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PubMed2003

Interaction of quinidine, disopyramide and metoprolol with melanin in vitro in relation to drug-induced ocular toxicity.

The aim of this work was to evaluate binding capacity of quinidine, disopyramide and metoprolol to melanin in vitro. The antiarrhythmics studied cause adverse reactions to the eye. Synthetic DOPA-melanin was used in the studies and a UV spectrophotometric method was employed to determine the drugs. The studies of the kinetics of the formation of quinidine-melanin, disopyramide-melanin and metoprolol-melanin complexes indicate that for all the complexes investigated the maximum time to reach reaction equilibrium is 24 h. Binding parameters, i.e., the numbers of independent binding sites and the association constants were determined on the basis of the Scatchard plots. An analysis of the binding curves obtained supports our conclusion that both strong (n1) and weak (n2) binding sites are involved in the formation of the complexes investigated. The total numbers of binding sites in synthetic DOPA-melanin complexes with quinidine, disopyramide and metoprolol were 0.525, 0.493 and 0.387 micromol/mg, respectively. The quinidine-melanin complex is characterized by greater stability (K1 = 3.00 x 10(5) M(-1), K2 = 1.75 x 10(3) M(-1)) in comparison with biopolymer complexes with disopyramide (K1 = 1.12 x 10(4) M(-1), K2 = 6.04 x 10(2) M(-1)) and metoprolol (K1 = 1.42 x 10(4) M(-1), K2 = 7.89 x 10(2) M(-1)). The ability of these drugs to form complexes with melanin in vitro may be one of the reasons for their ocular toxicity in vivo, as a result of their accumulation in melanin in the eye.

Anti-Arrhythmia Agents↗
PubMed1992

[Effects of disopyramide on normal and pathological atrioventricular conduction].

Disopyramide is a Vaughan-Williams class Ia antiarrhythmic, which is distinguished by its anticholinergic activity, which is due to its active metabolite: mono-N-alkyl disopyramide. In cells with a rapid response, such as those in the His-Purkinje tissue, it depresses conduction. In slow-responding cells (sinus node and Tawara's node) direct depression of conduction and automatism, and anticholinergic stimulation have opposing effects. In terms of clinical electrophysiology, this is a Touboul class IIa compound: and action mainly on the His-Purkinje system involving extension of the conduction time and of the refractory time. Nodal conduction is improved according to measurement of the alternate Wenckebach; according to studies of the denervated heart in transplanted patients, there is a depressant effect on automatism and conduction at all levels, but the vagolytic effect corrects this activity at Tawara's node. Clinical trials have demonstrated the absence of any deterioration, and in some cases and actual improvement of nodal conduction disorders in response to disopyramide and good safety in the presence of non-major intraventricular conduction problems (such as bundle branch block). In practice, these properties mean that moderate nodal conductive disorders and simple bundle branch block do not constitute an obstacle to the use of disopyramide. In junctional tachycardia, it is particularly indicated for use in tachycardia involving an accessory pathway, but is also effective in intranodal tachycardia due to its twofold action.

Arrhythmias, Cardiac↗
PubMed1991

[Comparison of the efficacy of moricizine and disopyramide in the treatment of ventricular extrasystoles].

Moricizine chlorhydrate (Ethmozine), a relatively unknown antiarrhythmic agent in France, is a derivative of Phenothiazine, related to the Vaughan-Williams Class IB drugs. A randomised, double-blind, crossover trial with Disopyramide 600 mg/day after a placebo period in 10 patients with ventricular extrasystoles, half of whom had underlying cardiac disease, showed that moricizine 750 mg/day significantly reduced (p less than 0.05) the overall number of ventricular extrasystoles by 81 +/- 46% (disopyramide 72 +/- 69%; NS) and that this drug is effective in 2/3 of patients by suppressing 70 to 100% of ventricular extrasystoles, whereas disopyramide was effective in only 40% of the same patients and never gave better results than Moricizine. Cardiac and extracardiac tolerance of Moricizine was good in this study, confirming previously reported results and its superiority when compared with disopyramide (20% of unwanted effects in this series).

Adolescent↗
PubMed1990

Simultaneous determination of disopyramide and mono-N-dealkyldisopyramide enantiomers in plasma and urine by use of a chiral cellulose-derivative column.

This assay allows simultaneous determination of the enantiomers of both disopyramide and its active metabolite, mono-N-dealkyldisopyramide, in 1 mL of plasma or 0.1 mL of urine within approximately 35 min by HPLC with a chiral cellulose-derivative column and ultraviolet detection. Recoveries for the analytes and the internal standard (racemic verapamil) with an extraction from alkalinized plasma or urine into diethyl ether were greater than 90%. Intra- and interassay CVs for disopyramide enantiomers were less than 5.5% at 2.5 mg/L in plasma and less than 6.5% at 25 mg/L in urine; for mono-N-dealkyldisopyramide enantiomers they were less than 6.3% and less than 8.9%, respectively. Intra- and interassay relative errors for determining these analytes in plasma and urine at 2.5 and 25 mg/L, respectively, ranged from -5.9% to +2.5%. The calibration curves for the respective analytes were linear (r = 0.995 or greater, P less than 0.01) from 0.025 to 5.0 mg/L in plasma and from 0.5 to 10 mg/L in urine. The lower detection limits (signal-to-noise ratio of 3) for S(+)-disopyramide and the other analytes were 0.010 and 0.025 mg/L, respectively. We evaluated clinical applicability of this method by determining steady-state plasma concentrations and urinary excretions of the respective analytes in a pediatric patient being treated with racemic disopyramide.

Anti-Arrhythmia Agents↗
PubMed1986

[Comparison between amiodarone and disopyramide in the treatment of ventricular extrasystoles].

The authors have compared the anti-arrhythmic activity and tolerance of disopyramide and amiodarone in the treatment of ventricular extrasystoles (VES) by using two quantitative methods of assessment. The stability of the rhythmic disorder was confirmed by two control Holter recordings in 20 patients without treatment, 16 of whom were bearers of an organic cardiopathy. The ventricular extrasystole was greater than 90 VES/hour in 18 patients. After the first control, Holter recording, each patient was treated successively with 400 mg of disopyramide/day in 4 doses for average period of 31 days, then a second Holter control recording without treatment, then 600 mg/day of amiodarone for 8 days followed by a maintenance dose varying from 200 to 400 mg/day: this second period of treatment lasted for an average of 38 days. The reduction of the number of VES was greater than 65 percent (SAMI criterion) in 2 of the 20 patients treated with disopyramide and in 13 of the 20 patients treated with amiodarone. Using the method of variance analysis, disopyramide was found to be efficacious in 5 cases out of 20 and amiodarone in 15 cases out of 20. Both methods indicate that the greater efficacy of amiodarone is statistically significant (p less than 0.01). All of those who did not respond to amiodarone were also non-responders to disopyramide.

Adult↗
PubMedDate not supplied

Effects of aprindine and disopyramide on reperfusion-induced arrhythmias and cardiac function in isolated rat hearts.

The effects of aprindine and disopyramide on reperfusion-induced arrhythmias and cardiac function were investigated in the isolated perfused rat heart. Occlusion of the left anterior descending coronary artery for 15 min and subsequent reperfusion provoked ventricular tachycardia in 9 out of 10 hearts and ventricular fibrillation in 7 out of 10. Aprindine or disopyramide was infused 15 min prior to the coronary occlusion in concentrations of 0.1 and 5.4 micrograms/ml, which were comparable to therapeutic free plasma concentrations in patients. Aprindine significantly decreased the incidence of ventricular tachycardia and fibrillation, compared with control (2/10, p less than 0.01 and 1/10, p less than 0.05, respectively). Disopyramide depressed only the occurrence of ventricular tachycardia (3/10, p less than 0.05). Neither of the drugs induced changes in heart rate, left ventricular systolic pressure, coronary flow or PR intervals, but they significantly improved the recovery of the left ventricular systolic pressure within 15 min after reperfusion, at which time most of the hearts had restored sinus rhythm. It is concluded that, at clinically effective concentrations, aprindine and disopyramide inhibit reperfusion-induced arrhythmias without deteriorating cardiac function in the isolated rat heart.

Animals↗
PubMed1977

Effects of disopyramide and aprindine on arrhythmias after acute myocardial infarction.

The incidence of ventricular arrhythmias after myocardial infarction was compared in a double blind study of disopyramide (33 patients), aprindine (34 patients) and placebo (31 patients). Total ventricular arrhythmias were less frequent in the aprindine group than in the disopyramide group (P less than 0.05) or than in the combined disopyramide and placebo groups (P less than 0.05). The incidence of life-threatening arrhythmias and of ventricular arrhythmias in high risk patients was also reduced by aprindine compared to disopyramide (P less than 0.001) or placebo (P less than 0.001). It is concluded that aprindine is effective in reducing ventricular arrhythmias and that further investigations on its preventive use after the onset of myocardial infarction are justified.

Acute Disease↗
PubMed1986

Homogeneous substrate-labeled fluorescent immunoassay for disopyramide in human serum: semi- and fully automated procedures.

In this immunoassay for disopyramide in serum, to form the label, disopyramide is covalently attached to a fluorogenic enzyme substrate, 7-beta-galactosylcoumarin-3-carboxylic acid, which is nonfluorescent under the conditions of the assay. Hydrolysis, catalyzed by beta-galactosidase, yields a fluorescent product. As a result of competitive protein binding reactions between drug and label for limited antibody binding sites, this fluorescence is proportional to disopyramide concentration. The assay is sensitive to less than 0.5 mg of disopyramide per liter. Results obtained with either the semi-automated procedure (Ames TDA) or the fully automated (Optimate) procedure correlated well with those obtained by liquid chromatography (r = 0.98 and 0.99). For commercial controls containing various concentrations of the drug, the respective coefficients of correlation were 1.00 and 0.99 for the TDA and Optimate procedures. Within-run CVs for the two procedures were less than or equal to 5.1%, overall CVs less than or equal to 6.5%.

Antibody Specificity↗
PubMed1980

Disopyramide-induced ventricular tachycardia.

A patient with ischemic cardiomyopathy and congestive heart failure was treated with disopyramide phosphate for ventricular arrhythmias. The development of ventricular tachycardia was associated with elevated plasma disopyramide levels and prolongation of the QRS and QT intervals, suggesting a disopyramide-induced depression of ventricular conduction and a prolongation of recovery. Thus, in patients with congestive heart failure, as well as in patients with renal and/or hepatic dysfunction, special care must be exercised with respect to the use of disopyramide.

Alcoholism↗
PubMed1976

[Antiarrhythmic effect of disopyramide in ventricular extrasystole and auricular fibrillation].

Disopyramide (B 712) was tested in 39 patients with chronic arrhythmias of different kind: 23 cases with atrial fibrillation, 16 cases with ventricular ectopic beats, two cases with supraventricular tachycardias. The effect of disopyramide was compared to a pretreatment with one or several antiarrhythmic drugs (quinidine, beta-blocking agents, verapamil, ajmalin-bitartrat, aprindine, propafenone, diphenylhydantoin) which had been discontinued either due to ineffectiveness or the occurrence of intolerable side effects. Therapeutical effectiveness was controlled by on-line arrhythmia computers in the CCU or Holter monitoring. 15 patients were treated longer than 4 weeks up to 16 months (mean 35+/-22,6 weeks). The following results were achieved: 1 atrial fibrillation, abolition or significant reduction of the rate of recurrence in 10 out of 23 patients; slight reduction or no effect in 13 patients; 2. ventricular ectopic beats: abolition or significant reduction in 6 out of 16 patients, slight reduction or no effect in the remaining 10 patients. Patients who were treated successfully received the same dosis as those without therapeutical success. In cases with atrial fibrillation, the success was dependent on the duration of this arrhythmia prior to treatment. In comparison to the pretreatment with one or several of the above-mentioned anti-arrhythmic drugs, disopyramide was as effective as the drug given before. The analysis of the Ecg revealed a slight but insignificant prolongation of the time intervals. In 22 patients reversible dosage-dependent side effects were observed which are due to the vagolytic action of the drug: dry mouth, blurred vision, urinary hesitancy, nausea, headache. These side effects occurred at daily dosages between 400 to 800 mg increasing markedly in patients on 800 mg a day. The drug had to be discontinued in 4 cases because of side effects. During long-term treatment no severe side effects were observed. Thus, disopyramide may serve as an alternative to quinidine, especially if the latter has to be stopped because of side effects.

Adolescent↗
PubMedDate not supplied

Effect of disopyramide on left ventricular performance: the relationship of free and total concentrations of the drug and of its mono-N-dealkylated metabolite to noninvasive indices of function.

We used M-mode echocardiography and recordings of systolic time intervals to follow changes in left ventricular systolic function of 10 normal subjects during administration of 200 mg oral disopyramide every 8 h. Left ventricular function was significantly depressed (peak rate of change of dimension - 17%, p less than 0.001; mean velocity of circumferential fiber shortening - 15%, p less than 0.01; percent fractional shortening - 16%, p less than 0.05) for as long as 7 h after a dose. These changes could be correlated with those in plasma concentrations of free and total disopyramide, and of its mono-N-dealkylated metabolite (change in peak rate of change of dimension versus levels of disopyramide plus metabolite, r = -0.41, p less than 0.03; changes in ratio preejection time/ejection time versus levels of disopyramide and metabolite, r = 0.62, p less than 0.002).

Adult↗
PubMedDate not supplied

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide.

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.

Animals↗
PubMed1984

[Comparative study on the efficacy of disopyramide and propafenone in the prevention of the recurrence of ventricular tachycardia].

The purpose of our study was to assess the efficacy of Propafenon in comparison with Disopyramide in the long-term treatment of repetitive ventricular tachycardia. We studied 34 patients suffering from episodes of repetitive ventricular tachycardia of different etiology. Propafenon and Disopyramide was administered in doses of 300 mg and 200 mg three times a day respectively. The number of ventricular tachycardias has been evaluated during a period of 4 months of basal observation and during two periods of 4 months each of treatment respectively with Disopyramide and Propafenon. Moreover a dynamic electrocardiogram was recorded to assess the efficacy of Propafenon in suppressing ventricular ectopic beats in 17 patients. We conclude that Propafenon shows greater efficacy than Disopyramide in the treatment of repetitive ventricular tachycardias and a comparable efficacy in the control of ventricular ectopic beats. Moreover Propafenon shows also a minor incidence of side effects.

Anti-Arrhythmia Agents↗
PubMed1984

[Clinical application of immuno-precipitation inhibition technique for determination of disopyramide in human plasma].

Immuno-precipitation Inhibition Technique (IPIT) method of determining disopyramide levels in human plasma was reevaluated in respect to factors affecting assay procedure, specificity and recovery. With this method only 20 microliters of plasma is required to obtain a rapid, sensitive and specific determination. Due to little intra-assay and inter-assay variation, the IPIT method is suitable for clinical determinations for disopyramide. Furthermore pharmacokinetic parameters calculated from the disopyramide concentrations coincided with the reported data determined by other methods. It was demonstrated, however, that precise temperature control and sample mixture are essential for accurate plasma disopyramide determination using this method.

Disopyramide↗
PubMed1983

Effect of intra-individual change in serum protein binding on the pharmacologic response of R- and S-disopyramide in the rabbit.

The influence of altered serum protein binding on the pharmacologic response to R- and S-disopyramide was studied in the rabbit. Binding changes of disopyramide were achieved by the injection of human glycoprotein fraction VI. During constant infusion of R-disopyramide, the glycoprotein injection increased the total drug concentration in serum at steady state, while the unbound concentration was unaltered. The glycoprotein injection, however, decreased the unbound concentration and increased the total concentration during the steady-state infusion of S-disopyramide. In both experiments, the measured pharmacological response (delta QRS duration) reflected the change in the unbound drug concentration.

Animals↗
PubMed1981

Comparative antidysrhythmic profiles of bepridil, amiodarone and disopyramide in the guinea-pig and dog.

The antiarrhythmic effects of a novel antianginal agent, bepridil, were compared with four reference products. Bepridil increased the effective refractory period in isolated guinea-pig atria slightly more than hydroquinidine, and much more than disopyramide and lidocaine. Amiodarone was without effect. The doses of bepridil necessary for correcting atrial fibrillation induced by local application of aconitine, were similar for hydroquinidine, higher than for lidocaine and disopyramide but lower than for amiodarone. Bepridil depressed the tachycardia and ventricular fibrillation induced by perfusing aconitine in anesthetized guinea-pigs at doses of the same order of magnitude as for disopyramide and hydroquinidine. Lidocaine only exerted weak activity in this system, while amiodarone was without effect. Bepridil was less active than the four reference products, particularly disopyramide, on rhythm disorders induced by coronary artery ligation.

Aconitine↗
PubMed1982

Inhibition of platelet function of antiarrhythmic drugs, verapamil and disopyramide.

Various cardiovascular drugs such as nitrates and propranolol, used in the treatment of coronary artery disease have been shown to have an antiplatelet effect. We have studied the in vitro effects of two antiarrhythmic drugs, verapamil and disopyramide, and have shown their inhibitory effect on platelet function. Verapamil, a calcium channel blocker, inhibited the second phase of platelet aggregation induced by adenosine diphosphate (*ADP) and inhibited aggregation induced by collagen. Disopyramide similarly inhibited the second phase of platelet aggregation caused by ADP and aggregation induced by collagen. Either drug in synergism with propranolol inhibited ADP or collagen-induced platelet aggregation. Disopyramide at high concentrations inhibited arachidonic acid whereas verapamil was without effect. Verapamil, but not disopyramide, inhibited aggregated induced by the ionophore A23187.

Adenosine Triphosphate↗
PubMed1982

Effect of altered disopyramide binding on its pharmacologic response in rabbits.

This study was undertaken to determine whether pharmacologic response to disopyramide is related to unbound or to total plasma concentration. Pharmacologic response, measured as changes in QRS duration of the EKG, was determined in rabbits at various steady-state concentrations of disopyramide under normal and altered plasma protein binding conditions. Plasma protein binding was increased by injection of 40 mg/kg of human glycoprotein fraction VI. The concentration-response curve for total concentration was displaced toward higher concentrations after increasing the plasma protein binding of disopyramide. The concentration-response curves obtained for unbound drug with and without the increased binding were superimposable. The displacement of the concentration-response curve for total drug was identical to the increase in concentration of the bound drug in plasma. These results demonstrate that the unbound concentrations of disopyramide in plasma are a better measure of the pharmacologic response than is the total plasma concentration.

Animals↗