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Biomedical subjects

R A Winkle

Publications and source records attributed to R A Winkle.

At least 109 records · Page 6Linked to original sources
PubMed1978

Dose-dependent acebutolol disposition after oral administration.

The relationship between dose and area under the blood concentration-time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

Acebutolol↗
PubMed1978

Cardiac biopsy evidence for a cardiomyopathy associated with symptomatic mitral valve prolapse.

Right ventricular endomyocardial biopsy was performed in 14 patients with mitral valve prolapse to determine the existence of an associated cardiomyopathic process. All 14 patients had echocardiographic, angiographic or auscultatory evidence of mitral valve prolapse, and all were symptomatic. The group had a high incidence rate of conduction system abnormalities (50 percent) and arrhythmias (64 percent), but only one patient had a significant hemodynamic abnormality. Light microscopy revealed an increase in endocardial and interstitial fibrosis in eight patients (57 percent). Electron microscopy, performed in 11 patients, showed mitochondrial degenerative changes in all 11. Nuclear chromatin clumping, intracell edema and myocyte degeneration were frequently present. It is concluded that endomyocardial and myocardial abnormalities exist in some symptomatic patients with idiopathic mitral valve prolapse.

Adult↗
PubMed1978

Antiarrhythmic drug effect assessed from ventricular arrhythmia reduction in the ambulatory electrocardiogram and treadmill test: comparison of propranolol, procainamide and quinidine.

A 5 week study was performed in 17 patients with frequent ventricular ectopic complexes. The study design comprised an initial control period, 1 week each of treatment with propranolol (240 mg daily), procainamide (3.0 g daily) and quinidine (1.8 g daily) and a final control period. Twenty-four hour ambulatory electrocardiograms and maximal exercise tests were performed each week. For the group, the total number and qualitative types of ventricular ectopic complexes were similar during the two control periods; however, there were large variations among individual patients. Each drug reduced the total number of ventricular ectopic impulses and the percent of patients with each qualitative type. There was agreement between the ambulatory electrocardiogram and treadmill test in three quarters of the drug evaluations. Although it is possible to determine antiarrhythmic drug effects for a group, spontaneous variability in the occurrence of ventricular arrhythmias makes it difficult to evaluate the effects in individual patients.

Adult↗
PubMed1978

Clinical electrophysiologic effects of tocainide.

The electrophysiologic properties of tocainide were evaluated by electrophysiologic studies in 11 patients before, during and after a constant intravenous infusion of the drug for 15 minutes. Peak plasma tocainide concentrations averaged 11.0 +/- 1.7 microgram/ml (SEM), range 3.7 to 22.7. AH, HV, QRS, QTc and RR intervals were measured every 5 minutes during sinus and atrial-paced rhythms and showed small changes which were not statistically significant for HV and QRS. Mild shortening of RR was significant (P less than 0.05) at 15 minutes only. AH tended to increase slightly for spontaneous (but not paced) rhythm, becoming significant at 15 minutes only (P less than 0.05). QTc decreased slightly, a change which was significant (P less than 0.05) for paced but not spontaneous rhythm. A progressive rise in mean arterial pressure occurred during infusion and persisted through 30 minutes (P less than 0.001). Comparison of electrophysiologic studies at 0 and 30 minutes showed decreased in mean effective refractory periods of atrium, A-V node, and right ventricle by 17, 22, and 23 msec, respectively (P less than 0.05, 0.01, 0.01). Functional refractory period of the A-V node showed an average decrease which was not significant. Sinus node recovery time and Wenckebach cycle length were unchanged. The drug was well tolerated in all 11 patients. Hypotension in a twelfth patient may or may not have been drug related. These results obtained at therapeutic plasma concentrations suggest qualitative similarities between the conduction system effects of tocainide and those published for lidocaine.

Aged↗
PubMed1978

The hemodynamic effects of intravenous tocainide in patients with heart disease.

In order to evaluate its hemodynamic actions, tocainide, a new orally effective antiarrhythmic drug, was given intravenously over a 15 minute period to 12 patients with compensated left ventricular dysfunction. Doses were 0.5 (4 patients) or 0.75 (8 patients) mg/kg/min. Hemodynamics and drug plasma concentrations were measured at the end and 15 minutes after the end of the infusion. Tocainide infusion produced small but statistically significant increases in the pulmonary and systemic vascular resistance, aortic and pulmonary arterial pressure, and left and right ventricular end-diastolic pressure. There was no significant change in left ventricular dp/dt, heart rate, or cardiac index. In patients with compensated left ventricular dysfunction, tocainide produces a small rise in vascular resistance and arterial pressure. Overall cardiac function is maintained with a small increase in left ventricular end-diastolic pressure.

Adult↗
PubMed1978

Long-term tocainide therapy for ventricular arrhythmias.

Long-term tocainide therapy has been evaluated in 17 patients with ventricular arrhythmias. Ventricular tachycardia and/or fibrillation was recurrent and sustained in nine patients, and symptomatic but unsustained in three others. Five patients had frequent but only mildly symptomatic ventricular irritability. In all patients, arrhythmias could not be managed with quinidine, procainamide or propranolol. Tocainide doses ranged from 300 to 700 mg every 8 hours (mean steady-state plasma concentrations ranged from 5.75 to 12.18 microgram/ml). Tocainide therapy was unsuccessful in eight patients; three died during therapy and five had no antiarrhythmic response. The data suggest that evaluation of long-term drug efficacy, using the criterion of reduction of asymptomatic arrhythmias, is best documented by multiple sequential ambulatory electrocardiographic recordings, both on and off the drug. Tocainide controlled arrhythmias in nine patients (53%), with criteria of success being continued reduction of ectopic beats and/or control of symptomatic recurrences. Seven patients remain on therapy. Side effects generally have been minor and well-tolerated.

Adult↗
PubMed1978

Antiarrhythmic drug effect mimicked by spontaneous variability of ventricular ectopy.

Twenty patients with frequent ventricular ectopic beats had a 5 1/2 hour ECG rhythm strip recorded. Individual patients showed a marked spontaneous variability from one half-hour to the next in the total number of ectopic beats (-99% to +1100%) and the occurrence of pairs or salvos. Although no patient received antiarrhythmic drugs, some patients showed a spontaneous change in arrhythmia which mimicked either drug suppression or drug-induced worsening of arrhythmias. If an antiarrhythmic drug had been given to these patients after the first half-hour, 65% would have been termed "drug responders," using the criteria of 50% reduction in ectopic beats and elimination of pairs or salvos during any half-hour period in the subsequent three hours. Spontaneous variability in ventricular ectopic beats causes serious problems when using ECG monitoring to evaluate antiarrhythmic drug response in individual patients. The arrhythmias averaged for the entire group remained stable during the recording period. Evaluating antiarrhythmic drugs by examining group response rather than individual patient response minimizes the effect of spontaneous variability.

Adult↗
PubMed1978

Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia.

We performed intracardiac electrophysiologic studies in 33 patients with recurrent ventricular tachycardia. Nineteen patients underwent one, 10 patients two, and four patients three serial electrophysiologic studies. Ventricular tachycardia was successfully induced in 83% of the patients, and pacing methods were successful in terminating tachycardia in 71% of the studies, although pacing-induced acceleration of ventricular tachycardia occurred at least once in 36% of the studies. Seventeen of the 33 patients (52%) required a total of 24 external direct current cardioversions during study. In 21 patients a variety of antiarrhythmic drugs were given I.V. and attempts at ventricular tachycardia induction were repeated to assess prophylactic effects of the drugs. An acutely effective drug or combination of drugs was found in 15 of the patients (71%). Fourteen of the 15 were placed on chronic oral therapy with the effective agent and were followed for an average period of 8.1 months (range one to 33 months). In all 14 patients we could document complete (13 patients) or partial (one patient) long-term prophylaxis against ventricular tachycardia. We conclude that drug efficacy trials in patients with recurrent ventricular tachycardia using intracardiac pacing techniques is a rapid and accurate method of selecting effective long-term antiarrhythmic therapy.

Administration, Oral↗
PubMed1977

Response optimization of drug dosage: antiarrhythmic studies with tocainide.

The benefits of using antiarrhythmic response to optimize dosage regimens of antiarrhythmic drugs in individual patients have been examined. Graded antiarrhythmic response and simultaneously measured plasma drug concentrations have been obtained in 15 patients receiving multiple oral doses of a new antiarrhythmic, tocainide. Plasma drug concentration-antiarrhythmic response data from each of 11 subjects responding to the drug have been fitted by a generalized concentration effect function which is valid over the entire range of response. With the use of experimentally determined pharmacokinetic parameters to define the dose-plasma concentration relationship and plasma drug concentration-response parameters estimated for individual patients, simulations were carried out to show the effect of various dosage regimens on antiarrhythmic response in individual patients. Such simulations provide a means of assessing antiarrhythmic effect in the range of clinical interest (80% to 100% of maximum effect), where the antiarrhythmic effect is a nonlinear function of dose, plasma drug concentration, or their logarithms. The simulations also demonstrate that for identical daily doses and dosing intervals patients show marked variability in antiarrhythmic response.

Administration, Oral↗
PubMed1977

Acebutolol disposition after intravenous administration.

The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 ml/min/kg and the mean renal clearance, 2.68 ml/min/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two-compartment model. The mean fast and slow half-lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady-state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15-min infusions were used to predict plateau blood concentrations with good accuracy during an 8-hr dosage regimen.

Acebutolol↗
PubMed1977

Hemodynamic effects of intravenously administered quinidine on the transplanted human heart.

The acute hemodynamic effects of intravenously administered quinidine were studied in five heart transplant recipients with an anatomically denervated heart. Quinidine, 10 mg/kg body weight, was infused over a 20 minute period, and mild wall left ventricular dynamics were measured with a new technique using metallic markers surgically implanted in the myocardial wall. Heart rate was maintained constant with atrial pacing, and aortic blood pressure was measured through an indwelling catheter. In each patient the hemodynamic responses to quinidine were similar. End-diastolic, end-systolic and stroke volumes decreased by an average of 19, 26 and 18 percent, respectively. Cardiac output decreased by a mean 0.92 liters/min (-18%), and the mean aortic blood pressure decreased by 10 mm Hg (-11%). All of these changes were statistically significant. Three indexes of the contractile state of the left ventricle--mean circumferential velocity, mean systolic diameter shortening and ejection fraction--were not significantly changed. We conclude that quinidine exerts no acute inotropic myocardial effects in the human transplanted heart and that, when given intravenously, its hemodynamic action is most consistent with venodilatation.

Blood Pressure↗
PubMed1977

Propranolol for patients with mitral valve prolapse.

This study evaluates propranolol's effect on symptoms, arrhythmias, and exercise tolerance in 16 patients with mitral valve prolapse. Three patients (19 per cent) experienced symptomatic deterioration with propranolol therapy, seven (44 per cent) were unchanged, and six (37 per cent) noted an over-all symptomatic improvement, primarily due to a reduction in palpitation. Symptomatic improvement continues in these six patients an average of 12.5 months after beginning propranolol therapy. Treatment with propranolol alleviated chest pain in only two of eight patients and it did not improve the ability to perform treadmill exercise. Fatigue did not improve, and in three patients appeared for the first time during propranolol therapy. Premature ventricular contractions were reduced by at least 75 per cent in five of nin patients (56 per cent), and paroxysmal ventricular tachycardia was eliminated in three of four patients. We conclude that propranolol is not uniformly effective in patients with mitral vale prolapse. A trial of propranolol may be instituted fro patients with mitral valve prolapse who have severe symptoms and/or arrhythmias, but the drug should only be continued in those who demonstrate clinical and/or antiarrhythmic response.

Adult↗