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Biomedical subjects

D L Keefe

Publications and source records attributed to D L Keefe.

83 records · Page 5Linked to original sources
PubMed1982

Randomized double-blind placebo controlled crossover trial documenting oral lorcainide efficacy in suppression of symptomatic ventricular tachyarrhythmias.

Lorcainide, a new antiarrhythmic drug, was given to 10 patients with frequent (greater than 1/min) premature ventricular contractions (PVCs) on a baseline 24-hour Holter monitor. Each patient received lorcainide, 100 mg twice daily, and an identical placebo, in a randomized double-blind crossover trial, with 1 week in each treatment period. Before the trial and at the end of each period, routine laboratory, clinical evaluation, 12-lead ECG's, and 24-hour ambulatory ECG recordings were performed. Trough drug plasma concentration measurements were done at the end of each treatment period. All patients had reduction in PVCs, comparing drug to placebo, averaging 82.3 +/- 19.7% (mean +/- SD, p less than 0.01 by Wilcoxin ranked sum), and there was also significant decrease in the number of ventricular pairs and runs. Levels of the major metabolite, norlorcainide, ranged from 34 to 254 ng/ml (mean 160 ng/ml) and exceeded those for lorcainide, range 6 to 169 ng/ml (mean 79 ng/ml). Prolongation of PR, QRS, and QTc intervals was evident during drug therapy, as was decrease in heart rate, but these changes were minimal. The major adverse effect noted was sleep disturbance, which was often initially severe, but improved during the week of therapy.

Administration, Oral↗
PubMed1982

Programmed ventricular stimulation in predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy.

In predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy, several factors and questions need to be considered, including the following. (1) Ventricular tachycardia (VT) can be induced in most patients who have recurrent sustained VT. (2) Because induced VT can often be pace terminated, termination by pacing should be attempted before cardioversion is applied. (3) Acutely effective antiarrhythmic agents are no longer being found for the majority of patients undergoing electrophysiologic-pharmacologic study in our series. (4) Specific VT-induction programs affect both the inducibility of VT and acute efficacy of drugs at electrophysiologic study; this point requires examination. (5) Arrhythmia-induction studies may not product high yield in patients with clinical ventricular fibrillation or unsustained VT. (6) It is as yet unclear whether some drugs, such as amiodarone, can be accurately evaluated by using arrhythmia-induction techniques. (7) Induction of the repetitive ventricular response by V2 stimulation is not a useful method for antiarrhythmic drug selection in patients with recurrent ventricular tachyarrhythmias. (8) Adequate data do not yet exist to identify either the ECG-monitoring technique or the arrhythmia-induction technique as the preferred method for selecting antiarrhythmic drugs for chronic therapy of patients with recurrent ventricular tachyarrhythmias. A study to compare the accuracies of the two techniques is both feasible and needed.

Amiodarone↗
PubMed1982

Antiarrhythmic drug combinations in the treatment of ventricular tachycardia.

Combinations of antiarrhythmic drugs are frequently used to treat refractory ventricular tachycardia (VT), but few scientific data support this practice. We examined the efficacy and electrophysiology of 110 antiarrhythmic drug combination trials at electrophysiologic study in 74 patients with recurrent ventricular tachycardia. Lidocaine was combined with quinidine in 33 trials, procainamide in 22 and encainide in 20. Propranolol was combined with quinidine in 17 trials, procainamide in 12 and encainide in six. All individual drugs tested (except propranolol, which was usually not tested individually) had failed at electrophysiologic study or clinically in the presence of usually accepted plasma concentrations. Lidocaine in combination with quinidine was effective in 3% of the trials, with procanamide in 5% and with encainide in none of the trials. Propranolol in combination with quinidine was effective in 18% of the trials, with procainamide in 17% and with encainide in none of the trials. The electrophysiologic effects of the tested drug combinations were dominated by the individual effects of the type 1 antiarrhythmic agents. We conclude that the tested antiarrhythmic drug combinations are infrequently effective in preventing VT induction at electrophysiologic study when each agent has failed individually. The addition of lidocaine or propranolol to quinidine, procainamide or encainide does not produce significant synergistic or new effects on the electrophysiologic variables analyzed.

Aged↗
PubMed1982

Myocardial disposition and cardiac pharmacodynamics of verapamil in the dog.

The disposition of verapamil was studied in anesthetized open-chested dogs following administration of intravenous doses of 0.5 mg/kg. The plasma and myocardial verapamil concentration-time data were fit to a three-compartment model to describe the disposition kinetics. The distribution equilibrium between myocardium and plasma was achieved rapidly and the concentration of verapamil decayed in parallel in these two tissues. The partition coefficient which describes the time averaged myocardial/plasma concentration ratio was 6.21 +/- 2.38. Examination of the relationship between the plasma and myocardial concentrations and the time course of the effect of verapamil, as defined as PR interval prolongation, revealed a hysteresis effect in some dogs. Despite this hysteresis, there was a linear relationship between plasma and myocardial concentrations of verapamil and the degree of prolongation of the PR interval. The results of this study indicate that the concentration in the plasma is in equilibrium with the myocardium and changes in plasma concentration are indicative of parallel changes in myocardial levels. The effect of verapamil on the atrioventricular node is related to the concentration in the myocardium and plasma, but there is substantial interanimal variability in the sensitivity to verapamil.

Animals↗
PubMed1981

Verapamil disposition kinetics in chronic atrial fibrillation.

Verapamil disposition was studied in 12 patients with chronic and fibrillation. After an intravenous bolus of 15 mg plasma concentration was determined and the data fit in a three-compartment model. Model independent parameters were calculated and values for half-life (t 1/2), clearance, and steady-state distribution volume were 6.3 +/- 4 hr, 13.3 +/- 7.7 ml/min/kg, and 4.3 +/- 1.9 l/kg. The model was used to design a multistep infusion scheme, which was employed successfully to achieve predetermined plasma concentrations. Following single oral doses of 120 mg, plasma levels of verapamil and norverapamil were determined. The elimination t 1/2 for verapamil and norverapamil were 8.3 +/- 6.1 and 10.5 +/- 5.6 hr, respectively. The bioavailability of oral verapamil was 35 +/- 16%. During long-term oral therapy the mean verapamil plasma concentration was twice the value predicted from the single-dose studies. This suggests that verapamil may have reduced clearance during long-term oral use.

Administration, Oral↗
PubMed1981

Verapamil protein binding in patients and in normal subjects.

Verapamil plasma protein binding was studied in four groups of 12 subjects each: (1) normal subjects; (2) patients with moderate renal insufficiency and patients requiring dialysis; (3) patients 1 to 4 days after coronary artery surgery; and (4) patients undergoing cardiac catheterization. In normal subjects, plasma protein binding of verapamil was 89.6 +/- 0.17% and was concentration independent over a range of 35 to 1,557 ng/ml, which includes the usual clinical plasma range. In normal subjects, plasma protein binding of verapamil was not affected by addition of its major metabolite, norverapamil, in ratios of 1.2 to 26.3 (norverapamil/verapamil) or by the addition of 10 micrograms of warfarin. The plasma protein binding of verapamil was not altered in the postsurgical state or in the dialysis patients. Verapamil protein binding was initially lower in the cardiac catheterization patients (mean = 86.34 +/- 2.13%, p less than 0.001) than in normal subjects and was still lower (mean = 83.29 +/- 3.04%, p less than 0.02) after heparinization. There was also a small increase in binding in the patients with renal insufficiency (p less than 0.05). Plasma protein binding of verapamil in mongrel dogs (mean = 90.7%) was the same order. We found verapamil to be approximately 90% bound in man and dogs and not markedly changed by any of the conditions studied.

Adult↗
PubMed1980

Influence of prolonged recumbency on drug disposition.

The disposition of lidocaine and penicillin was studied in normal subjects before and after 7 days of total recumbency. Penicillin (1,000,000 U) and lidocaine (100 mg) were administered intravenously. Lidocaine protein binding was also followed. Total body clearance, elimination half-life, and volume of distribution were calculated. There were no statistically significant differences in these disposition parameters before and after 7 days of recumbency. The binding of lidocaine also was not changed after bed rest. We conclude that the physiologic changes that occur during prolonged bed rest do not affect distribution or elimination of lidocaine or penicillin.

Bed Rest↗
PubMedDate not supplied

Comparative electrophysiology of lorcainide and norlorcainide in the dog.

Electrophysiologic effects of intravenous lorcainide and its major metabolite, norlorcainide, were examined in 18 anesthetized dogs, using intracardiac electrophysiologic measurements and programmed stimulation. Lorcainide and norlorcainide were studied separately, using six dogs for each experiment. Each compound was administered by a series of 5 one-h graded infusions each involving a loading dose over 15 min followed by a 45-min maintenance infusion. Plasma concentrations ranged from 94 +/- 34 to 1345 +/- 471 ng/ml for lorcainide and 81 +/- 22 to 1344 +/- 458 ng/ml for norlorcainide. Six additional dogs were studied, using a combination of a constant lorcainide infusion and four progressively increasing doses of norlorcainide. Both lorcainide and norlorcainide caused concentration-dependent prolongation of PR interval, QRS duration, AH and HV intervals, atrial and ventricular effective refractory periods, and the atrioventricular nodal functional refractory period. For each electrophysiologic parameter, plots of percent change as a function of log plasma concentration were nearly superimposable for lorcainide and norlorcainide. Plots for the combined treatment group using the total plasma concentration of lorcainide and norlorcainide were similar to those for each compound alone. We conclude that in dogs norlorcainide has considerable electrophysiologic activity, and is approximately equieffective and equipotent when compared with lorcainide, and that the electrophysiologic effects of the two compounds appear additive.

Animals↗
PubMedDate not supplied

Estrogen mustard induces cell cycle arrest of human epithelial ovarian cancer cell lines.

OBJECTIVE: Pharmacologic disruption of microtubule function may provide effective therapy for advanced epithelial ovarian cancer, as has been observed in clinical trials using taxol. However, the limited availability of taxol and taxol's side effects emphasize a need to develop alternative antimicrotubule agents. Estramustine (EM) inhibits binding of microtubule-associated proteins (MAPs) to microtubules, promotes microtubule disassembly, disrupts spindle formation, and induces metaphase arrest in human prostate carcinoma and glioma cells in culture. We studied the effect of EM on DNA synthesis and on the cell cycle in four human ovarian carcinoma cell lines and examined the cell lines for evidence of MAP-like immunoreactivity. METHODS: The effect of EM on DNA synthesis and on the cell cycle was determined using [3H]thymidine incorporation assays and flow cytometry, respectively. Microtubule-associated protein-like immunoreactivity was determined using monoclonal antibodies directed against MAP 1A, MAP 1B, and MAP 2(2A + 2B) for Western analysis after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. RESULTS: We demonstrated a dose-dependent inhibitory response to EM in BIXLER, DK2NMA, and SKOV3. BIX3 showed a dose-dependent inhibitory response to EM concentrations from 25 micrograms/mL to 100 micrograms/mL, but a stimulatory response at 10 micrograms/mL. Estramustine inhibited exponentially growing cells by causing mitotic arrest with subsequent accumulation of cells in G2/M phase of the cell cycle in all four cell lines. We found MAP 1A, MAP 1B, and MAP 2-like immunoreactivity in all four cells lines studied. CONCLUSIONS: These results are consistent with a MAP-microtubule mechanism of action for EM in ovarian carcinoma cells and provide reason to conduct further study of EM for potential use in the treatment of human epithelial ovarian cancer.

Antineoplastic Agents, Hormonal↗