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PubMed1979

Disopyramide determination by gas chromatography, liquid chromatography, and gas chromatography--mass spectrometry.

Disopyramide is determined in serum by gas chromatography with a nitrogen-selective detector, by liquid chromatography, and by gas chromatography--mass spectrometry. Comparable results are obtained with the three techniques, with a within-run and between-run precision of 5 to 10% (coefficient of variation). Least-squares analysis of data on patients' sera, analyzed first by gas chromatography (y) and then liquid chromatography (x), gave a slope of 1.12; y-intercept, -0.31; standard error of estimate, 0.46; and correlation coefficient, 0.94. Comparison of patients' sera by gas chromatography (y) and then by gas chromatography--mass spectrometry (x) gave a slope of 0.94; y-intercept, 0.42; standard error of estimate, 0.38; and correlation coefficient, 0.97. Interferences observed when using one technique--for example, gas chromatography--can be eliminated by analyzing the sample extract with one of the other techniques.

Chromatography, Gas↗
PubMedDate not supplied

Stereoselectivity in the metabolism of disopyramide enantiomers in rat and dog.

The metabolism and pharmacokinetics of (S)-(+)- and (R)-(-)-disopyramide (DP) were compared in laboratory animals. In rats, after oral administration of (S)-(+)-DP phosphate salt at a dose of 38.8 mg of DP free base per kg, the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.43 micrograms/ml and 4.47 micrograms . hr/ml, respectively, and after (R)-(-)-DP administration, the values were 4.93 micrograms/ml and 17.05 micrograms . hr/ml, respectively. Similar recoveries (approximately 55% of the dose) of DP and its metabolites in the urine and bile of rats were obtained after administration of the individual (S)-(+)- and (R)-(-)-enantiomers of DP. These results indicate similar oral absorption of the two enantiomers, but greater metabolism with (S)-(+)-DP in rats. In dogs, the AUC of DP after iv administration of (R)-(-)-DP phosphate salt at a dose of 15 mg of DP free base per kg was 1.6 times greater than that after (S)-(+)-DP phosphate salt. Inasmuch as volumes of distribution of the two enantiomers were similar, this difference can be attributed to a difference in the elimination rates of the enantiomers. After an oral dose, the difference in AUC of the two enantiomers was greater than that after an iv dose. The mean values of Cmax and AUC after a 15-mg/kg oral dose of (S)-(+)-DP were 1.32 micrograms/ml and 4.07 micrograms . hr/ml, respectively, and with (R)-(-)-DP the values were 2.88 micrograms/ml and 9.21 micrograms . hr/ml, respectively. The Cmax and AUC of the total drug-related materials (drug plus its metabolites) were similar. These results, together with the similarity in the urinary excretion of total drug related compounds, indicated that after equivalent doses of the two enantiomers, oral absorptions were similar, but the first-pass metabolism was greater with (S)-(+)-DP. The present study also demonstrated that N-dealkylation in dogs and arylhydroxylation in rats are stereoselective metabolic pathways, thus illustrating species differences in the stereoselective metabolism of DP.

Administration, Oral↗
PubMed1981

[Dynamic electrocardiography evaluation of the effectiveness of prajmalium bitartrate, disopyramide and procainamide in patients with stabilized ventricular extrasystole].

20 patients with chronic premature ventricular contractions (P.V.Cs) underwent several Holter ECG monitorings to assess clinical effectiveness of three antiarrhythmic drugs: Prajmalium Bitartrate (P.B.) 80 mg/daily, Disopyramide (D.) 600 mg/daily and Procainamide (P.) 2400 mg/daily, to assess the most effective antiarrhythmic medication in every patient. Clinical effectiveness was considered as 80% reduction of P.V.Cs or 50% reduction with suppression of all complex ventricular ectopy (repetitive, polymorph, bigeminy). These results were observed respectively, for 80% reduction, in 5/20 patients for P.B., in 9/20 for D., and in 3/19 for P; and for 50% reduction in 11/20 for P.B., in 18/20 for D., and in 9/19 for P. Comparison in the same patient, using Holter ECG monitoring with a computer assisted analysis, of the effects of different antiarrhythmic medications, is a rational procedure to assess clinical efficacy of new antiarrhythmic drugs and to choose the most effective in each case.

Adolescent↗
PubMedDate not supplied

Pharmacokinetic-hemodynamic studies of disopyramide.

The hemodynamic effects and pharmacokinetics of two doses of disopyramide (DP) given as a two-stage intravenous load and maintenance infusion were studied in anesthetized dogs. One group (n = 4) received 4 mg/kg for 30 min and 1 mg/kg/h for 30 min (low-dose group). The high-dose group (n = 4) received 8 mg/kg for 30 min and 4 mg/kg/h for 30 min. In the low-dose group, there was a fall in cardiac output which reached statistical significance at 300 min [from 3.4 +/- 0.4 (SD) to 2.7 +/- 0.7 L/min; p less than 0.05, analysis of variance (ANOVA)]. In the high-dose group, there also was a fall in cardiac output (from 4.6 +/- 1.4 to 3.0 +/- 0.4 L/min; p less than 0.01, ANOVA), and this was associated with a rise in total peripheral resistance (from 39 +/- 11 to 58 +/- 9 units; p less than 0.01). Peak total venous DP concentrations were 3.0 +/- 0.2 and 7.5 +/- 1.0 micrograms/ml for the low- and high-dose groups, respectively, and were achieved at the end of the load infusion. The free fraction of DP was not dependent on total venous DP concentration and approximated 0.66. Elimination half-life, clearance, and apparent volume of distribution were 3.91 +/- 0.53 h, 0.39 +/- 0.02 L/kg/h, and 2.22 +/- 0.32 L/kg, respectively, for the low-dose group and 3.67 +/- 0.91 h, 0.36 +/- 0.06 L/kg/h, and 1.84 +/- 0.29 L/kg, respectively, for the high-dose group. There were no significant differences between these measurements for low- versus high-dose groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The use of intravenous disopyramide for the conversion of supraventricular tachyarrhythmias.

A study of the efficacy of intravenous disopyramide in the conversion of supraventricular tachyarrhythmias to sinus rhythm was undertaken in a group of 23 patients with a variety of cardiological diagnoses. An intravenous bolus (2 mg/kg) followed, where appropriate, by an infusion (0.4 mg/kg) resulted in an overall conversion rate of 63% (43% in atrial fibrillation, 50% in atrial flutter, 89% in atrial tachycardias). Serious cardiotoxic side effects occurred in 15%. The study shows that such a regime is useful in a selected group of patients provided certain precautions are observed.

Adolescent↗
PubMed1983

[Comparative studies on the cardiodepressant effect of disopyramide, mexiletine and propafenon].

The effect of clinical antiarrhythmic doses of disopyramide (Di), mexiletine (Me), and propafenon (Pr) on cardiac function was studied in 7 normal volunteers by M-mode echocardiography and the extent of functional changes caused by the three drugs was compared. For each of the substances echocardiographic parameters of left ventricular function were determined before injection, 5-25 min. after an intravenous administration (Di 2.0 mg/kg, Me 3.0 mg/kg, Pr 1.5 mg/kg) at intervals of 5 min., and after 3 days of oral therapy (Di 4 X 200 mg/day, Me 4 X 200 mg/day, Pr 3 X 300 mg/day). Di, Me, and Pr each showed significant negative inotropic activity, though of varying degree. For each drug the effect was more pronounced after intravenous administration than under oral therapy. Maximum decreases in myocardial contraction occurred 5-15 min. after termination of injection, with an increase in endsystolic diameter (Di 30.3%, Me 13.6%, Pr 9.7%), no change in preejection diameter, and a reduction in the percentage and velocity of mean circumferential fiber shortening and systolic ventricular wall thickness (Di 18.1%-45.1%, Me 9.6%-23.7%, Pr 11.8%-16.7%). While the cardiodepressant activity of orally administered Di, Me and Pr did not statistically differ, for the first 20 min. after intravenous administration Di exhibited a marked negative inotropic effect that was significantly greater than those of Me and Pr. In view of the considerable hemodynamic side effects of Di, Me, and Pr observed in this study, the benefit to risk ratio must be evaluated carefully and individually before commencement of antiarrhythmic therapy. Because of its acute and pronounced cardiodepressant activity, intravenous Di should be used with particular caution; a dose reduction and slow injection are recommended in patients with left ventricular dysfunction.

Adult↗
PubMed1980

Simultaneous liquid-chromatographic determination of three antiarrhythmic drugs: disopyramide, lidocaine, and quinidine.

We report a common methodology for determining three antiarrhythmic drugs: disopyramide, lidocaine, and quinidine. Alkalinized serum and internal standard (p-chlorodisopyramide) are extracted into dichloromethane, the organic phase is evaporated, and the redissolved residue is injected onto a reversed-phase column (micron Bondapack C18). Quantitation is via peak-height ratios of analyte vs internal standard (as detected at 205 nm) referenced to a serum-based multiple-drug standard. A mobile phase of 30 mmol/L phosphate buffer and acetonitrile (72/28 by vol) is used. These conditions yiel; optimum separation and band symmetry for the analytes and some of their metabolites. Crucial factors in this simultaneous assay include pH of the mobile phase and injected solution, extraction time, and evaporation technique. Day-to-day precision (CV) for all drugs was less than 5%, and correlation with other assay techniques for each drug is reported. The method enables more efficient use of personnel and instrumentation without sacrificing analytical quality.

Chromatography, High Pressure Liquid↗
PubMed1981

[Disopyramide poisoning].

Acute intoxications with the antiarrhythmic drug disopyramide (Norpace) are often life-threatening. After an almost asymptomatic interval of 1 to 4 hours, cardiogenic shock of sudden onset occurs. The usual methods of cardiac resuscitation such as adrenaline and antiarrhythmic drugs should not be used, and transvenous pacemakers often prove ineffective. To lower the high rate of mortality, early appropriate monitoring and facilities for rapid intervention are necessary. Isoprenaline is the most suitable positive inotropic and chronotropic drug. Hemoperfusion with Amberlite XAD 14 is effective but not always needed.

Acid-Base Equilibrium↗
PubMed1982

[The effect of disopyramide, mexiletine and propafenon after intravenous and oral administration on left ventricular function in the M-mode echocardiogram].

The effects of the antiarrhythmic drugs disopyramide (D), mexiletine (M), and propafenone (P) on left ventricular function after intravenous injection and after oral therapy of at least 48 hours, and of the combined oral application of D and M, were studied by M-mode echocardiography in patients with ventricular arrhythmias in whom antiarrhythmic therapy was indicated. The drugs were given in doses comparable in terms of clinical efficacy. The results showed that the three drugs had varying negative inotropic power. The intravenous injection resulted in a more pronounced cardiac depression than the oral therapy. The most significant decrease in left ventricular wall motion after intravenous and oral application was seen after D, the smallest negative inotropic effect after M. P caused a cardiac depression between these extremes. After the combined oral application of D and M the impairment of left ventricular function was more pronounced than after therapy with the single drugs.

Administration, Oral↗
PubMed1982

[Intravenously disopyramide phosphate administration for treatment of arrhythmias].

Disopyramide phosphate (DF) was administered intravenously to 50 patients during 55 episodes of arrhythmias. The mean dosage employed was 2 +/- 1.4 mg/kg over a period of 3 minutes to 60 minutes (mean 16 +/- 6'), followed by an infusion at a dose of 0.4 mg/kg/hr in 9 cases. Atrial premature beats were suppressed in 3 of 4 treated cases (75%). Conversion to sinus rhythm was achieved in 4 of 5 (80%) cases of paroxysmal supraventricular tachycardia, unresponsive to vagal maneuvers in 7 of 10 cases (70%) of atrial flutter of recent onset (less than 48 hours) and in 13 of 17 (76%) cases of atrial fibrillation (less than one week in duration). In 9 of 11 cases (81%) with frequent, multiform, repetitive ventricular premature beats and in 7 of 8 cases (87%) of ventricular tachycardia, DF completely suppressed the arrhythmia. The drug increased sinus rate, PR and QRS intervals, but the difference was not statistically significant: the QRS of patients with complete bundle branch block and the QTc interval were significantly prolonged. Severe hypotension was observed in 10 patients after DF i.v., in 5 of whom withdrawal of therapy was deemed to be necessary. Nine other patients had anticholinergic side effects. Our study shows that DF administered i.v. can be used successfully in 75% of supraventricular arrhythmias and in 82% of ventricular arrhythmias.

Adult↗
PubMed1981

[Quantitative evaluation of an antiarrhythmic therapy (disopyramide) in patients with frequent premature ventricular contractions (PVC) using a computer-assisted long-term ECG analysis system (author's transl)].

15 patients (pts.) - 12 males, 3 females - with frequent PVC (greater than 3%/16 hr during a qualifying period = LP) of different causes underwent after one-day placebo application (PL) drug treatment (disopyramide: loading dose 600 mg, 300 mg t.i.d.) over two days (D1, D2). The ambulatory continuously recorded long-term ECG was analysed using "Multipass-Scanning", a computer-supported analysis system for quantification of therapeutic success. The mean PVC rate of 17% prior treatment could be diminished in 87% of the pts. significantly. 5 pts. (group I) demonstrated a maximal PVC-reduction rate of more than 90 rel %. Among them in 2 pts. the PVC-rate did not exceed the 1%-level during D1 and D2 demonstrating an optimal therapeutic success. The max. PVC-reduction rate ranged between 80 and 90 rel % in 3 pts. (group II) and between 38 and 78 rel % in 5 pts. (group III). 2 pts. did not respond on DP. The mean DP-plasma level was higher in group-III pts. than in group-I or -II pts. in spite of a less therapeutic success. 7 pts. demonstrated a circadian behaviour of PVCs. Therefore the circadian variability increased. Also lower PVC rates under DP (D1, D2) led to an increase of spontaneous variability of PVCs. The maximal PVC depressant effect of DP appeared while the heart rate was 70 b.p.m. or higher. In conclusion, 87% of the pts. demonstrated a drug effect, but an effective antiarrhythmic therapy occurred only in 2 pts. (13%). A decrease of the frequency of rhythm disturbances led to a decrease of arrhythmia's variability and requires a prolongation of the ECG-recording time to eliminate the variabilities of arrhythmia occurred (spontaneous, circadian) and to avoid a mimicked therapeutic success.

Adolescent↗
PubMed1981

[Acute voluntary or accidental disopyramide poisoning. A multicentric study of 106 cases (author's transl)].

Between 1972 and 1978, 106 case-records of disopyramide poisoning were collected from French anti-poison center. Acute intoxication was voluntary in 90% of the cases and occurred in young adults. Clinical symptoms appeared early and consisted mostly of cardiovascular disorders, which were present in 60 patients: cardiogenic shock (24 cases), circulatory arrest (17 cases), atrio-ventricular block (21 cases), intraventricular block (24 cases) and severe ventricular arrhythmia (12 cases). The toxic dose in otherwise healthy adults was 1,5 g and the mortality rate was high (12,2%). An analysis of therapeutic measures and outcome indicated that the best treatment consists of early gastric lavage, cardiorespiratory manoeuvres, electric heart stimulation, administration of sodium lactate in cases with intraventricular conduction disturbances and isoprenaline in cases with cardiogenic shock.

Acute Disease↗
PubMed1980

Disopyramide (Norpace) distribution at autopsy of an overdose case.

A 44-year-old female died as the result of an overdose of disopyramide. An analytical method was developed and the distribution of the drug in various tissues was determined. Analysis of the blood sample indicated a drug concentration far exceeding that of the therapeutic concentration.

Adult↗
PubMed1980

Clinical evaluation of antiarrhythmic effects of disopyramide by multiclinical controlled double-blind methods.

Used orally, in double-blind cross-over controlled trials conducted on 73 patients, disopyramide, a newly developed antiarrhythmic agent, was found to be more effective than an inert placebo (lactose), with a statistically significant difference, and to be as effective as quinidine sulfate in suppressing ventricular and supraventricular premature beats. In double-blind studies with 42 patients, it was also found to be as effective as quinidine sulfate in preventing the recurrence of atrial fibrillation after successful cardioversion. In non-blind studies attacks of paroxysmal supraventricular and ventricular tachycardia and transient atrial fibrillation were effectively prevented in the respective arrhythmias in more than 70% of the cases.

Arrhythmias, Cardiac↗
PubMed1978

Clinical and electrophysiological observations with disopyramide in drug-resistant and recurrent symptomatic arrhythmias.

Seventeen patients with recurrent symptomatic arrhythmias were treated with oral disopyramide (DP). Fifteen of the 17 patients had received other currently conventional anti-arrhythmic therapy, to which only 1 patient responded, yet 13 of these 15 patients with resistant arrhythmias responded to DP. Electrophysiological studies were performed on 9 patients. The most impressive electrophysiological findings were the depressant effect of DP on ventricular automaticity and its action in slowing conduction through the His-Purkinje system (including the bundle branches) without depressing sino-atrial rate and atrioventricular (AV) nodal conduction time. Retrograde ventriculo-atrial (VA) conduction was markedly prolonged in 4 patients with reciprocating supraventricular tachycardia (SVT), including 2 patients with Wolff-Parkinson-White syndrome. All 4 patients with reciprocating SVT appear to be cured of their arrhythmia, probably by this mechanism.

Adult↗
PubMed1977

[Oral longterm therapy with disopyramide phosphate in patients with atrial and ventricular arrhythmias (author's transl)].

The antiarrhythmic effect of longterm therapy with disopyramide phosphate (DP) was investigated in a single controlled trial in 34 patients. Of 11 patients with atrial fibrillation, 5 were successfully cardioverted to sinus rhythm with DP in the long run. In the treatment of extrasystole, the arrhythmia was eliminated or reduced by 75% in 15 of 23 patients. In 6 cases a moderate improvement was achieved and there was no change in 2. The average daily dose initially was 4.2 capsules, the maximum dose was 5.4, and for longterm therapy 4.3 capsules. With respect to its indications, DP is largely similar to quinidine, but in our experience it is characterized by better tolerance.

Adolescent↗
PubMed1979

Gas-chromatographic determination of disopyramide in serum, with use of a nitrogen-selective detector.

In this procedure for disopyramide in serum, the drug is extracted into n-heptane/isobutanol (96/4 by vol), then back-extracted into 1 mol/L H2SO4. The acidic solution is made basic with sodium hydroxide, extracted with diethyl ether, and the extract evaporated. The residue is redissolved in ethanol and analyzed by gas-chromatography, with use of a nitrogen-selective detector. p-Chlorodisopyramide is used as internal standard. Concentration and instrument response for serum extracts are linearly related from 1 to 5 mg/L, the slope being 0.61, the y-intercept -0.10, the standard error of estimate 0.01, and the correlation coefficient 0.99. Within-run precision was 6 and 4% for 3 and 5 mg/L concentrations, respectively, with a between-run precision of 7% at the 3 mg/L concentration. Diazepam interferes, but procainamide, chlordiazepoxide, quinidine, lidocaine, propranolol, sulfanilamide, and many other basic drugs do not.

Chromatography, Gas↗
PubMed1994

Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by human and mouse liver microsomes.

The interspecies differences in the enantioselective metabolism of disopyramide (DP) were studied with human and mouse liver microsomes. Mono-N-dealkylation of both DP enantiomers was biphasic, suggesting an involvement of two enzymes in the metabolism in both species. The human data indicated that the metabolism of both DP enantiomers at the therapeutic concentrations (i.e., 5-14 microM) was mediated by the high-affinity components. The mean (+/- S.D.) affinity constant (Km) of the high-affinity component for S-(+)-DP (4.86 +/- 2.66 microM) was significantly (P < .05) lower than that for R-(-)-DP (24.61 +/- 17.52 microM), whereas no difference was observed between the maximum velocities (Vmax) for S-(+)- and R-(-)-DP. The mean intrinsic clearance (CL(int)), defined as Vmax/Km, of the high-affinity component for S-(+)-DP was significantly greater (P < .01) than that for R-(-)-DP, consistent with the reported in vivo pharmacokinetic data. In contrast, the CL(int) of the low-affinity component for R-(-)-DP was significantly (P < .01) greater than that for S-(+)-DP. Coincubation of DP enantiomers as a racemate showed mutual competitive inhibition. With mouse liver microsomes, a preferential metabolism of S-(+)-DP over R-(-)-DP was also observed only for the high-affinity components. Although the mean Vmax for the high-affinity component of mouse microsomes was about 6- to 8-fold greater than that of human's, the differences in Km were at most 2.5-fold. In addition, metabolic competition between the enantiomers also occurred with mouse microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗