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PubMed1990

Moricizine: a new class I antiarrhythmic.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.

Arrhythmias, Cardiac↗
PubMed1986

Open and inactivated sodium channel block by class-I antiarrhythmic drugs.

Inhibitory action of six Class-I antiarrhythmic drugs on cardiac sodium channel was examined in isolated guinea-pig ventricular muscles. Transmembrane potential of the tissue was controlled by single sucrose gap voltage clamp technique. Following 30 sec quiescent period, a conditioning clamp pulse was applied from resting potential level to 0 mV for 10 msec to 800 msec. 100 msec after returning to the resting potential, voltage clamp was released and an action potential was elicited to measure its maximum upstroke velosity (Vmax) as an index of sodium channel availability. Under control condition such clamp pulse application did not affect the value of Vmax. In preparations treated with quinidine, and disopyramide, Vmax was decreased appreciably by the shortest clamp pulse application, but the Vmax reduction was enhanced only slightly by prolongation of the clamp pulse duration. In cases with lidocaine, mexiletine, tocanide and aprindine, the decrease in Vmax was enhanced much more remarkably by similar prolongation of the clamp pulse duration. These findings suggest the quinidine and disopyramide may block sodium channel mainly during open state. In contrast, lidocaine, mexiletine, tocainide and aprindine may block the channel mainly during inactivated state. Such a difference would cause wide variety of action potential duration dependency for the effects of Class-I drugs.

Action Potentials↗
PubMed1989

[Electrophysiological testing of multiple antiarrhythmic drugs in patients with paroxysmal supraventricular tachycardia after chronic oral administration].

Serial electrophysiological testing of multiple antiarrhythmic drugs was performed in 98 patients with paroxysmal supraventricular tachycardia (WPW syndrome 32, concealed WPW syndrome 46, atrioventricular nodal reentrant tachycardia 20). Of 32 patients with WPW syndrome, twelve patients had atrial fibrillation and atrioventricular reentrant tachycardia. Serial supraventricular tachycardia induction was attempted after chronic oral administration of verapamil (120-320 mg/day, 86 pts), diltiazem (180 mg/day, 10 pts), disopyramide (300-600 mg/day, 27 pts), propafenone (300-600 mg/day, 25 pts), flecainide (100-300 mg/day, 7 pts), SUN 1165 (150-300 mg/day, 10 pts), and combination therapy (18 pts) by using six polar electrode left in the heart in almost all patients. In 96 of 98 patients, one or more drugs prevented induction of SVT. Combination therapy alone was effective in 14 pts. The site of action of verapamil and diltiazem was antegrade and retrograde normal pathway AV conduction in circus movement. The site of action of disopyramide, propafenone, flecainide, SUN 1165 was antegrade and retrograde accessory pathway conduction and retrograde normal pathway conduction. Eighty two pts were successfully followed for 17.7 +/- 9.6 months. In 68 of these 82 pts, PSVT did not recur. Therefore, serial electrophysiological testing proved useful for the selection of prophylactic antiarrhythmic drugs.

Administration, Oral↗
PubMed1989

[The role of drugs and lymphocytes in granulocyte-macrophage colony formation in patients with drug induced agranulocytosis].

The in vitro effects of the causative drugs and lymphocytes from the patients with agranulocytosis were tested against granulocyte-macrophage colony formation (CFU-C) of bone marrow cells from normal individuals and the patients in recovery stage. A semisolid culture system was used for CFU-C assay. The drug concentrations were adjusted to the therapeutic levels in sera, and the lymphocytes were obtained from the patient's peripheral blood. Three patients with agranulocytosis and one patient with pancytopenia caused by disopyramide, methimazole, sodium valproate, and Towasaal, respectively, were examined. Each of the four drugs except disopyramide suppressed the CFU-C of normal and patient's bone marrow cells in a dose-dependent manner. When the patient's bone marrow cells were cultured with respective drugs and their own lymphocytes or with the culture supernatant of the drug and lymphocytes, CFU-C suppressions was significantly augmented. Phenacetin, an agent of Towasaal, significantly suppressed CFU-C and also CFU-E. These results indicate that humoral factor(s) produced from patient's lymphocytes by reacting with the drugs may function as an immunological mechanism in the patients with drug-induced agranulocytosis.

Adult↗
PubMed1988

Pirmenol: preclinical pharmacology.

Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology. Animal pharmacology studies showed that pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin; chemically, mechanically, or electrically induced; or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which pirmenol could be used either alone or in combination. Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention, or termination of cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of pirmenol, plasma levels, and antiarrhythmic efficacy. Administration of pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for pirmenol compared with other class I agents. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of potassium levels. To test the relevance of the in vitro electrophysiologic results, pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum potassium was either increased or decreased. Studies comparing pirmenol and disopyramide clearly showed a relative lack of serum potassium dependence for pirmenol, suggesting a potential clinical advantage over disopyramide and other antiarrhythmics in variable potassium settings. The clinical relevance of these observations will have to be established in patients with variable potassium levels. Overall, pirmenol compared favorably with other reference agents in efficacy and safety in extensive preclinical investigations.

Animals↗
PubMed1987

Ameroid constriction of the proximal left circumflex coronary artery in swine. A model of limited coronary collateral circulation.

Gradual narrowing and occlusion of a coronary artery in patients with atherosclerotic heart disease frequently causes enlargement of the collateral circulation. Although these vessels may protect from development of myocardial infarction, they frequently do not supply sufficient blood flow to prevent ischemia during periods of augmented myocardial oxygen demand. The purpose of this study was to develop a model of the collateral circulation in pigs, a species that previously has been shown to develop sparse collateral vessels. Eighteen pigs were instrumented with an Ameroid constrictor around the proximal left circumflex artery and left atrial and aortic catheters. In four animals the constrictor was placed just distal to a large proximal obtuse marginal vessel. Seven of the pigs were treated daily with oral aspirin (325 mg) and disopyramide (200 mg) throughout the study; the other 11 served as controls. After an average of 24 days postoperatively, radioactive microspheres were injected at rest, during exercise (mean heart rate = 245 beats/min), and during intravenous infusion of dypridamole (700 micrograms/kg). At autopsy the extent of necrosis was assessed by a point counting technique in the bed at risk. We found that 75-83% of the bed at risk remained viable. Although aspirin and disopyramide did not significantly alter the extent of infarction (37 +/- 36% untreated vs 17 +/- 6% treated), there was less variability of infarction in the treated group, and subendocardial blood flow during exercise was higher in the treated group compared to controls. The majority of infarction occurred in the subendocardial region. Animals with a large obtuse marginal branch developed significantly smaller infarcts (8 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effect of antiarrhythmic drugs on the premature action potential duration in canine cardiac Purkinje fibers.

We studied the effect of six class I antiarrhythmic drugs, i.e., quinidine (5 micrograms/ml), disopyramide (10 micrograms/ml), procainamide (30 micrograms/ml), flecainide (4 micrograms/ml), lidocaine (4 micrograms/ml) and mexiletine (4 micrograms/ml), on the durations of the basic action potential (APDb) at a cycle length of 500 ms and on the premature APD (APDt) elicited at progressively increasing diastolic intervals (DI) in canine Purkinje fibers. The difference between APDt elicited at diastolic intervals of 100 msec and the earliest APDt elicited at the onset of effective refractory period was defined as the range of APDt. In control this range was 98 +/- 1.8 ms (n = 59). Disopyramide and procainamide did not change the range significantly but the other four drugs decreased it significantly (P less than .01) as follows: quinidine by 50.2%, lidocaine by 60.2%, mexiletine by 61.6% and flecainide by 61.4%. The following four factors contributed to this decrease in range of APDt: shorter duration of APDb, increased effective refractory period/APD ratio, slower kinetics of APD restitution, and shift of normalized restitution curve toward longer APDt values. The magnitude of the contribution made by each of the above factors varied with different drugs. The greatest contributing factor for quinidine was an increased effective refractory period/APD ratio, for lidocaine a slower restitution and for flecainide and mexiletine the shift of the restitution curve. We concluded that antiarrhythmic drugs belonging to the same class have different effects on the range of premature APD and that these effects cannot be predicted from the effect of the drug on APDb alone.

Action Potentials↗
PubMed1979

[The anesthesiologist and the hemodynamic effect of anti-arrhythmic agents (excluding beta blockers)].

On the basis of a haemodynamic study involving the intravenous administration of disopyramide, a review is undertaken of the haemodynamic action of various anti-arrhythmics likely to be used pre- or peroperatively by the anaesthetist. All anti-arrhythmic agents have possible haemodynamic properties which may prove troublesome for the anaesthetist: --all (with the possible exception of bretylium tosylate) have negative inotropic properties; --all (with the exception of disopyramide) decrease peripheral resistance. These effects are as a rule slight in the healthy subject but may give rise to difficulties during anaesthesia of a patient with a damaged myocardium.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Pirmenol hydrochloride (CI-845): antiarrhythmic profile in coronary artery ligated conscious dogs.

The antiarrhythmic profile of CI-845 (pirmenol hydrochloride) was assessed in conscious, coronary artery ligated dogs. In single-dose studies in these arrhythmic dogs, CI-845 administered by the intravenous, intranuscular, and oral routes was highly effective in restoring normal sinus rhythm. A 2.5 mg/kg dose was effective against the arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arhythmias of the first day after ligation. The reference agents ajmaline, aprindine, disopyramide, lidocaine, mexiletine, procainamide, and quinidine were also tested, and in this model, CI-845 had greater efficacy, a longer duration of activity, and/or a wider safety margin. In slow rate intravenous infusion studies, 1-2 mg/kg/hr of CI-845 maintained near total arrhythmia conversion in first-day postligation dogs. Rapid rate intravenous infusion studies (10 mg/kg/hr) demonstrated a good correlation between the CI-845 dose, plasma level, and arrhythmia conversion, as well as a wide margin of safety. Mean conversions to 80% normal rhythm were achieved at 2.5 mg/kg, with associated plasma levels of 0.8 +/- 0.1 micron/ml, while first sings or gross toxicity occurred at 21.7 +/- 2.4 mg/kg at plasma levels of 6.2 +/- 0.4 micron/ml. There were minimal effects on cardiac conduction and blood pressure even at large doses. In drug interaction studies, CI-845 was safe and effective in combination with disopyramide, lidocaine, procainamide, propranolol, and quinidine. The results clearly show CI-845 to be an orally effective, long-acting antiarrhythmic agent with a favorable margin of safety in the coronary artery ligated dog model.

Administration, Oral↗
PubMed1982

Anti-arrhythmic agents in ischemic heart disease: supraventricular arrhythmias, digitalis toxicity and chronic stable ventricular ectopic beats.

Digoxin remains a very useful agent for chronic atrial fibrillation or for the ectopic beats associated with heart failure. But when rapid control of the ventricular rate is required to arrhythmias such as atrial fibrillation, atrial flutter, or paroxysmal atrial tachycardia, a slow infusion of verapamil is the agent of choice. In general, verapamil may be added to digoxin or given intravenously while a digoxin effect is awaited, unless there is digitalis toxicity. In digitalis toxicity, lignocaine remains the agent of choice for ventricular arrhythmias, and is given in the same doses as for acute myocardial infarction; phenytoin is used for digitalis-arrhythmias with A-V block. Verapamil may be infused very cautiously for digitalis-induced supraventricular tachyarrhythmias. The use of oral agents such as quinidine, disopyramide and mexilitene for chronic prophylaxis of ventricular ectopic beats is of doubtful effectiveness, unless the ectopic activity is symptomatic. Serious ventricular arrhythmias may be induced by quinidine and disopyramide. Beta-blockade is especially useful for ectopic beats associated with anxiety, or when arrhythmias are associated with angina of effort or hypertension. As always, major contraindications to the use of beta-blockade include cardiomegaly, heart failure or asthma.

Aged↗
PubMed1994

Evaluation of negative inotropic and antiarrhythmic effects of class 1 antiarrhythmic drugs.

The effects of 6 class 1 antiarrhythmic drugs (aprindine, cibenzoline, disopyramide, lidocaine, pirmenol, and quinidine) on myocardial action potential, its maximal upstroke velocity (Vmax) and isometric contractile force were evaluated by electrophysiological techniques. All the class 1 antiarrhythmic drugs examined had dose-dependent negative inotropic effects. The inhibitory effects on contractile force (Fc) was compared with the inhibitory effects on sodium channels under fast response. This ratio was indicated by IC50 Vmax/IC50Fc, and when evaluated and arranged in order of descending magnitude, these were the results: pirmenol, disopyramide, lidocaine, quinidine, cibenzoline and aprindine. The negative inotropic effects and the effects on action potential duration induced by these antiarrhythmic drugs were independent of each other; it had been found that classification of the drugs according to their effects on action potential duration did not provide sufficient information about negative inotropic effects. Class 1 antiarrhythmic drugs can be divided into 3 groups depending on the regression pattern of myocardial contractile force and the Vmax of action potentials under fast response and slow response. Drugs, whose inhibitory effects on sodium channels, are the main cause of negative inotropic effects. Drugs, whose inhibitory effects on calcium channels, are the main cause of negative inotropic effects. Drugs for which it is difficult to determine whether sodium channel or calcium channel blockade contributes more to their negative inotropic effects.

Action Potentials↗
PubMed1997

[Tilt-table test. Value in children and adolescents].

The tilt test is a non-invasive investigation which reproduces malaises or vagal syncope. This is a common condition in children and adolescents and the value of this investigation in this population is therefore self-evident. The tilt test was performed from 4 years of age in 105 children aged 4 to 18 years (mean 10 +/- 4 years) who had suffered one or several malaises with syncope. This test, using a resting period of 20 minutes, then a tilt of 70-80 degrees for 40 minutes, was considered to be positive if the symptoms could be reproduced or if the heart rate slowed to less than 50/min or if the blood pressure fell by more than 30 mmHg. The test was positive in 46 children (44%). Ten remained asymptomatic but had significant reductions in blood pressure: 36 children reproduced their symptoms. The positivity was related to a cardio-inhibitory response in 4 cases, vasodepressive in 20 cases, mixed in 20 cases and "psychiatric" in 2 cases: sinus tachycardia preceded positivity in 43 of the 46 cases. Only 21 children were treated either by disopyramide (12 cases) or betablockers (9 cases). All but one of the children became asymptomatic but the tilt test remained positive in 7 of the 9 patients treated with betablockers and in 3 children treated with disopyramide. The essential value of this investigation was to stop investigations in positive cases, to reassure parents and the children and to allow the pursuit of sporting activities. The authors conclude that the tilt test is an investigation easy to carry out in the young child and which spares complementary investigation in cases of positivity and guides medical treatment.

Adolescent↗
PubMed1979

Atrial bigeminy with block associated with bradycardia and paroxysmal atrial fibrillation -- an important variant of the tachycardia-bradycardia syndrome.

Serial 2-channel 24 h dynamic ECGs in 7 patients who were referred with the "tachy-brady" syndrome for consideration for permanent cardiac pacing revealed: 1. atrial premature beats (APBs) which were conducted to the ventricles normally or aberrantly; 2. intermittent atrial bigeminy with block towards the ventricles (this rhythm mimicked sinus bradycardia with ventricular rates of 38-45 beats/min and the ectopic P waves were visible on only one of the ECG channels); 3. paroxysms of atrial fibrillation initiated by closely coupled APBs. These findings suggested that both the ventricular bradycardia and the atrial fibrillation were caused by frequent APBs and that pacing therapy was unnecessary. Disopyramide was given to 5 patients resulting in suppression of the arrhythmia and relief of symptoms. In one patient there was spontaneous resolution and one patient refused treatment. This variant of the "tachy-brady" syndrome can be successfully treated by suppression of abnormal atrial impulse formation without recourse to pacemaker implantation.

Adult↗
PubMed1994

Characterization of ATP-sensitive potassium channels in intestinal, cholecystokinin-secreting cells.

In the present study, the electrophysiologic properties of ATP-sensitive potassium channels were evaluated in an intestinal, cholecystokinin-secreting cell line (STC-1). Channels were operative under basal conditions and, in cell-attached membrane patches, channel activity was decreased by glucose or disopyramide, agents which classically inhibit ATP-sensitive potassium channels. Channel activity was increased by the KATP channel opener, diazoxide. Intestinal ATP-sensitive potassium channels appear to behave in a similar manner to those found in cardiac and pancreatic beta cells.

Adenosine Triphosphate↗
PubMed1987

Uncorrected pre-ejection period: a simple non-invasive measurement for pharmacodynamic screening of inotropic activity.

Since heart rate (HR) is an important determinant of the duration of systole, systolic time intervals (STI) from 8 healthy subjects were examined after infusion of atropine. As no overall correlation was found between HR and pre-ejection period (PEP), the results confirm the need for individual estimates of the correction of the left ventricular ejection time (LVET) and the total electromechanical systole (OS2). In the same subjects the sensitivity of PEP to minor negative inotropic effects of mexiletine and disopyramide measured at Cmax was confirmed. Thus, in addition to its simplicity and reliability, the sensitivity of the uncorrected PEP should encourage use of this technique as part of any screening system for the early detection of an inotropic effect of new chemical entities.

Adult↗
PubMed1993

Effect of E-4031, a new class III antiarrhythmic drug, on reentrant ventricular arrhythmias: comparison with conventional class I drugs.

We evaluated the antiarrhythmic efficacy of E-4031, a new class III drug, and compared it with that of conventional class I and II antiarrhythmic agents in terms of electrophysiological actions on refractoriness and conduction in a 7-day-old canine model of myocardial infarction. Sustained monomorphic VT was reproducibly induced in 26 dogs by a premature stimulation method from the right ventricle. Class I drugs (disopyramide, aprindine, flecainide) prevented VT induction in 5 of 13 dogs, and propranolol and E-4031 prevented it in 6 of 6 and 6 of 7 dogs, respectively. The effective refractory period (ERP) was determined at 47 epicardial sites overlying the infarct in each experiment by a S1S2 method. The standard deviation (SD) of the mean ERP of these sites was used as an index of ERP dispersion. The extent of ERP prolongation produced by class I drugs and E-4031 was significantly more marked than that produced by propranolol. However, the SD was increased by class I drugs and E-4031, but not by propranolol. Class I drugs increased the ERP dispersion mainly by an effect on the transmural infarct zone in which the control ERP was more prolonged than in the normal zone. E-4031 tended to prolong the ERP in both the normal and infarct zones, and had a minimal tendency to increase ERP dispersion. In contrast, propranolol decreased the ERP dispersion between zones. Conduction velocity calculated by epicardial mapping was significantly decreased by flecainide, but not by E-4031. We conclude that the antiarrhythmic effect of E-4031 depends largely on its ability to prolong refractoriness without suppressing conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Modeling of drug response in individual subjects.

Pharmacokinetic and drug response data from individual subjects are analyzed empirically by two different mathematical techniques. The drugs involved are the antiarrhythmic agent disopyramide, whose kinetics can be described by a two-compartment model, and two cardiac glycosides, digoxin and beta-methyl digoxin, for which three-compartment models are appropriate. The first analytical approach uses multiple linear regression to describe response in terms of the amount of drug in several kinetic compartments. The second approach describes response in terms of the drug concentration in an "effect" compartment. Both approaches describe the data equally well and require the same number of parameters for model specificaton.

Digoxin↗
PubMed1980

[Electrophysiological classification of newer antiarrhythmic drugs (author's transl)].

Newer antiarrhythmic drugs are tentatively classified on the basis of their influence on the transmembrane action potential, the fast sodium inward current and its kinetics, and the slow inward current which is primarily carried by calcium ions. Disopyramide is probably a quinidine-like antiarrhythmic drug, while the effects of aprindine, lorcainide, and tocainide resemble those of lidocaine. Mexiletine and propafenon cannot be classified definitely on the basis of the hitherto available electrophysiological data. Besides their effects on the fast inward current these substances may have additional calcium antagonistic properties.

Action Potentials↗