Familial dilated cardiomyopathy.
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Black People↗
Biomedical subjects
R L Woosley
Publications and source records attributed to R L Woosley.
The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.
The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.
Anti-Arrhythmia Agents↗
Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin.
Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients. Nine subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral erythromycin (500 mg every 8 hours). All subjects increased metabolite concentrations after the addition of erythromycin for 1 week. The maximum concentration of metabolite increased by a mean of 107% and the mean metabolite area under the concentration-time curve increased by 170%. Three subjects accumulated unmetabolized terfenadine after administration of erythromycin for 1 week. Electrocardiographic data revealed changes in QT intervals and ST-U complexes in a subset of subjects who accumulated terfenadine. We conclude that erythromycin alters the metabolism of terfenadine, leading to accumulation of terfenadine in certain individuals that is associated with altered cardiac repolarization.
Administration, Oral↗
The clinical value of FDA class C drugs approved from 1981 to 1988.
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Drug Therapy↗
Biomedical research funding: view of the National Caucus of Basic Biomedical Science Chairs.
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Financing, Government↗
Clinical implications of variable antiarrhythmic drug metabolism.
Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.
Anti-Arrhythmia Agents↗
Efficacy and safety of ACC-9358, a new antiarrhythmic agent.
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Aged↗
Lack of triggered automaticity despite repolarization abnormalities due to bepridil and lidoflazine.
Bepridil and lidoflazine are calcium channel antagonists that also prolong action potential duration, produce QT interval prolongation on the surface ECG, and have been associated with the distinctive form of ventricular tachycardia, torsade de pointes. It has been demonstrated that quinidine, which also prolongs QT interval and induces torsade de pointes, produces early afterdepolarizations and triggered activity in canine Purkinje fibers driven at slow rates. The effects of bepridil (1-10 microM) and of lidoflazine (5-15 microM) on the transmembrane action potential from canine Purkinje fibers were therefore studied. At long cycle lengths, unlike with quinidine, triggered activity arising during phase 3 was rare; phase 3 secondary plateaus (early afterdepolarizations) were, however, common. Arrest of transmembrane potential between -50 and -60 mV during stimulation at long cycle lengths was also frequently observed (7/20 of bepridil and 3/15 of lidoflazine-treated fibers). In preparations with prominent phase 3 secondary plateaus, addition of epinephrine resulted in triggered activity; similarly, epinephrine caused automaticity from a depolarized membrane potential in 8/9 fibers quiescent at -50 to -60 mV. Thus, the calcium channel blocking drugs bepridil and lidoflazine produced striking repolarization changes at slow stimulation rates, but unlike quinidine, triggered activity was rare. The effect of epinephrine on these drug-treated fibers suggests that the slow inward calcium current plays a role in the generation of triggered activity in the presence of prolonged repolarization.
Action Potentials↗
Evidence for the biotransformation of procainamide to a reactive metabolite.
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Acetylation↗
Agranulocytosis during combined procainamide and phenytoin therapy.
We have presented two cases of agranulocytosis occurring in patients receiving a combination antiarrhythmic regimen. As multiple drug therapy for ventricular arrhythmias becomes more commonplace, increased scrutiny should be given to agents chosen, in an effort to prevent any possible adverse interactions. When future cases are encountered, the acetylator pheontype should be determined. This information would aid in assessing the predicative value of the acetylator phenotype in the development of agranulocytosis. Due to the inherent danger, neither patient was rechallenged with procainamide nor phenytoin.
Acetylation↗
Suppression of chronic ventricular arrhythmias with propranolol.
The antiarrhythmic efficacy of propranolol was evaluated in 32 patients with chronic high frequency ventricular arrhythmias in a placebo-controlled protocol. After a placebo control period, propranolol was begun and the dosage increased sequentially until arrhythmia suppression was achieved, side effects appeared, or a maximum dosage of 960 mg/day was reached. Computerized analysis of ambulatory recordings was used to quantify the arrhythmias. Twenty-four patients had 70--100% arrhythmia suppression at plasma levels ranging from 12--1100 ng/ml (end of dosing interval). Eight patients in this group had frequent episodes of ventricular tachycardia that were totally suppressed at or below the dosage that produced greater than or equal to 70% suppression of ventricular ectopic depolarizations (VEDs). A biphasic dose-response curve was seen in five patients who responded with a decrease in arrhythmia frequency in the lower ranges of dosages but had increased frequency of ectopic rhythms as the dosage was increased above the optimal level. Only one-third of patients responded at doses less than or equal to 160 mg/day. However, with dosages of 200--640 mg/day, an additional 40% responded. Propranolol appears to control ventricular arrhythmias safely and effectively in many patients. The finding that the antiarrhythmic effect in many patients required plasma concentrations greater than those that produce substantial beta-adrenergic blockage raises a question whether blockade of cardiac beta receptors can directly account for all of the antiarrhythmic actions of propranolol.
Adult↗
Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome.
To investigate the relation between acetvlator phenotype and the development of procainamide-induced lupus, we determined the rate of development of antinuclear antibodies in 20 patients of known acetylator phenotype receiving chronic procainamide therapy. The duration of therapy required to induce antibodies in 50 per cent of slow (11) and rapid (nine) acetylators was 2.9 and 7.3 months respectively. The median total dose that produced ant;bodies was 1.5 g per kilogram and 6.1 g per kilogram respectively. After one year antibodies had developed in 18 patients. Retrospective studies of patients in whom procainamide lupus had developed revealed that the duration of therapy required for induction in 14 slow and seven rapid acetylators was 12 +/- 5 and 48 +/- 22 months respectively (P less than 0.002). We conclude that acetylator phenotype influences the rate at which procainamide induces antinuclear antibodies and probably the lupus syndrome. Antibody production is probably related to the parent compound or a non-acetylated metabolite.
Acetylation↗
Pharmacokinetics of antiarrhythmic drugs.
A knowledge of the determinants of the plasma concentrations of antiarrhythmic drugs is important because variation in plasma levels is often greater than the desired therapeutic range. The basic principles of pharmacokinetics are outlined and their application to the design of dosage regimens described. These principles are illustrated in a review of the pharmacokinetics of lidocaine and its congeners, procainamide and its active metabolite (N-acetylprocainamide), quindine, disopyramide, phenytoin and propranolol, with particular emphasis of the factors that contribute to altered disposition.
Administration, Oral↗
Normal distribution of acetylation phenotypes in systemic lupus erythematosus.
Previous reports have indicated that idiopathic systemic lupus erythematosus (SLE), like drug-induced lupus, is more frequent in "slow" hepatic acetylators. Using dapsone acetylation rate to determine phenotypes, we found that of the 18 SLE patients studied, 9 were fast acetylators, 8 were slow, and 1 was indeterminate. This result (53% fast) is similar to acetylator phenotypes in our normal controls (50% fast) and in the population at large (52%).
Acetylation↗
Simultaneous analysis of dapsone and monoacetyldapsone employing high performance liquid chromatography: a rapid method for determination of acetylator phenotype.
1 A rapid, accurate and convenient technique for determination of acetylator phenotype of patients or subjects has not been available for routine clinical application. 2 An improved method for rapid and convenient determination of acetylator phenotype is described. 3 The plasma concentrations of dapsone (DDS) and monoacetyldapsone (MAD) were measured 3 h after a single oral 100 mg dose of dapsone using a specific and sensitive high performance liquid chromatographic assay. 4 The plasma concentration ratio of monoacetyldapsone to dapsone can accurately assess acetylator phenotype in patients or subjects. 5 The clinical applications for this method are discussed.
Acetylation↗
Cumulation of N-acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function.
N-Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 microgram/ml 3 hr after a dose of procainamide which is well above the 3-hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 microgram/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 microgram/ml) and 38 days (0.9 microgram/ml) after procainamide was stopped, indicating a half-life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.
Acetylation↗
Suppression of ventricular ectopic depolarizations by tocainide.
In a previous clinical study we demonstrated that tocainide is effective in the suppression of ventricular ectopic depolarizations (VEDs) after single oral doses. This information provided the basis for evaluating this drug's antiarrhythmic efficacy after multiple dose administration according to a loading-maintenance regimen. Twelve patients with stable VEDs were given loading doses of tocainide (400-600 mg) with maintenance doses every 12 hours. Every 48 hours the dose was increased until either arrhythmia suppression to less than 25% of VED frequency during placebo administration or side effects occurred. Computer analysis of 12-hr telemetric ECGs taken 24-36 hr after each dosage increment documented effective suppression (76-95%) in 8 of 12 patients. Those subjects demonstrating suppression were randomly assigned to a cross-over study of placebo or active drug at the dosage found effective in the dose-ranging phase. Dosages for the cross-over stage ranged from 400 to 1100 mg every 12 hours. Comparison of the two five-day periods documented suppression in these patients (mean +/- SE = 83.3 +/- 4%). No serious side effects or undue drug accumulation occurred during the study. The data indicate that tocainide can effectively suppress VEDs for 8-12 hours in many patients and that continuous suppression could be possible on an 8-12 hr dosage regimen.
Anti-Arrhythmia Agents↗