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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 181 records · Page 10Linked to original sources
PubMed1980

Total suppression of ventricular arrhythmias by encainide. Pharmacokinetic and electrocardiographic characteristics.

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Adult↗
PubMed1980

Tocainide therapy for refractory ventricular arrhythmias.

Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.

Adult↗
PubMed1980

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patient's procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

Acecainide↗
PubMed1979

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↗
PubMed1979

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↗
PubMed1978

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↗
PubMed1978

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↗
PubMed1978

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↗
PubMed1978

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↗
PubMed1977

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↗
PubMed1977

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↗
PubMed1977

Guanethidine.

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Guanethidine↗
PubMed1976

Simultaneous quantification of procainamide and N-acetylprocainamide with high-performance liquid chromatography.

A rapid, precise and specific method for the simultaneous determination of procainamide and N-acetylprocainamide (NAPA) in plasma using high-performance liquid chromatography is described. N-Formylprocainamide was utilized as internal standard. The coefficients of variation of the method for both procainamide and NAPA were 3.6% in the range of plasma levels to be expected clinically. The method is especially useful for rapid determination of acetylator phenotype in patients requiring procainamide for control of arrhythmias.

Arrhythmias, Cardiac↗
PubMed1976

Guanethidine.

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Administration, Oral↗
PubMed1976

Antiarrhythmic effects of a lidocaine congener, tocainide, 2-amino-2',6'-propionoxylidide, in man.

Eight patients with frequent premature ventricular contractions (PVCs) were given single oral doses of 2-amino-2', 6'-propionoxylidide hydrochloride (APX), a lidocaine congener, to investigate the drug's efficacy, toxicity, and pharmacokinetics. Of the 7 patients receiving more than 100 mg, 5 demonstrated at least 60% reduction in PVCs in the 5-hour period following one of the doses; the responsiveness to APX was similar to that observed when intravenous lidocaine was given to the same patients. There were side effects of transient dizziness, lightheadedness, and nausea in 3 patients 20 to 30 min after doses of 400 to 800 mg; slightly smaller doses in 2 of these patients retained efficacy without side effects. There were no effects on arterial blood pressure, heart rate, or the electrocardiogram of normally conducted beats. Laboratory values remained within normal limits, although the hemoglobin level and hematocrit showed a small but significant fall probably related to repeated blood sampling during the study. Drug plasma levels at 1 and 2 hr after administration and the area under the plasma concentration-time curve were proportional to dose, and the drug disappeared with a mean elimination half-life of 14.7 +/- 1.7 hr (mean +/- SD). Plasma levels resulting in suppression of PVCs ranged from 1 to 5 mug/ml. A mean of 39.7 +/- 12.4% of an orally administered dose was recovered unchanged in 48-hr urine collections. Comparison of the present results with those previously obtained after intravenous administration of APX indicates that oral bioavailability of the drug was essentially complete. APX appears to be a promising orally effective antiarrhythmic drug with suitable pharmacokinetic characteristics to warrant studies designed to establish dosage regimens for chronic therapy.

Adult↗