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Ventricular pacing in atypical ventricular tachycardia.

Ventricular pacing was effective in controlling recurrent bouts of atypical ventricular tachycardia (Torsade de Pointes), in four patients. This arrhythmia was induced by quinidine or disopyramide therapy. Isoproterenol, which is the usually recommended therapy, was ineffective in two of the patients and was considered hazardous in two others. We consider ventricular pacing as a safe and reliable method for treatment of AVT, which should be applied if isoproterenol is ineffective or contraindicated.

Aged↗

Is neurally mediated hypotension an unrecognised cause of chronic fatigue?

Neurally mediated hypotension is now recognised as a common cause of otherwise unexplained recurrent syncope, but has not been reported in association with chronic fatigue. We describe seven consecutive non-syncopal adolescents with chronic post-exertional fatigue, four of whom satisfied strict criteria for chronic fatigue syndrome. Upright tilt-table testing induced significant hypotension in all seven (median systolic blood pressure 65 mm Hg, range 37-75), consistent with the physiology of neurally mediated hypotension. Four had prompt improvement in their chronic fatigue when treated with atenolol or disopyramide. These observations suggest an overlap in the symptoms of chronic fatigue syndrome and neurally mediated hypotension.

Adolescent↗

Effects of several class I antiarrhythmic drugs on isolated rat aortic vascular smooth muscle.

1. The vasorelaxant effects of seven NA+ channel blockers (i.e., class I antiarrhythmic agents), quinidine, disopyramide, imipramine, lidocaine, mexiletine, flecainide, and desipramine, were investigated in isolated endothelium-denuded rat aorta. 2. All drugs induced a concentration-dependent relaxation in aorta precontracted with either 80 mM KCl or 10(-5) M noradrenaline and, with the exception of mexiletine, they were more potent in inhibiting KCl-induced contractions. 3. The degree of inhibition of high KCl-induced contractions produced by quinidine and desipramine increased with the time of depolarization. Furthermore, the inhibitory effect of quinidine also increased in aorta preincubated in 40 mM KCl, whereas the inhibitory effects of other antiarrhythmics were almost similar in 5 or 40 mM KCl solution. 4. In conclusion, all these class I antiarrhythmic drugs inhibited Ca2+ entry through voltage- and receptor-gated channels as well as Ca2+ release from intracellular stores. As a consequence, they decrease the availability of intracellular free Ca2+ required for vascular smooth muscle contraction.

Animals↗

Sensitivity and specificity of invasive and noninvasive testing for risk of sudden death in Wolff-Parkinson-White syndrome.

Invasive electrophysiologic testing and noninvasive testing were compared as methods for identifying patients with Wolff-Parkinson-White syndrome at risk for sudden death. Sixty-seven patients were studied, including nine with a history of ventricular fibrillation. Electrophysiologic testing, using the shortest interval between consecutive pre-excited beats (shortest RR interval) less than or equal to 250 ms during induced atrial fibrillation to define risk, identified seven of nine patients with previous ventricular fibrillation. The sensitivity increased to 87.5% if one patient with prior amiodarone therapy was excluded. Electrophysiologic testing had a specificity of 48.3% and a low predictive accuracy (18.9%) when using the shortest RR interval (less than or equal to 250 ms) to identify the risk for sudden death. Continuous pre-excitation after disopyramide (2 mg/kg body weight, intravenously) had a sensitivity of 71.4%, specificity of 26.1% and predictive accuracy of 12.8% for identifying patients with sudden death. Continuous pre-excitation during an exercise test identified these patients with a sensitivity of 80%, a specificity of 28.6% and a predictive accuracy of 11.8%. These noninvasive tests could also be used to predict the shortest RR interval observed during induced atrial fibrillation. Continuous pre-excitation on both tests used in combination had a sensitivity of 91.2%, a specificity of 66.7% and a predictive accuracy of 75.6% for predicting the shortest RR interval less than or equal to 250 ms. Thus, both invasive and noninvasive techniques have a good sensitivity but a low specificity for identifying patients with Wolff-Parkinson-White syndrome and sudden death.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

[Spinal reflexes and somatosensory evoked potentials studied in the baboon in the presence of anti-arrhythmic drugs].

Intragastric administration of the anti-arrhythmic drugs CM 7857 (Sanofi) or disopyramide, as expected, significantly reduced the heart rate in normal baboons at rest. At the same time, the variability in the heart rate increased. In vitro studies by Sanofi have previously shown the anti-arrhythmic effects of these drugs, i.e., a slowing of the transmembrane currents evidenced in several categories of heart cells especially when activated. Similar ion currents are known to be involved in extracardiac sensory-motor activities. However the H-reflex in soleus underwent no systematic changes in latency or amplitude with the drugs; the non-nociceptive early and nociceptive late polysynaptic responses elicited in the tibialis anterior muscle by sural nerve stimulation demonstrated a barely perceptible increase in integrated EMG value. No change could be seen in latency or amplitude of the cortical potentials evoked by sciatic or sural stimulation which was also used for reflex responses. Overall there was no definitive evidence of change in the extra-cardiac sensory-motor responses in the normal awake monkey, after administration of relatively high doses of the cardio-active compounds.

Animals↗

QT corrected for heart rate and relation between QT and RR intervals in beagle dogs.

The beagle dog has been widely used in cardiovascular research, but the adequacy of QT prediction formulas in dogs over a wide range of RR intervals has not been evaluated sufficiently. We investigated the QT-RR relation in beagles by analysis of the QT and preceding RR intervals obtained from 24-h ambulatory electrocardiograms. The acceptability of 14 QT prediction formulas was evaluated by use of 100-150 selected pairs of QT-RR points per animal in seven male and seven female beagles. The accuracy of fit with the measured data was assessed according to the minimum Akaike information criterion. The best fit was given by the logarithmic and inverse Kovács' formulas among one- and two-parameter linear regression equations, respectively. Exponential formulas produced a better fit than did the linear regression formulas, but are impractical because of the complicated interpretation of parameters due to the nonlinearity. In addition, the results obtained under physiological conditions were also confirmed by those of the pharmacological intervention study with disopyramide. Consequently, we propose a one-parameter logarithmic formula (QTc= log600 x QT/logRR) for correcting the QT interval for a heart rate of 100 bpm and the inverse Kovács' formula for evaluating a reverse-use-dependency of QT prolongation.

Animals↗

Evaluation of association constants between drug enantiomers and human alpha 1-acid glycoprotein by applying a partial-filling technique in affinity capillary electrophoresis.

The principles for evaluation of conditional association constants between drug enantiomers and proteins, exemplified here by alpha 1-acid glycoprotein (AGP), using capillary zone electrophoresis employing a partial filling technique, is presented. In the partial filling technique only the first part of the capillary is filled with the selector, and this selector zone (plug) length can be varied by introducing the selector solution at different times at constant pressure. An important feature of the technique is the low consumption of selector solution in this study only 40-290 nL is used per run, of special importance when the availability of the selector is limited, and also in case it is expensive. Conditions are chosen so that the protein has a net negative charge and migrates toward the anode, while the analytes migrate toward the detector at the cathodic side. The resolution is linearly related to the effective plug length, as shown in separations of the enantiomers of disopyramide and remoxipride. The effective plug length can be calculated, which forms the basis to apply this technique for determinations of association constants. The association between the enantiomers of the solutes and AGP varied with increasing temperature, as shown by determined association constants. It was found that the association between the enantiomers and AGP was strongest at 25 degrees C and decreased at both lower and higher temperatures. This unexpected finding may indicate conformational changes of the protein with temperature variations.

Disopyramide↗

Role of biantennary glycans and genetic variants of human alpha1-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis.

PURPOSE: To establish a clear understanding of the role of biantennary branching glycans and genetic variants of alpha1-acid glycoprotein (AGP) in enantioselective bindings of basic drug. METHODS: Human native AGP was separated using concanavalin A affinity chromatography into two subfractions, the unretained fraction (UR-AGP, defect of biantennary glycan) and the retained fraction (R-AGP, possessing biantennary glycan(s)). Imminodiacetate-copper (II) affinity chromatography was used to separate human native AGP into A variant and a mixture of F1 and S variants (F1*S variants). The mixed solutions of the (R)- or (S)-isomer of the model drugs (15 microM disopyramide (DP) or 30 microM verapamil (VER)) and 40 microM of respective AGP species were subjected to high-performance frontal analysis/capillary electrophoresis (HPFA/CE) to determine the unbound drug concentrations. RESULTS: The unbound concentrations (Cu) of DP in UR-AGP solutions were lower than those in R-AGP solutions, whereas there was no significant difference in the enantiomeric ratios (Cu(R)/Cu(S)) of DP between UR- and R-AGP solutions. In case of genetic variant, the Cu(R)/Cu(S) values of DP in F1*S and A solutions were 1.07 and 2.37, respectively. On the other hand, the enantiomeric ratio of VER in F1*S and A variant solutions were 0.900 and 0.871, respectively. CONCLUSIONS: The biantennary glycan structures are related to binding affinity of DP to AGP, but not responsible for the enantioselectivity. Genetic variants give significant effect on the enantioselectivity in DP binding, but not in VER binding.

Anti-Arrhythmia Agents↗

Correlation between the inhibitory effects of basic drugs on the uptake of cardiac glycosides and taurocholate by isolated rat hepatocytes.

The role of the multispecific bile acid transporter for cardiac glycoside uptake is still controversial. This study was designed to examine the inhibitory effects of basic drugs (verapamil, dipyridamole, nifedipine, chlorpromazine, disopyramide, quinidine, propranolol, and lidocaine) on taurocholate uptake by isolated rat hepatocytes and to compare these effects with inhibition of ouabain uptake. Sodium-dependent taurocholate uptake was significantly reduced, to 50-70% of the control value, by 50 microM verapamil, dipyridamole, and nifedipine. Sodium-independent taurocholate uptake was more extensively inhibited, to 20-40%, by these basic drugs. The inhibition of ouabain uptake correlated better with sodium-independent taurocholate uptake (gamma = 0.918) than with sodium-dependent taurocholate uptake (gamma = 0.714). Taurocholate competitively inhibited ouabain uptake in the absence of sodium. These results indicate that the cardiac glycoside transport system is similar to the sodium-independent taurocholate transport system.

Animals↗

The effects of flecainide on ATP-sensitive K(+) channels in pig urethral myocytes.

The effects of the antiarrhythmic drug flecainide on levcromakalim-induced hyperpolarization, macroscopic and unitary K(+) currents in pig urethra were investigated using patch-clamp techniques. The effects of flecainide were also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K(+) channel (Kir6.2) subunits (i.e. Kir6.2DeltaC36) which form ATP-sensitive K(+) channels (K(ATP) channels). In current-clamp mode, application of flecainide (> or =100 microM) caused a significant depolarization after the membrane potential had been hyperpolarized by levcromakalim. In voltage-clamp experiments, the levcromakalim-induced outward current was suppressed by 300 microM flecainide in quasi-physiological K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inward current still remained even after application of 300 microM flecainide in symmetrical 140 mM K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inwar=126 microM). In cell-attached configuration, the channel activity of the levcromakalim-induced K(ATP) channels was reversibly inhibited by flecainide (> or =30 microM) at -50 mV. Their activity was also suppressed by either disopyramide or cibenzoline. Flecainide reversibly inhibited the channel activity of Kir6.2DeltaC36 expressed in COS7 cells using inside-out configuration. Inhibitory effects of flecainide on the levcromakalim-induced currents became more potent when the value of external pH increased, although this slightly reduced the proportion of drug molecules carrying a positive charge. These results suggest that flecainide inhibits channel activity through blocking the pore site of the K(ATP) channel in pig urethra.

Adenosine Triphosphate↗

Is there a place for the late cardioversion of atrial fibrillation? A long-term follow-up study of patients with post-thyrotoxic atrial fibrillation.

AIMS: As atrial fibrillation is associated with significant mortality and morbidity, restoration of sinus rhythm is desirable. However, previous data suggest that cardioversion should be restricted to patients in whom the fibrillation is of limited duration (<1-2 years) because of high relapse rates. It may be the frequent association with cardiac disease, rather than the duration of fibrillation itself, which determined the high relapse of earlier studies. The aim of this study was to investigate rates of cardioversion, maintenance of sinus rhythm and predictors of subsequent relapse in a homogeneous group of patients without evidence of any co-existent cardiac disease. METHODS AND RESULTS: We report on a retrospective series of 106 patients with thyrotoxicosis-induced fibrillation but no other heart disease: 87% had been in atrial fibrillation for >12 months (median duration 28.5, interquartile range 15-47 months). Cardioversion was attempted using disopyramide and then electric shock. Ninety-eight patients were successfully cardioverted: at late follow-up, 80.6+/-37 months (mean+/-SD), 67% were in sinus rhythm. CONCLUSION: Although a relationship between the duration of fibrillation and maintenance of sinus rhythm was found, the high proportion remaining in sinus rhythm, compared with other series, suggests this influence may be less important than the presence or absence of structural heart disease.

Adult↗

Atrial fibrillation threshold predicted long-term efficacy of pharmacological treatment of patients without structural heart disease.

AIMS: To ascertain if an electrophysiological study could predict long-term efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation. METHODS AND RESULTS: Forty-four patients (36 males, 8 females, age 55.5 +/- 10.6) with paroxysmal atrial fibrillation were enrolled to undergo serial electrophysiological studies at the bedside. Two quadripolar catheters were inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C: 1.4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was 3.9 +/- 0.3 mA. Pharmacological treatment raised AFT as follows: D 5.9 +/- 0.9 mA, C 7.6 +/- 1.2 mA, A 8.1 +/-1.1 mA, P 6.0 +/- 0.8 mA, F 7.3 +/- 1.1 mA. Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of cases when they were treated with a drug that raised AFT by 5 mA or more. On the other hand, the recurrence rate was 87% when patients were treated with a drug that raised AFT by less than 5 mA (P = 0.001). CONCLUSION: AFT was a good predictor of long-term efficacy of pharmacological treatment against atrial fibrillation.

Aged↗

[Idiopathic ventricular tachyarrhythmia. Spontaneous variability and effect of various antiarrhythmic agents].

20 patients with idiopathic complex ventricular arrhythmias received propafenone 450 mg/d, disopyramide 600 mg/d and metoprolol 100 mg/d. Before commencement of the 3-week treatment period the 95% normal range for spontaneous changes in ventricular extrasystoles (VES), as couplets and runs, were determined from three 24 h-ECG recordings in each patient under drug-free conditions. A drug effect was assumed when the rate of VES/24 h for the control period decreased by greater than or equal to 83.5% or increased by greater than or equal to 505% in the test period. The frequency dependent normal range for couplets varied between a decrease from 100% to 92% (greater than or equal to 16 to greater than or equal to 44/d) and an increase from 650% to 1000% (greater than or equal to 3 to greater than or equal to 38/d) and for runs between a decrease from 100% to 85% (greater than or equal to 6 to 32/d) and an increase from 600% to 1000% (greater than or equal to 1 to 14/d). A decrease in all rhythm disturbances under the action of the 3 drugs could be shown for the whole group (P less than 0.01). On the basis of the calculated normal range, ventricular extrasystoles in the patients decreased significantly by 26-37%, couplets by 13-33% and runs by 0-55% depending to the drug. A drug dependent arrhythmogenic effect occurred in 4 patients. A preference for one or other of the drugs could not be established statistically.

Adult↗

[Long-term drug therapy in ventricular cardiac arrhythmias. Is an improvement of the prognosis possible?].

Oral long-term treatment with various antiarrhythmic drugs (aprindine, mexiletine, disopyramide, amiodarone) was assessed in 82 patients with recurrent tachycardias demonstrated in the ECG using programmed ventricular stimulation. It was shown that sudden cardiac death and recurrence of tachycardia were clearly reduced in the group of patients (n = 29) in whom drug treatment prevented ventricular tachycardia following electric stimulation. Amiodarone was demonstrated to be the most effective substance in this respect, notwithstanding some side effects.

Adult↗

Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy.

We retrospectively studied 28 patients with 38 episodes of newly occurring ventricular fibrillation during antiarrhythmic drug therapy. Twenty-six of these patients, who had ventricular fibrillation during single-drug therapy with quinidine, procainamide, or disopyramide, were compared with a control group of 62 patients who had been treated similarly for ventricular arrhythmias but did not have ventricular fibrillation during treatment. The median duration of therapy before ventricular fibrillation was three days. The left ventricular ejection fraction of the study group was lower than that of the control group (0.29 vs. 0.43; P less than 0.0001), and concomitant treatment with digitalis and diuretic agents was more common in the study group. The base-line QT interval (corrected for heart rate) was slightly longer in the study group than in the controls (0.47 vs. 0.44; P less than 0.005), although both groups had similar degrees of QT prolongation during drug therapy. Four of 13 patients (31 percent) who underwent multiple trials of antiarrhythmic drugs had recurrent episodes of ventricular fibrillation. Six patients died suddenly after a mean follow-up of 18 months--four who were receiving antiarrhythmic therapy and two who were not. We conclude that drug-associated ventricular fibrillation is an early event, that there may be an increased risk of its recurrence with subsequent trials of antiarrhythmic drugs, and that left ventricular dysfunction and concomitant therapy with digitalis and diuretic agents may predispose patients to this complication.

Anti-Arrhythmia Agents↗

Continuous monitoring of an endocardial index of myocardial contractility during head-up tilt test.

BACKGROUND: Previous studies suggest that vigorous myocardial contractions stimulate ventricular mechanoreceptors and lead to vasovagal syncope. We studied an endocardial index of myocardial contractility during the head-up tilt test in vasovagal patients and control patients, and we evaluated the effect of negative inotropic drugs on myocardial contractility and tilt test outcome. METHODS AND RESULTS: We investigated 19 patients with recurrent vasovagal syncope and positive tilt test (group 1) and 11 patients with no syncope and negative tilt test (group 2). Myocardial contractility was continuously measured during a tilt test (60 degrees ) through a microaccelerometer incorporated in the tip of a right ventricular electrode to sense left ventricular contractility. Patients in groups 1 and 2 were evaluated during an unmedicated tilt test, and patients in group 1 were reevaluated during a tilt test with infusion of esmolol (n = 10) or disopyramide (n = 9). During the unmedicated test, patients in group 1 exhibited a significant increase in myocardial contractility immediately on postural change (P <.05), unlike patients in group 2. Patients in group 1 also had a further increase in myocardial contractility before the end of tilt (P <.01). With drug administration, the changes in supine myocardial contractility were nonsignificant and were not related with the outcome of the tilt test (P <.05). CONCLUSIONS: An increase in myocardial contractility is detected by the sensor during the tilt test. The changes induced by the drugs on supine myocardial contractility are minor and not related with the outcome of the head-up tilt test.

Adrenergic beta-Antagonists↗

Supraventricular tachycardia and pre-excitation syndromes: pharmacological therapy.

Tachyarrhythmias which originate above the bifurcation of the bundle of His or incorporate tissue proximal to it are classified as supraventricular tachyarrhythmias (SVT). Primary treatment of SVT attempts to influence the underlying disease. Therapy is subdivided into drug therapy, electrotherapeutic tools (e.g. antitachycardia pacemakers, catheter ablation) and antiarrhythmic surgery. Antiarrhythmic agents which slow conduction and suppress premature beats are efficient for emergency and long-term treatment of supraventricular tachycardias. We evaluated some of the most relevant antiarrhythmic drugs for SVT including propafenone, diprafenone, cibenzoline, lorcainide and sotalol; in addition, usage and efficacy of quinidine/verapamil, disopyramide, amiodarone, ajmaline, adenosine and flecainide are summarized. The principles for acute management of tachycardia episodes with narrow and broad complexes are outlined. The reason for the selection as well as the efficacy in the termination of the tachycardias is described for different antiarrhythmic agents including verapamil, adenosine, ajmaline, propafenone and flecainide.

Ajmaline↗

Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing.

Class 1 antiarrhythmic drugs have been subdivided into 1a, 1b and 1c according to their effect on the action potential duration. The effects on the surface electrocardiogram of one drug from each subgroup were investigated in nine patients. Electrocardiographic recordings were taken during sinus rhythm and at identical atrial and ventricular paced rates. Disopyramide (1a) significantly prolonged the QT interval during sinus rhythm and at the identical paced rates, by increasing both the QRS duration and JT interval. Lignocaine (1b) significantly reduced the QT interval during sinus rhythm and at the identical paced rates, by reducing the JT interval. Lignocaine had no effect on the QRS duration. Flecainide (1c) significantly prolonged the QRS duration during sinus rhythm, but not the QTc. However the QT interval at the paced rates prolonged significantly, due entirely to an increase of the QRS duration. Flecainide had no effect on the JT interval. These characteristic electrocardiographic differences support the differentiation of class 1 drugs into three separate subgroups.

Action Potentials↗