8.0), aprindine and mexiletine indicated a depression of surface tension at a dose of 10(-4) M to 10(-3) M under all pH conditions. Lidocaine indicated a depression of surface tension at a dose of 10(-4) M at pH 8.0 only. Aprindine and mexiletine depressed the phase transition temperature (Tc) of DPPC-liposomes. The depression of Tc by aprindine was greater than that by mexiletine. The rank by order of surface activity was the same as that of enzyme leakage from hepatocytes, hemolysis of erythrocytes and depression of Tc in DPPC-liposomes in vitro. These results suggest that differences in membrane damage produced by antiarrhythmic drugs may by related to surface activity, which in turn may determine the extent of adsorption onto cell membranes.

Animals↗
PubMed1993

Antifibrillatory and profibrillatory actions of selected class I antiarrhythmic agents.

We wished to examine selected class I antiarrhythmic agents for their potential to exhibit proarrhythmic or antifibrillatory actions. Quinidine, lidocaine, aprindine, and flecainide were evaluated in an experimental model that made use of rabbit isolated perfused heart. Hearts were stabilized with oxygenated buffer (95% O2/5% CO2) with or without pinacidil (1.25 microM) and then were subjected to hypoxia (95% N2/5% CO2) for 12 min, followed by 40-min normoxic perfusion (95% O2/5% CO2). Test drugs were added to the perfusion medium 5 min before hypoxia was induced. Prevention of spontaneous ventricular fibrillation (VF) was determined. To characterize the electrophysiologic effects of the selected antiarrhythmic agents, we determined the changes in threshold current and effective refractory period (ERP) before and after drug treatment. Addition of the potassium channel agonist, pinacidil, to the perfusion medium invariably resulted in VF during the hypoxic interval or shortly after reoxygenation. Pretreatment of the heart with glibenclamide prevented pinacidil-induced VF. Quinidine, aprindine, lidocaine, and flecainide each were studied at a single concentration. The respective drug concentrations were selected to produce comparable changes in ventricular refractory period. Of the class I agents selected for study, only quinidine prolonged the ventricular ERP and provided significant protection against pinacidil-induced VF. In contrast, aprindine and lidocaine decreased ventricular ERP and did not prevent VF induced by the combination of pinacidil and hypoxia. Quinidine, aprindine, and lidocaine did not exhibit proarrhythmic effects in the presence of hypoxia when pinacidil was not added to the perfusion medium. Flecainide, when added to the perfusion medium without pinacidil elicited proarrhythmic activity leading to VF when the hearts were made hypoxic. Flecainide-induced VF was antagonized by glibenclamide. The data suggest that VF can be provoked by the potassium channel agonist pinacidil or by flecainide under conditions that reduce intracellular ATP concentration. Glibenclamide, a selective antagonist of the KATP channel prevented the profibrillatory actions of pinacidil and flecainide. Quinidine, but not lidocaine and aprindine, prevented VF induced by pinacidil and hypoxia.

Adenosine Triphosphate↗
PubMed1987

Prophylactic antiarrhythmic therapy of high-risk survivors of myocardial infarction: lower mortality at 1 month but not at 1 year.

To determine whether prophylactic antiarrhythmic therapy influences mortality in high-risk patients after acute myocardial infarction, 143 such patients were randomized in a double-blind individually dose-adjusted, placebo-controlled trial an average of 14 +/- 7 days after myocardial infarction and followed for 1 year. Patients were judged to be at high risk on the basis of (1) ejection fraction less than 40% (n = 60), (2) arrhythmias of Lown class 3 or higher (n = 26), or (3) both (n = 57). Aprindine was chosen because of its long half-life, few side effects, and antiarrhythmic efficacy. Baseline characteristics in the treatment arms did not differ. Holter-detected arrhythmias were reduced in aprindine-treated patients at 3 months (p less than .001) and at 1 year (p less than .001). One patient was lost to follow-up; in the remaining patients 1 year mortality was 20% (28/142; 12 aprindine and 16 placebo). There was no significant difference between the two study arms in overall mortality and sudden death. However, among those who died, median duration of survival was longer in aprindine-treated patients (86 vs 21.5 days) (p = .04). Although antiarrhythmic treatment with aprindine of high-risk patients after myocardial infarction does not affect 1 year survival, mortality appears to be delayed; thus there may be a role for short-term treatment before more definitive therapy such as surgery.

Aprindine↗
PubMed1982

Electrophysiologic drug testing in prophylaxis of sporadic paroxysmal atrial fibrillation: technique, application, and efficacy in severely symptomatic preexcitation patients.

Electrophysiologic drug testing was performed in nine patients with severely symptomatic sporadic (2 to 13 [mean 4.2] attacks/24 months) paroxysmal atrial fibrillation (PAF). All patients had control inductions of sustained (greater than 30 seconds) AF by high right atrial stimulation, and attempted inductions following serial administration of drugs. Drugs tested were intravenous procainamide (1.0 to 1.5 gm) (five patients), intravenous propranolol (0.1 mg/kg) (three patients), oral quinidine (1.6 to 2.4 gm/day) six patients), oral disopyramide (1.2 to 1.6 gm/day) (four patients), and oral aprindine (100 to 250 mg/day) (four patients). In all patients, one or more drugs prevented induction of sustained AF: procainamide (one patient), quinidine (five patients), disopyramide (four patients), and aprindine (four patients). All patients were treated with drugs which prevented induction of sustained AF and followed for 8 to 40 (mean 24) months. Seven patients tolerated their drugs: six had no AF and one had several short nonsustained attacks. Two patients did not tolerate their drugs: one had paroxysmal palpitation (on decreased aprindine dosage), and one had AF (while off of aprindine). In conclusion, electrophysiologic drug testing is feasible in patients with sporadic PAF. Inability to induce sustained AF following drug administration suggests successful prophylaxis of spontaneous PAF with the same drug.

Administration, Oral↗
PubMed1995

Complex frequency-dependent interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction.

We investigated the interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction of human hearts in vivo. QRS duration in signal-averaged electrocardiograms and standard electrocardiograms were measured as an index of intraventricular conduction time in 17 patients with implanted pacemakers at various pacing rates (100-180 ppm, VVI mode). Single intravenous administration of lidocaine, disopyramide or aprindine prolonged the QRS of signal-averaged electrocardiograms in a frequency-dependent manner. Lidocaine (n = 17) produced significant QRS prolongation from pre-drug control at rates > or = 120 ppm (6.2 +/- 1.4% at 180 ppm), whereas disopyramide (n = 17) and aprindine (n = 17) did so from the lowest rate (8.9 +/- 1.8% to 12.3 +/- 2.9% at 100-180 ppm with disopyramide; 14.7 +/- 1.3% to 19.3 +/- 2.2% at 100-180 ppm with aprindine). Addition of lidocaine to disopyramide (n = 17) showed an additive effect; QRS prolongation was enhanced significantly by 1.4-2.8% at rates > or = 150 ppm. In contrast, addition of lidocaine to aprindine (n = 17) showed a subtractive effect; the QRS prolongation was attenuated significantly by 1.6-2.4% at rates < 150 ppm. Combined intravenous administration of class-I antiarrhythmic drugs causes not only additive but also subtractive effects on the intraventricular conduction of the human heart, probably through their interaction on the sodium channel receptor.

Aged↗
PubMed2006

Pharmacological cardioversion of persistent atrial fibrillation with and without a history of drug-resistant paroxysmal atrial fibrillation.

BACKGROUND: Suppression by antiarrhythmic drugs of the maintenance mechanisms could convert persistent atrial fibrillation (AF) to sinus rhythm (SR). Whether a history of drug-resistant paroxysmal AF (PAF) would affect the outcome of pharmacological conversion of persistent AF by bepridil or in combination with aprindine was evaluated in the present study. METHODS AND RESULTS: The study group comprised 51 consecutive patients (24 men, 61+/-8 years) undergoing pharmacological conversion of persistent AF lasting >1 month. Drug-resistant PAF was defined as AF and at least 2 ineffective antiarrhythmic drugs for suppression of AF recurrence. Fast Fourier transform analysis of fibrillation waves was used to measure fibrillation cycle length (FCL) from the peak frequency. Fifteen patients had a history of drug-resistant PAF (Group I), and the remaining 36 did not (Group II) before diagnosis of persistent AF. Ten patients (67%) in Group I and 26 patients (72%) in Group II were restored to SR by bepridil alone or in combination with aprindine after 29+/-15 days of drug administration. Before conversion to SR, bepridil increased the FCL more in Group II than in Group I. During a 12-month follow-up period, 4 of 10 patients in Group I and 2 of 26 patients in Group II (p<0.01) had recurrence of persistent AF with bepridil alone or in combination with aprindine. CONCLUSIONS: A history of drug-resistant PAF does not affect the efficacy of pharmacological conversion by bepridil or in combination with aprindine. However, recurrence of AF was significantly higher in patients with such a history.

Anti-Arrhythmia Agents↗
PubMed1986

Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade.

The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz. The ratio of the molar concentration producing 50% reduction of Vmax to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing Vmax. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l). Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)o. In contrast, the -log molar IC50(Fc) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l). We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).

Action Potentials↗
PubMed1977

Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs.

The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 42 minutes after administration of aprindine (2.85 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 microng/min). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmias. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation time produced by coronary ligation alone (P less than 0.05), whereas verapamil reduced by 10 msec the extent of ischemia-induced conduction delay (P less than 0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decresed by verapamil (from 3 in 7 to 0 in 7 dogs) and was not changes by quinidine or isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel-dependent conduction, verapamil improved and isoproterenol worsened conduction during ischaemia.

Animals↗
PubMed1990

Combined application of class I antiarrhythmic drugs causes "additive", "reductive", or "synergistic" sodium channel block in cardiac muscles.

STUDY OBJECTIVE: The aim was to study the differences in cardiac sodium channel block among combinations of class I antiarrhythmic drugs. DESIGN: Conventional glass microelectrode techniques were used to record transmembrane action potentials and their maximum upstroke velocity (dV/dtmax) reflecting the sodium channel availability, during treatment of the preparations with mexiletine (20, 40 microM) in combination with aprindine (5 microM), disopyramide (40 microM), and flecainide (5 microM). EXPERIMENTAL MATERIAL: Guinea pig papillary muscles (n = 6.8 per experiment) were used for the study. MEASUREMENTS AND MAIN RESULTS: In preparations constantly stimulated at 1 Hz, a shortening of action potential duration by aprindine was further enhanced, while prolongation by disopyramide or flecainide was reduced, after additional application of mexiletine. Trains of stimuli (0.5-2.0 Hz) were applied following a long quiescent period to evaluate "tonic" and "use dependent" decrease (block) of dV/dtmax. Additional application of mexiletine to the other three drugs resulted in an enhancement of tonic block. Use dependent block by aprindine at 0.5-1.0 Hz was reduced by 8-9% after admixture of mexiletine, reflected in net increase in dV/dtmax at steady states (reductive effect). Dual exponential components of dV/dtmax recovery from use dependent block in presence of both drugs suggest their competitive interaction on a common receptor site associated with sodium channels. Use dependent block by flecainide at 0.5-2.0 Hz was increased (p less than 0.01) after admixture of mexiletine. Steady state dV/dtmax was therefore largely inhibited by the drug combination (synergistic effect). Use dependent block in the presence of both disopyramide and mexiletine was similar to that predicted from the algebraic sum of each treatment. CONCLUSION: Combined application of class I antiarrhythmic drugs causes not only additive but also reductive or synergistic effects on dV/dtmax through modulation of use dependent block.

Action Potentials↗