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PubMed1987

Antiarrhythmic efficacy of penticainide and comparison with disopyramide, flecainide, propafenone and mexiletine by acute oral drug testing.

The antiarrhythmic efficacy of a new class I agent, penticainide, was evaluated by acute oral drug testing and compared in the same patient population with the efficacy of disopyramide, flecainide, mexiletine and propafenone. Twenty-five patients with high-grade chronic ventricular arrhythmias entered the study. During acute oral drug testing, penticainide (7 mg/kg) was effective (more than 90% reduction in ventricular premature complexes and complete abolition of class 4A and 4B arrhythmias) in 17 of 25 subjects (68%). The mean plasma level of the drug at 90 minutes was 4.4 +/- 1.9 micrograms/ml; at the same time increases in the PQ interval (from 168 +/- 27 to 189 +/- 31 ms, p less than 0.0001) and QRS duration (from 89 +/- 14 to 96 +/- 18 ms, p less than 0.001) were observed. The QTc was slightly but not significantly shortened in the overall population; however, in the subgroup with a basally prolonged QTc (n = 8), a significant reduction was observed (from 456 +/- 8 to 440 +/- 18 ms, p less than 0.02). No adverse effects were reported. The antiarrhythmic efficacy of the other drugs tested in the same population was: disopyramide, 12 of 19 (63%); flecainide, 13 of 24 (54%); propafenone, 13 of 24 (54%); and mexiletine, 7 of 20 (35%). Penticainide appears to be a well-tolerated and effective compound of potential value for treatment of ventricular arrhythmias.

Administration, Oral↗
PubMed1989

Effects of disopyramide on cycle length, effective refractory period and excitable gap of atrial flutter, and relation to arrhythmia termination by overdrive pacing.

The administration of class IA antiarrhythmic drugs facilities termination of atrial flutter by overdrive pacing. To investigate the electrophysiologic determinants of this effect, changes in the cycle length, the effective refractory period and the excitable gap of spontaneous type I atrial flutter were studied in 11 patients given intravenous disopyramide (3 mg/kg in 1 hour). After drug infusion, the cycle length of atrial flutter increased from 238 +/- 26 to 298 +/- 38 ms (+25%; p less than 0.001) and the effective refractory period prolonged from 169 +/- 19 to 192 +/- 25 ms (+14%; p less than 0.01). The excitable gap prolonged from 62 +/- 16 to 96 +/- 27 ms (+55%; p less than 0.001). Atrial flutter was terminated by overdrive pacing (mean cycle 203) in 10 of 11 patients; in 1 patient atrial fibrillation resulted after high rate stimulation. In the setting of an anatomically defined reentry circuit, as in type I atrial flutter, the administration of disopyramide prolongs both cycle length and refractory period. The finding of an increased excitable gap suggests that the drug exerts its prominent effect by depressing conduction velocity. A wider excitable gap allows easier penetration of the stimulus in the reentry circuit and accounts for the beneficial effects of type IA antiarrhythmic drugs on the termination of atrial flutter by overdrive pacing.

Aged↗
PubMed1976

Dehydrobenzperidol and disopyramide in A-V conduction.

The effects on A-V conduction of dehydrobenzperidol (Droperidol) 0.35 and 1.0 mg/kg i.v.) and disopyramide (1, 5 and 10 mg/kg i.v.) were tested in anesthetized, open chest and paced dogs. His's bundle electrograms were recorded by means of a catheter electrode or by a sutured electrode-bearing plaque in the A-V nodal region. Droperidol at the lower dose did not modify conduction time, while 1.0 mg/kg (3 times the usual clinical dose), prolonged atrial-His conduction without modifying H-V interval. Disopyramide 1 mg/kg caused a non-significant decrease in atrial-His concuction time, while in doses of 5 and 10 mg/kg it prolonged both conduction times (S-H and H-V), due to a predominant direct depressant effect, which is opposite to the atropinic actions of the drug.

Animals↗
PubMed1989

The influence of acidosis on the myocardial uptake and electrocardiographic effects of disopyramide.

The time course for the ECG effects and myocardial uptake of disopyramide was studied in isolated perfused guinea pig hearts under different pH conditions. At pH 7.46 the drug depressed the overall AV conduction time (PR) by 16.64%, the His-ventriculum conduction time (HV interval) by 30.46% and delayed the ventricular repolarization (QT interval) by 8.08%, on average. The maximum intraventricular pressure (Pmax) was also depressed by 35.6%. The maximum effect on the QT interval (constant rate: 0.609 min-1) was reached faster than the maximum effect on the PR and HV intervals (constant rates: 0.399 and 0.400 min-1, respectively), while the myocardium uptake process was complete before any ECG parameter reached a steady state (uptake constant: 1.58 min-1). Under conditions of extracellular acidosis (pH 6.92), the disopyramide disposition parameters (uptake rate constant and myocardial concentration) were not modified. However, the drug exerted significantly smaller effects on the HV and QT intervals and on myocardial contractility. These results are in contrast with those obtained previously with lidocaine and quinidine, and indicate that the influence of acidosis on class 1 antiarrhythmic agents may also depend on the characteristics of the individual drug.

Acidosis↗
PubMed1985

Effect of low oral doses of disopyramide and amiodarone on ventricular and atrial arrhythmias of chagasic patients with advanced myocardial damage.

Low-dose (7 mg/kg per day) disopyramide administration to arrhythmic chagasic patients decreased the frequency of ventricular extrasystoles in 4 of 17 patients (24%) and suppressed most complex ventricular arrhythmias in 12 of 15 patients (80%). This assessment was made from 72-h continuous Holter monitoring recorded during the course of this double blind, placebo-controlled randomized crossover study. Seven patients (41%) complained of anticholinergic side effects, but no contractile or conduction system depression was seen. Amiodarone (200 mg) given on a single blind, placebo-controlled basis to 9 of these patients reduced the frequency of ventricular extrasystoles in 6 of 9 patients (67%) and suppressed complex ventricular ectopy in 6 of 7 patients (85%). One patient was unable to tolerate this drug (11%). Both drugs seemed less effective in controlling supraventricular arrhythmias, although disopyramide eliminated paroxysms of supraventricular tachycardia in 9 of 13 (69%) and amiodarone in all 6 patients with this arrhythmia. Amiodarone appears to be a better antiarrhythmic drug for chagasic patients, due to its greater effectiveness and lower incidence of side effects.

Administration, Oral↗
PubMed1992

Automated determination of disopyramide and N-monodealkyldisopyramide in plasma by reversed-phase liquid chromatography with a column switching system.

A rapid and simple column liquid chromatographic method involving a column switching system for the determination of disopyramide and its N-monodealkyl metabolite (NMD) in plasma is described. The deproteinized plasma is applied to an automated system. Purification and concentration were performed using a precolumn connected to a six-position valve; analytical separation was done on-line using a cyano reversed-phase column with a mobile phase consisting of 10 mmol/l trimethylamine (pH 2.5, adjusted with phosphoric acid)-acetonitrile-tetrahydrofuran (78:20:2, v/v/v). Absorbance was measured at 265 nm, with a minimum detectable amount of disopyramide and NMD of 0.1 micrograms/ml. The method can be applied to drug monitoring and pharmacokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed2000

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide.

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose-response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio-adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1, 3-dimethyl-6-2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]eth ylamino-2,4 (1H,3H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[N-(3, 4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (KCB-328) and E-1-[(5-(4-chlorophenyl)-2-furanyl)methylene]amino-3-[4-(4-methyl-1 -piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.

Animals↗
PubMed1978

Gas-liquid chromatographic method for the routine estimation of disopyramide in plasma or serum.

A rapid, sensitive and specific gas-liquid chromatographic method is presented for the routine monitoring of plasma concentrations of the anti-arrhythmic compound, disopyramide. The procedure involves extraction of the drug from alkaline plasma into ether, purification of the extract and gas chromatographic analysis using OV-101 liquid phase and flame ionization detection. The results demonstrate the accuracy and reproducibility of the method. Contrary to a previous report, it has been shown that delay in separating plasma from erythrocytes does not affect the disopyramide level in plasma.

Chromatography, Gas↗
PubMed1975

Determination of disopyramide and its mono-N-dealkylated metabolite in blood serum and urine.

A rapid, precise and accurate assay for disopyramide and mono-N-dealkylated disopyramide concentrations in blood serum and urine is described. The method involves extraction of the drugs from a basic aqueous medium into chloroform, derivatization of the metabolite, purification of the extract and gas chromatographic analysis using an OV-17 liquid phase and flame ionization detection. Unique characteristics of the procedure, direct derivatization in the organic phase and the use of Florisil to separate the drugs from interfering materials, should be applicable to the analysis of other basic drugs in biological specimens.

Acetates↗
PubMed1985

Blockage of the sodium current in isolated single cells from rat ventricle with mexiletine and disopyramide.

The blocking effects of local anesthetics, mexiletine and disopyramide on the sodium currents (INa) of enzymatically isolated, single cells from rat ventricle were studied under voltage clamp conditions. A suction pipette technique was used for voltage clamp and internal perfusion. Potassium currents were blocked by replacing K+ with Cs+ in the internal and external solutions; calcium currents were blocked by replacing Ca2+ with Co2+ in the external solution to isolate INa. When the cells were stimulated infrequently (less than 1 Hz), both drugs produced dose-dependent depression of INa, which was correlated with one-to-one binding to sodium channel. A half-blocking concentration (KD) of 2.8 X 10(-5) M was observed for both agents. The shape of the current-voltage curve along the voltage axis remained unchanged in the presence of either drug. Both drugs shifted the inactivation curve of INa to more negative potentials. Mexiletine produced a marked use-dependent blockage of INa, whereas disopyramide did not produce significant use-dependent block under similar experimental conditions. Both drugs prolonged the recovery of INa from inactivation. The results suggested that both drugs interact with the inactivation mechanism of the sodium channels of rat myocardial cells.

Action Potentials↗
PubMed1980

Intravenous and oral disopyramide after myocardial infarction.

Patients with acute myocardial infarction admitted to a coronary care unit were given either intravenous and oral disopyramide or matching placebo on admission and throughout their hospital stay. 199 patients entered the trial, and 138 were subsequently shown to have had a myocardial infarct. The placebo and study groups were well matched. There were no significant differences in mortality or observed arrhythmias between the two groups. These results do not confirm earlier observations that prophylaxis with disopyramide reduces mortality after acute myocardial infarction.

Acute Disease↗
PubMed1980

Simultaneous analysis of disopyramide and quinidine in plasma by high-performance liquid chromatography.

A new reversed-phase high-performance liquid chromatographic method allowing simultaneous measurement of plasma concentrations of disopyramide and quinidine is described. Disopyramide and quinidine were separated on a reversed-phase column using 0.05 M phosphate buffer (pH 3.0)--acetonitrile (73:27, v/v), as mobile phase and the peaks were monitored by UV absorbance at the wavelengths of 254 and 325 nm. The drugs were extracted from alkaline plasma with chloroform containing the internal standard. The organic phase was evaporated to dryness and the residue was redissolved in a small volume of the mobile phase before analysis by high-performance liquid chromatography. The method is convenient and reliable in routine monitoring of both drugs.

Chromatography, High Pressure Liquid↗
PubMed1983

Simultaneous determination of disopyramide and its mono-N-dealkyl metabolite in plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure is described for the determination of disopyramide and its mono-N-dealkyl metabolite which offers simplicity of extraction with excellent selectivity, sensitivity and reproducibility. The drug and metabolite, following basic diethyl ether extraction and back-extraction with acetic acid, are injected into a reversed-phase high-performance liquid chromatographic column and the absorbance of the eluate measured at 254 nm. Detectability limits of 0.05 micrograms/ml were obtained with both compounds, and studies of the reproducibility, precision, recovery, stability during storage and effect of time in separating plasma from erythrocytes are described. Applications of this high-performance liquid chromatographic procedure to plasma samples from patients on disopyramide therapy and to plasma and urine from a healthy dog administered single doses are reported.

Animals↗
PubMed1997

Electrophysiologic effects of sodium channel blockade on anisotropic conduction and conduction block in canine myocardium: preferential slowing of longitudinal conduction by flecainide versus disopyramide or lidocaine.

OBJECTIVES: The purpose of this study was to determine the effects of sodium channel blockade on anisotropic excitation propagation in the intact canine left ventricle. BACKGROUND: Anisotropic ventricular conduction- electric conductivity dependent on the myocardial fiber direction-is one of the important mechanisms of ventricular arrhythmia. However, the effects of sodium channel blockade, especially the differential effect of a subclass of this agent, on the anisotropic properties remain unknown. METHODS: In 28 anesthetized, open chest dogs, a small cannula was inserted into the left anterior descending coronary artery. Saline (control), disopyramide, lidocaine or flecainide was infused selectively into the cannula. An array of 64 epicardial electrodes was placed on the anterior surface of the ventricle. Activation time (AT) was measured along the longitudinal (L) and transverse (T) directions. RESULTS: High dose flecainide (100 microg/kg body weight per min) delayed the AT along the L direction markedly (mean [+/-SE] 227 +/- 38%, p < 0.02) and mildly (121 +/- 10%, p < 0.02) along the T direction in regular beats (p < 0.007, L vs. T). Lidocaine and disopyramide did not show direction-dependent prolongation of the AT on regular beats. When examined on premature beats, AT was delayed, depending on the coupling interval and the fiber direction when saline, flecainide or lidocaine was infused. The conduction blocks along the L direction were observed in three of seven dogs on regular beats after flecainide and ventricular fibrillation ensued in two of these three dogs. CONCLUSIONS: A peculiar slowing of L conduction by flecainide may relate to the character of proarrhythmia.

Animals↗
PubMed1981

Synthesis and anticholinergic properties of the enantiomers of 4-(isopropylamino)-2-(2-pyridyl)-2-phenylbutyramide, the mono-N-dealkylated metabolite of disopyramide.

The 2R and 2S enantiomers of 4-isopropyl-2-(2-pyridyl)-2-phenylbutyramide [(2R)-2 and (2S)-2] were prepared from the respective 2R and 2S enantiomers of disopyramide [(2R)-1 and (2S)-1] by oxidation with peracid, Cope elimination, and subsequent zinc/HCl reduction of the resulting hydroxylamines (2R)-3 and (2S)-3. The enantiomers were tested as antagonists to the contraction of guinea pig ileum longitudinal muscle produced in response to electrically stimulated release of acetylcholine. The enantiomers showed IC50 values of 5.0 X 10(-6) and 14 X 10(-6) M for (2S)-2 and (2R)-2 respectively, about a 3-fold difference between enantiomers. Data are presented showing direct antagonism of acetylcholine in the guinea pig ileum assay. In a comparison of the anticholinergic effects of 2 and 1, the metabolite (2) was slightly less potent than disopyramide (1).

Acetylcholine↗
PubMed1983

On the interaction between digoxin and disopyramide.

Combined oral therapy with digoxin (0.375 mg/dl) and disopyramide (300 and 600 mg/dl) in nine subjects did not alter steady-state digoxin serum concentrations just before the daily single digoxin dose. Digoxin and creatinine clearances were not changed. After a bolus IV dose of 0.8 mg digoxin, volume of distribution (from 672 +/- 176 l to 407 +/- 153 l) and elimination t1/2 beta of digoxin were reduced significantly in five subjects after 600 mg oral disopyramide daily (from 40.2 +/- 11.7 hr to 22 +/- 7.3 hr). Total clearance and digoxin distribution t1/2 alpha did not change significantly. The clinical significance of this interaction is not clear.

Adult↗
PubMed1985

Kinetics and dynamics of disopyramide and its dealkylated metabolite in healthy subjects.

The kinetics and dynamics of total and free (unbound) disopyramide (D) after dosing with D, 1.5 and 2 mg/kg iv, were compared with those of the dealkylated metabolite (MND) after dosing with MND, 0.5 and 1.5 mg/kg iv, in six healthy subjects. Dynamic parameters included ECG with measurement of the QT interval corrected for heart rate (QTc), systolic time intervals, vitamin C-stimulated saliva secretion, pupil size, and maximum accommodation capacity. Mean values of total clearance, apparent volume of distribution, and elimination t1/2 of MND were 5.9, 2.3, and 0.4 times those of total D, respectively. D significantly prolonged the QTc and systolic time intervals and induced transient inhibition of stimulated saliva secretion. In contrast, MND induced no substantial change in either the QTc or systolic time intervals, but did induce more persistent inhibition of salivary secretion. If anticholinergic potency is determined as the degree of inhibition of stimulated saliva flow per plasma concentration unit, MND was three times as potent as its parent when measured at maximum inhibition. There were no consistent drug effects on the ocular parameters. The effect of D on QTc correlated with both total and free plasma concentrations. Furthermore, its transient salivary inhibitory effect paralleled its initial rapid decline in plasma concentration. There was no relationship between the MND plasma concentration and its salivary inhibitory effect. We conclude that disopyramide significantly affected the QTc and systolic time intervals in healthy subjects, while MND in a similar dose had no such effects. MND more strongly inhibited stimulated saliva flow, indicating a more potent anticholinergic effect than D.

Adult↗
PubMed2000

Sinus node recovery time assessment by the overdrive suppression test employing an intravenous injection of disopyramide phosphate.

Although sinus node recovery time (SNRT) assessment by the overdrive suppression test (ODST) is important in detecting sick sinus syndrome (SSS), its sensitivity is still inadequate. We have evaluated the effect of intravenous injection (i.v.) of disopyramide phosphate (DP) in ODST. The subjects were 30 SSS patients (64.9 +/- 10.0 years old). If SNRT was <2,000 ms or the corrected SNRT (CSNRT) was < 1,000 ms, ODST was repeated after DP i.v. (2 mg. kg(-1), < or = 100 mg in total). Eleven normal subjects (59.3 +/- 9.0 years old) were also studied. Although SNRT was <2,000 ms or the CSNRT was < 1,000 ms in 13 of the 30 SSS patients (43%), SNRT was prolonged from 1,510 +/- 300ms to 3,400 +/- 1,160 ms (P<0.01), and CSNRT from 510 +/- 190 to 2,470 +/- 1,470 ms (P<0.01) after DP i.v. in these patients. Thus, SNRT was > or = 2,000 ms and the CSNRT was > or = 1,000 ms in 27 of 30 SSS patients (90%) after DP i.v. Using a combination of overdrive suppression and intravenous injection of disopyramide phosphate, the corrected sinus node recovery time was diagnostic (>525 ms) in 29 of the 30 patients (97%). In contrast, SNRT and CSNRT were shortened in the normal subjects during ODST after DP i.v. (P<0.01). The plasma concentration of DP estimated in nine patients was 4.1 +/- 1.0 microg.ml(-1). No serious side effect occurred. ODST employing DP i.v. is safe and seems to be highly effective in diagnosing SSS.

Aged↗