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PubMedDate not supplied

Cardiovascular effects of tiapamil (Ro 11-1781), a new calcium-entry blocker.

We studied the hemodynamic effects of the new calcium antagonist tiapamil (Ro 11-1781) in anesthetized open-chest dogs and compared them with those of verapamil. Increasing doses of tiapamil injected intravenously caused the following hemodynamic effects: increase in coronary flow and decrease in coronary vascular resistance, followed by decreases in heart rate, blood pressure, and total peripheral resistance. Tiapamil did not depress myocardial contractility over a rather wide dose range, while verapamil did. Tiapamil was more effective in increasing coronary flow than verapamil. Cardiac autonomic denervation did not modify the tiapamil-induced decrease in coronary vascular resistance and did not cause tiapamil to display negative inotropism. Both tiapamil and verapamil reduced the extent of S-T segment elevation in the epicardial electrocardiogram produced by transient occlusion of the left anterior descending coronary artery. Neither drug had this effect when heart rate was kept constant by atrial pacing. In contrast to nitroglycerin, tiapamil dilated small but not large coronary arteries. Tiapamil raised PO2 relatively more in the subendocardial than in the subepicardial layers of the myocardium. The hemodynamic and electrocardiographic effects of tiapamil were not changed by diphenylhydantoin and disopyramide or by pindolol, a beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity. However, the decreases in heart rate and blood pressure in response to propranolol were enhanced by tiapamil.

Animals↗
PubMedDate not supplied

Effective plasma concentrations of antiarrhythmic drugs against sustained halothane-adrenaline arrhythmia in dogs.

We determined the minimum effective plasma concentrations of several antiarrhythmic agents against canine halothane-adrenaline arrhythmia. Sustained ventricular tachycardia was produced by continuous adrenaline infusion at rates of 1.5 to 4 micrograms/kg/min under 1.5% halothane anesthesia. Procainamide, 20 mg/kg, produced ventricular fibrillation in three of nine dogs. Disopyramide, 3 mg/kg, suppressed the arrhythmia in nine of 11 dogs at a minimum effective plasma concentration of 4.2 micrograms/ml, but produced ventricular fibrillation in the remaining two dogs. Phenytoin, 5 mg/kg, was effective at a minimum concentration of 12 micrograms/ml. Lidocaine, 10 mg/kg, suppressed the arrhythmia at a minimum concentration of 15 micrograms/ml, which is much higher than the human toxic plasma level. These drugs may have suppressed the adrenaline arrhythmia by inhibiting the sodium channel, because their effective concentrations were very close to membrane-stabilizing concentrations in vitro. Small doses of 30 micrograms/kg propranolol and 0.1 mg/kg N-696, two beta-blockers, and 0.1 mg/kg verapamil, a calcium channel blocker, yielding a concentration of 0.03 micrograms/ml, suppressed the arrhythmia, probably by indirectly or directly blocking the calcium channel.

Animals↗
PubMed1992

Electrophysiologic effects of RS-2135, a new antiarrhythmic compound, on canine Purkinje fibers.

RS-2135 is the (+) isomer of a novel, fused carbazol derivative. The agent, when administered orally, shows long-lasting antiarrhythmic effects in several models of arrhythmia. We used standard microelectrode techniques to characterize the electrophysiological effects of the agent on canine Purkinje fibers. RS-2135 reduced the maximum upstroke velocity of the action potential (Vmax) and shortened the action potential duration (APD) in a concentration-related manner (0.3-3 microM). RS-2135 decreased Vmax at lower concentrations than disopyramide, flecainide, and mexiletine. RS-2135 shortened the effective refractory period (ERP), but significantly increased the ratio of ERP to APD90. Additionally, the effects of the (-) optical isomer of RS-2135 were compared with those of RS-2135, the (+) enantiomer. The (-) isomer was much less potent than RS-2135 in decreasing Vmax. These data suggest that RS-2135 belongs to the class I or "local anesthetic" type of antiarrhythmic agent and that the stereochemistry of the drug molecule is an important determinant of Na channel blocking activity.

Action Potentials↗
PubMed1995

Changes in the binding capacity of alpha-1-acid glycoprotein in patients with renal insufficiency.

The elevation of alpha-1-acid glycoprotein (AAG) concentration and the binding characteristics of disopyramide (DP) to AAG in patients with renal insufficiency were investigated. The serum AAG concentration and protein binding of DP in patients were significantly greater than those in healthy subjects. However, in both the serum and the purified AAG, Scatchard analysis showed that the number of binding sites per molecule of AAG in patients was significantly lower than that in healthy subjects, although there was no difference in the dissociation constant (Kd). These results suggest that the AAG induced in renal insufficiency is qualitatively different from normal AAG. Moreover, the change of the unbound DP fraction when DP concentration was increased was larger in the patients than in the healthy controls. Therefore, monitoring of the unbound DP would be important for therapeutic drug monitoring in patients with renal insufficiency.

Adult↗
PubMed1982

OPT: a package of computer programs for parameter optimisation in clinical pharmacokinetics.

1 OPT is a series of computer programs designed to assist dose optimisation for individual patients. It is based on Bayesian Statistical Theory and Maximum Likelihood Estimation. 2 OPT uses prior information on the distribution of population pharmacokinetic parameters and plasma drug concentration measurements to obtain the "most likely' set of parameters for the individual. 3 Complex dosage regimes and non-steady state conditions can be handled. 4 OPT is designed for use in a Clinical Pharmacokinetics Laboratory where informed interpretation of results is essential. 5 The drugs for which the system is currently available include theophylline, digoxin, lignocaine, disopyramide, gentamicin and phenytoin (steady state data only).

Administration, Oral↗
PubMed1984

Comparison of beta-adrenoceptor antagonists as modulators of drug metabolism: effect of lipophilicity on microsomal phase I and II reactions.

The effect of beta-adrenoceptor antagonists with varying lipophilicity on microsomal phase I and II reactions was investigated using rat hepatic microsomes. The degree of inhibition of ethoxyresorufin deethylase paralleled octanol/water partition coefficients: propranolol greater than alprenolol greater than timolol greater than metoprolol greater than atenolol. Propranolol (highly lipophilic) and atenolol (hydrophilic) also had widely different effects on 7-ethoxycoumarin deethylase inhibition and on disopyramide N-dealkylation. However the inhibition of harmol conjugation was not related in the same way to octanol/water partition coefficient as was the phase I reactions.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1991

Differential effects on action potential duration of class IA, B and C antiarrhythmic drugs: modulation by stimulation rate and extracellular K+ concentration.

1. Standard microelectrode techniques were used to study the effects on the action potential duration (APD) of canine Purkinje fibres of a therapeutic concentration of nine Class I antiarrhythmic drugs. At an extracellular K+ concentration of 5.6 mmol/L all nine agents reduced APD at all drive rates studied (range of interstimulus intervals = 200-1000 ms). At lower levels of K+, quinidine (5 mumol/L) and disopyramide (10 mumol/L) (Class Ia agents) revealed dual effects on APD. At the lowest levels of K+ (2 mmol/L) and the longest interstimulus interval used (2000 ms), both agents significantly prolonged APD. Under all other conditions, APD was either unchanged or reduced. Lignocaine, 15 mumol/L (Class Ib agent) reduced APD at all rates and all K+ concentrations and this effect was greatest at the slowest rates. 2. Flecainide (1 mumol/L) (Class Ic) shortened APD at K+ = 5.6 and 4 mmol/L but had no effect at K+ = 2 mmol/L. 3. We conclude that these data result from opposing drug actions on inward sodium and outward potassium currents flowing during the plateau of the action potential. 4. Class Ia drugs exhibit significant depression of both currents, with the resultant effect on APD being modulated by external K+ concentration and drive rate. 5. Class Ib agents predominantly depress the sodium current and hence shorten APD, and Ic compounds have intermediate actions. 6. These differential effects on APD must be considered when planning antiarrhythmic therapy, and are directly relevant to the proarrhythmic propensities of these agents.

Action Potentials↗
PubMed1981

Development of a severe model of early coronary artery ligation-induced dysrhythmias in the anaesthetized rat.

1. The potential use of catecholamines to increase the severity of dysrhythmias evoked by coronary artery ligation in the anaesthetized rat was investigated. Drugs were given intravenously prior to ligation. 2 Pressor doses of adrenaline (5 microgram/kg) noradrenaline (1 microgram/kg) phenylephrine (5-10 microgram/kg), and angiotensin (0.25 microgram/kg) conferred protection against the development of dysrhythmias. 3 Atropine (1 mg/kg) increased mortality from ventricular fibrilloflutter (VF) and abolished the protective effects of phenylephrine (10 micrograms/kg). 4 Administration of isoprenaline (10 microgram/kg) significantly increased the incidence of and the mortality from VF. 5 The order of antidysrhythmic drug potency of Org 6001 (1-10 mg/kg), disopyramide (2-10 mg/kg) and practolol (2-10 mg/kg) was similar in both the standard (without isoprenaline) and modified (with isoprenaline) models. 6 Use of the modified method for antidysrhythmic screening purpose allows demonstration of statistically meaningful results with the use of relatively few animals. 7 Comparison of the pattern of VF in the rat heart induced by various means suggests that the diagnosis of ventricular fibrillation can be made with more confidence in the modified method compared to the standard method.

Androstanols↗
PubMed1988

Electrophysiological effects of melperone on isolated rabbit heart muscles.

1. Electrophysiological effects of melperone on isolated atrial and ventricular muscle preparations of the rabbit were studied by a conventional microelectrode technique. 2. Melperone (3.3 microM) prolonged the action potential duration and effective refractory period of the atrial preparations without affecting the maximum rate of depolarization (Vmax). These effects of melperone on action potential duration and effective refractory period were inhibited by a low potassium perfusate (2.7 mM). 3. A high concentration of melperone (16.6 microM) decreased Vmax of atrial preparations. In ventricular muscles, melperone at either concentration decreased Vmax, although the increase in action potential duration was greater than in the atrium. 4. Depression of Vmax of ventricular muscles by melperone was found to be augmented by an increase of stimulation frequency and drug concentration. 5. The rate of onset of rate-dependent block of Vmax in ventricle was increased with drug concentration and frequency of stimulation. However, the time constant of recovery from rate-dependent block was almost constant. The kinetics of rate-dependent block of Vmax by melperone were approximately similar to those of quinidine and disopyramide. Consequently it is concluded that melperone possesses class 1a antiarrhythmic activity as well as class 3 activity.

Action Potentials↗
PubMed1988

Pacemaker syndrome with AAI rate variable pacing: importance of atrioventricular conduction properties, medication, and pacemaker programmability.

A patient who received an AAI Activitrax rate variable pacemaker for treatment of symptomatic sinus bradycardia is described. disopyramide prolonged the anterograde effective refractory period of the fast conducting atrioventricular (AV) nodal pathway to such an extent, that conduction switched to the slow AV nodal pathway at low atrial pacing rates. This gave rise to symptoms of the pacemaker syndrome during moderate exercise because the paced atrial event was conducted with a long, spike to Q interval with occurrence of the paced atrial event just after the preceding QRS complex. A change of medication solved this problem. Programming a bipolar electrode configuration avoided sensing of far-field QRS signals with the associated problems of resetting the basic pacing interval as well as the upper rate interval. AAI rate variable pacing requires careful evaluation of AV conduction properties, AV conduction intervals as well as the influence of medication to be given. The use of multiprogrammable pacemakers with marker channel capability will significantly facilitate the understanding and resolution of anomalous behavior.

Aged↗
PubMed1991

Repetitive nonsustained monomorphic ventricular tachycardia aborted by methoxamine and sleep "heart rate dependent ventricular tachycardia".

Methoxamine, an alpha adrenoreceptor agonist, and sleep abolished repetitive nonsustained monomorphic ventricular tachycardia in a 41-year-old man without detectable underlying heart disease. Detailed pacing studies revealed that the occurrence of ventricular tachycardia was totally dependent on the basic heart rate. Sleep and the alpha adrenoreceptor agonist abolished the ventricular tachycardia by slowing the basic heart rate. Verapamil, propranolol, and disopyramide were able to decrease the upper limit of the tachycardia-initiating heart rate, but none of them were able to increase the lower limit (75/min). Failure to increase the lower limit of the tachycardia-initiating heart rate was a major reason why these conventional antiarrhythmic drugs were unable to suppress his daytime episodes of repetitive ventricular tachycardia.

Adult↗
PubMed1993

Efficacy of type 1C antiarrhythmic agents for treatment of resistant atrial fibrillation.

In order to determine the efficacy of type 1C agents (flecainide, encainide, propafenone) in patients with atrial fibrillation who have failed to maintain sinus rhythm with type 1A agents (quinidine, procainamide, disopyramide), 147 patients, that were admitted into the John Dempsey Hospital with new or recurrent atrial fibrillation between 1987-1991, were studied retrospectively. Out of the total, 29 patients converted spontaneously to sinus rhythm, 14 patients were left in atrial fibrillation, and 104 patients were given a type 1A antiarrhythmic. Sixty-five of these patients remained in sinus rhythm (54% converted on drug alone, 46% required electrical cardioversion) for at least 6 months. Of the remaining 39 patients, 28 were given a type 1C antiarrhythmic; 13 were successfully converted (61% chemical, 39% electrical) to and remained in sinus rhythm for at least 6 months; the remaining 15 either failed to convert or reverted to atrial fibrillation. New onset atrial fibrillation had a significantly lower incidence of congestive heart failure (10%) than recurrent atrial fibrillation (33%; P < 0.01). No differences in digoxin, beta blocker use, or other clinical characteristics were seen either between type 1A or type 1C successes or failures. Similarly, echocardiographic dimensions did not predict success or failure with either class of agent. In conclusion, type 1C antiarrhythmics for suppression of recurrent atrial fibrillation represent a reasonable therapeutic alternative for suppression of atrial fibrillation in patients who have failed type 1A agents. Prognostic factors predicting success or failure remain undetermined.

Aged↗
PubMed1995

Efficacy of different treatment strategies for neurocardiogenic syncope.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of different therapeutic approaches for patients with a history of syncope and positive head-up tilt testing. BACKGROUND: Head-up tilt testing has gained broad acceptance as a reliable diagnostic method for the assessment of patients with recurrent unexplained syncope. However, once the diagnosis is established, there is no consensus on the most appropriate treatment. In this respect, efficacy of drug therapy in preventing recurrence of symptoms in such patients is not entirely clear, and controversies exist regarding the need to confirm the effects of pharmacological interventions. METHODS: Clinical follow-up was obtained in 303 patients with a history of syncope and positive head-up tilt testing. After the diagnostic head-up tilt, patients were assigned to different therapeutic approaches according to their preference or logistic impediments. Of 303 patients, 44 received empiric therapy, 210 were treated with medications proven effective during repeated head-up tilt testing, and 49 refused or discontinued medical therapy. The three groups were similar with regard to age, sex, and clinical presentation. The mean follow-up was 2.8 +/- 1.8 years. Among the patients treated according to head-up tilt guided therapy, 130 were on beta blockers, 35 on theophylline, 10 on ephedrine, 31 on disopyramide, and 4 on miscellaneous regimens. Empiric treatment consisted of beta blockers in 37 of 44 patients and other drugs in the remaining patients. RESULTS: During the follow-up, recurrence of symptoms was experienced in 12 (6%) of the 210 patients receiving the head-up tilt guided therapy, 16 (36%) of 44 in the empiric therapy group, and 33 (67%) of 49 in the no therapy group. Recurrence of symptoms in patients on empiric or no therapy was significantly more frequent as compared to the head-up tilt guided therapy group (P < 0.01). CONCLUSIONS: In patients with unexplained syncope and positive upright tilt testing, therapeutic strategies identified on the basis of response during head-up tilt have a more positive impact on the recurrence of symptoms during follow-up.

Adolescent↗
PubMed1996

The use of methylphenidate in the treatment of refractory neurocardiogenic syncope.

Recurrent neurocardiogenically mediated episodes of hypotension and bradycardia are a common cause of recurrent syncope that can be identified by head upright tilt table testing. While the use of beta-blockers, theophylline, fludrocortisone, disopyramide, and serotonin re-uptake inhibitors can be helpful in preventing further episodes, some patients are unresponsive to or poorly tolerant of these agents. We investigated the use of the central nervous system stimulant and peripheral vasoconstrictor methylphenidate in preventing both tilt induced and spontaneous neurocardiogenic syncope. Seven patients (all women, mean age 31 +/- 15 years) with recurrent syncope and positive head upright tilt induced hypotension/bradycardia (refractory to normal therapy) were placed on methylphenidate 10 mg orally three times per day. Six of the seven patients became both tilt negative and clinically asymptomatic over a 7-month follow-up period. We conclude that methylphenidate may be an effective therapy in patients with recurrent neurocardiogenic syncope refractory to other forms of therapy.

Administration, Oral↗
PubMed1997

The medical therapy of cardioinhibitory syncope in pediatric patients.

A small percentage of pediatric patients with neurally mediated syncope will have an asystolic response during upright tilt table testing. The purpose of this study is to evaluate the incidence of asystole during tilt table testing, and to assess the outcome of medical management of such patients. Of 398 patients undergoing evaluation for recurrent syncope between January 1989 and 1994, 18 (4.5%) experienced asystole lasting > or = 5 seconds during baseline tilt test. Patients had experienced a mean of four episodes of syncope, with a mean age at the time of tilt test of 11.1 +/- 4.0 years. The median duration of asystole was 10 seconds (range 5-40 s). Treatment was individualized to increased fluids and salt intake (3 patients), metoprolol (8 patients), pseudoephedrine (4 patients), disopyramide (1 patient), or combination therapy with fludrohydrocortisone (2 patients). During a median duration of follow-up of 31 months, no additional syncope was experienced by 78% of patients. Recurrent syncope in 4 patients was associated with either noncompliance or discontinuation of therapy in 3 patients; in 1 patient, increasing the dose of metoprolol was effective in preventing recurrences. We conclude that young patients with recurrent syncope and asystole during tilt test may be safely and effectively managed with pharmacological therapy, without resorting to pacemaker implantation.

Adrenergic Agonists↗
PubMed1994

Electrical proarrhythmia with procainamide: a new ICD-drug interaction.

A 78-year-old man with a transvenous cardioverter defibrillator system developed frequent shocks during oral procainamide therapy. Electrophysiologic evaluation demonstrated failure to terminate ventricular tachycardia with maximal energy shocks, but consistent termination by low energy discharges. Procainamide had no effect upon the defibrillation threshold. The failure of therapy with disopyramide and mexiletine to reproduce this observation suggests either a previously unreported electrophysiologic effect of, or idiosyncratic response to, procainamide.

Aged↗
PubMed2000

Clinical characteristics of patients with spontaneous or inducible ventricular fibrillation without apparent heart disease presenting with J wave and ST segment elevation in inferior leads.

INTRODUCTION: The clinical characteristics of three patients with spontaneous or inducible ventricular fibrillation (VF) without apparent heart disease, who presented with J wave and ST segment elevation in inferior leads, are described. METHODS AND RESULTS: All patients were male and experienced syncope. Their symptoms occurred at night or early in the morning. Holter ECG revealed infrequent premature ventricular complexes. Injection with disopyramide 2 mg/kg augmented ST segment elevation. CONCLUSION: These characteristics were very similar to those of patients with Brugada syndrome. These three patients with these specific features might have a variant of Brugada syndrome.

Adult↗
PubMed2000

Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping and its application to twelve-lead electrocardiograms.

INTRODUCTION: Body surface distribution and magnitude of ST segment elevation and their reflection in 12-lead ECGs have not been clarified in Brugada syndrome. METHODS AND RESULTS: Eighty-seven-lead body surface potential mapping and 12-lead ECGs were recorded simultaneously in 25 patients with Brugada syndrome and 40 control patients. The amplitude of the ST segment 20 msec after the end of QRS (ST20) was measured from all 87 leads, and an ST isopotential map was constructed. The maximum ST elevation (maxST20) was distributed in an area of the right ventricular outflow tract in all Brugada patients, and it was larger than that in control patients (0.37 +/- 0.13 vs 0.12 +/- 0.04 mV; P < 0.0005). The maximum was observed on the level of the parasternal fourth intercostal space, on which the V1 and V2 leads of the standard 12-lead ECG were located, in 18 of the 25 Brugada patients in whom typical coved- or saddleback-type ST elevation was seen in leads V1 and V2. The maximum was located on the second intercostal space in the remaining seven Brugada patients in whom only a mild saddleback-type ST elevation was seen in leads V1 and V2 of the 12-lead ECG. Typical ST segment elevation was recognized in leads V1 and V2, which were recorded on the second or third intercostal space. ST elevation in Brugada patients was dramatically normalized by isoproterenol, a beta-adrenergic agonist (maxST20 = 0.17 +/- 0.08 mV; P < 0.0005 vs control conditions), and accentuated by disopyramide, an Na+ channel blocker (maxST20 = 0.50 +/- 0.15 mV; P < 0.0005 vs control conditions), without any change in the location of the maxST20. CONCLUSION: Our data indicate that recordings of leads V1-V3 of the 12-lead ECG on the parasternal second or third intercostal space would be helpful in diagnosing suspected patients with Brugada syndrome. The data suggest that Na+ channel blockers are capable of accentuating ST elevation in leads V1-V3.

Action Potentials↗