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Biomedical subjects

D L Keefe

Publications and source records attributed to D L Keefe.

At least 73 records · Page 4Linked to original sources
PubMed1986

Prophylactic tocainide or lidocaine in acute myocardial infarction.

Twenty-nine patients with acute myocardial infarction (AMI) were studied in a randomized double-blind trial of intravenous lidocaine and tocainide, followed by either oral tocainide or placebo without regard to previous therapy, for the prophylaxis of arrhythmias associated with acute infarction. No patient had symptomatic ventricular tachycardia or fibrillation, although 1 patient taking lidocaine was withdrawn from therapy because of breakthrough arrhythmias. One patient in each group died from mechanical complications of AMI. Tocainide was administered to 16 patients and lidocaine to 13. Seven of the 13 patients receiving lidocaine had ventricular tachycardia or accelerated idioventricular rhythm, compared with 2 of 16 receiving tocainide (p less than 0.05). Adverse effects were noted in 11 of the 13 patients receiving lidocaine and 6 of the 16 patients receiving tocainide. The infusions used provided therapeutic levels of lidocaine or tocainide and the transition to oral tocainide was accomplished safely with maintenance of therapeutic antiarrhythmic levels. Thus, tocainide appears to be at least as efficacious and may be safer than lidocaine for the prophylaxis of ventricular arrhythmias associated with AMI. The transition to oral tocainide is well tolerated and can be accomplished with minimal difficulty.

Administration, Oral↗
PubMed1986

Multicenter trial of sotalol for suppression of frequent, complex ventricular arrhythmias: a double-blind, randomized, placebo-controlled evaluation of two doses.

Sotalol is a unique beta-adrenergic blocking agent with additional actions characteristic of Vaughn-Williams class III antiarrhythmic agents in experimental models. To test the efficacy of sotalol to suppress ventricular arrhythmias, a 6 week parallel, placebo-controlled out-patient study of two doses (320 and 640 mg/day, in two divided doses) was performed in four hospitals in 56 patients with chronic premature ventricular complexes at a frequency of 30/h or more (mean +/- SE, 528 +/- 60/h) on 48 hour ambulatory electrocardiographic recording. During a placebo week, no change occurred in arrhythmia frequency (532 +/- 76/h). Subsequent sotalol therapy significantly reduced median arrhythmia frequency in patients receiving both low (n = 19) and high (n = 18) doses compared with that in patients receiving placebo (by 77 and 83%, respectively, versus 6%; p less than 0.001). Twenty-two (59%) of 37 sotalol-treated patients, 11 in each group, reached the prospectively defined criterion of efficacy (greater than or equal to 75% arrhythmia reduction) versus 2 (11%) of 19 placebo control patients (p less than 0.001). Sotalol reduced the median frequency of couplets by 94% (p less than 0.0001) and that of runs by 89% (p less than 0.0007). The electrocardiographic effects of sotalol included reductions in heart rate (by 17 to 27%) and increases in the QTc (by 6 to 9%) and PR (by 6%) intervals. Ejection fraction was unchanged. The most common adverse side effect was fatigue, but drug discontinuation was required in only three patients taking 640 mg/day. No proarrhythmic events or biochemical abnormalities were observed. In summary, sotalol displays significant antiarrhythmic activity of moderately high degree with good tolerance in doses of both 320 and 640 mg/day. Its antiarrhythmic actions are distinguished from those reported for other beta-blockers by its effects on the QTc interval and its moderately high degree of antiarrhythmic activity.

Aged↗
PubMed1985

Chronic lorcainide therapy for symptomatic premature ventricular complexes: efficacy, pharmacokinetics and evidence for norlorcainide antiarrhythmic effect.

Chronic premature ventricular complexes (PVCs) have been effectively suppressed by oral lorcainide as reported in previous short-term studies. The plasma level-effect relation of lorcainide may be affected by the possible cardioactivity of norlorcainide, a metabolite that accumulates after repeated oral doses. This study evaluated the long-term efficacy of lorcainide in suppressing chronic symptomatic PVCs, and examined the relation of arrhythmia suppression to plasma concentrations of lorcainide and norlorcainide. Fourteen patients were treated with lorcainide, 200 to 400 mg/day, 12 of whom achieved nearly complete suppression of arrhythmias after treatment for 1 year. Chronic lorcainide treatment was well tolerated; no patient discontinued treatment because of adverse effects. Lorcainide and norlorcainide plasma concentrations remained stable after the first week of therapy. Antiarrhythmic activity persisted throughout the year. Upon drug withdrawal, the mean lorcainide washout half-life was 14.3 +/- 3.7 hours and the mean norlorcainide washout half-life was 31.9 +/- 8.9 hours. The return of arrhythmias occurred well after the lorcainide plasma concentration had decreased to subtherapeutic levels, suggesting an antiarrhythmic effect of norlorcainide. Thus, long-term lorcainide therapy is effective in treating chronic symptomatic PVCs and is well tolerated by most patients. The metabolite norlorcainide appears to have antiarrhythmic activity independent of lorcainide.

Benzeneacetamides↗
PubMed1985

Atrioventricular conduction abnormalities in patients undergoing isolated aortic or mitral valve replacement.

Cardiac conduction defects are common in patients with aortic valve disease. Several studies have suggested that the spontaneous occurrence of complete heart block in these patients is related to the extent of calcium deposits in the aortic valve and adjacent structures. No studies have been done to relate the occurrence of complete heart block at the time of valve replacement to predictive factors. We evaluated 102 consecutive patients undergoing isolated aortic valve replacement and 100 patients undergoing isolated mitral valve replacement. Although transient complete heart block was relatively common in each group (17.6% and 13%, respectively), we were not able to identify any factors predictive of its occurrence. There was a very low incidence of late heart block in a follow-up period of over four years. Thus, the capability for temporary pacing is mandatory in patients undergoing valve replacement. However, transient complete AV block during the perioperative period does not predict late recurrence of AV block and, therefore, prophylactic pacemaker or electrode implantation during or following transient block appears unnecessary.

Aortic Valve↗
PubMed1985

Clinical use of digitalis materials.

Digitalis is a drug widely used in modern medicine for the control of ventricular response in atrial fibrillation and the treatment of congestive heart failure (CHF). Recently, the use of digitalis for the treatment of CHF in patients in sinus rhythm has become quite controversial. The findings of several clinical studies suggest a small but definite hemodynamic or clinical improvement in patients treated with digitalis. These effects are limited by the onset of toxicity, which is at least partially mediated via the central nervous system. If the inotropic effect of the drug could be separated from the central nervous system effect, much higher doses of digitalis could be tolerated and presumably a greater therapeutic effect could be obtained.

Animals↗
PubMed1984

Pharmacology of lorcainide.

Lorcainide is a new type 1 antiarrhythmic drug that is well absorbed orally, with bioavailability increasing with both dose and continued administration. It is metabolized through the liver, and patients with significant liver disease will require dosage reduction. The drug has an active metabolite, norlorcainide, whose activity is similar to that of lorcainide but whose half-life is 26 hours instead of 8 for the parent compound. The levels of this metabolite are nearly twice those of lorcainide at steady state. The long half-life of the metabolite and the changing bioavailability of lorcainide require that a given dose be administered for 1 week for the maximum effect to be demonstrated.

Animals↗
PubMed1984

Pharmacodynamics of the initiation of antiarrhythmic therapy with lorcainide.

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Administration, Oral↗
PubMed1984

The effect of antiarrhythmic agents on myocardial contractility and arrhythmia frequency.

Most patients requiring antiarrhythmic therapy for ventricular arrhythmias have underlying organic heart disease which causes left ventricular dysfunction. Treatment of these patients' arrhythmias requires knowledge of the hemodynamic as well as antiarrhythmic effects of the available agents. These effects may differ during acute and chronic oral therapy. Several of the newer agents and quinidine are very effective in suppressing ventricular ectopic activity, allowing demonstration of drug effect during ambulatory monitoring. The clinical significance of this for prevention of sudden death has yet to be shown. However, prevention of ventricular tachycardia or fibrillation in the electrophysiology laboratory and suppression of ambient ectopy may generally be separate phenomena, as has been demonstrated for amiodarone.

Anti-Arrhythmia Agents↗
PubMed1983

Lorcainide disposition kinetics in arrhythmia patients.

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

Administration, Oral↗
PubMed1982

Prolongation of verapamil elimination kinetics during chronic oral administration.

The elimination of verapamil and its n-demethylated metabolite, norverapamil, was studied in nine patients with chronic atrial fibrillation after the first oral verapamil dose and during chronic oral verapamil administration. Significant increases (p less than 0.01) were seen in the elimination half-lives (t 1/2's) of both verapamil (6.4 +/- 3.5 to 12 +/- 5 hours, mean +/- SD) and norverapamil (10.3 +/- 6 to 16.5 +/- 7 hours) during chronic oral verapamil administration. These pharmacokinetic observations have important clinical implications for the rational long-term administration of this agent. Once steady-state serum concentrations have been achieved during chronic verapamil administration, verapamil doses should be given at less frequent intervals or in smaller doses in order to produce the desired serum concentration and therapeutic response and to minimize unwanted or toxic drug effects.

Administration, Oral↗