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Biomedical subjects

D G McDevitt

Publications and source records attributed to D G McDevitt.

At least 181 records · Page 10Linked to original sources
PubMed1977

Influence of intrinsic sympathomimetic activity and cardioselectivity on beta adrenoceptor blockade.

Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.

Adrenergic beta-Antagonists↗
PubMed1977

Simple lignocaine regimen for transit to hospital after myocardial infarction.

A simple combined intravenous/intramuscular regimen is described for lignocaine administration in the early vulnerable stage of myocardial infarction. Plasma levels in the therapeutic range are attained. This allows adequate drug protection during transport to hospital when an intravenous regimen may be impractical or impossible.

Adult↗
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↗
PubMed1976

Observations on the efficacy and pharmacokinetics of sotalol after oral administration.

The effects of sotalol after oral administration were measured on the tachycardia induced by strenuous exercise in normal subjects. Plasma sotalol levels were also determined. The oral administration of sotalol (50, 100, 200 and 400 mg) to 6 subjects produced a progressive reduction in the tachycardia induced by severe exercise. This was similar to the effects of 25, 50, 100, 200, 400 and 800 mg given to different subjects. Each increase in sotalol dose produced a successively greater reduction in exercise tachycardia. This did not appear to be maximum even with 800 mg. Oral sotalol was rapidly absorbed and produced peak blood levels in 2 - 3 hours. The plasma levels of sotalol measured 2 hours after the oral administration of 25 to 800 mg showed never more than a six-fold variation between different subject. The half-life of sotalol in plasma was 12.7 +/- SE 1.6 hours. There was a significant correlation between the logarithm of the plasma sotalol concentration and the percentage reduction of exercise heart rate. It is concluded that the oral administration of sotalol either once or twice daily (depending on dose level) will provide satisfactory 24-hour blockade of beta-adrenoceptors.

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↗
PubMed1976

Plasma binding and the affinity of propranolol for a beta receptor in man.

The effects of plasma drug binding on the relationship between propranolol concentration and the antagonism of isoproterenol tachycardia have been investigated in 8 normal subjects and 8 hypertensive patients. During chronic intravenous infusion of propranolol giving a narrow range of total plasma concentrations (22.5 to 50 ng/ml), there was, at best, a poor correlation with effects. On the other hand, there was excellent correlation between efficacy and free drug concentration, which fitted the predictions of the receptor theory of competitive antagonism. The true affinity constant for the binding of propranolol to its receptor can be calculated in terms of free drug concentration (KAfree) and was found to vary 2-fold compared to the affinity constant in terms of total plasma concentration (KAtotal) which varied 4-fold, the greater variation being due to plasma binding differences. Compared to normal subjects, KAfree and KAtotal were smaller in hypertensive subjects, implying lesser sensitivity to the drug, and plasma propranolol binding was greater. There was no difference in KAfree between high- and low-renin essential hypertensives, but KAtotal was smaller in the high-renin group due to increased plasma binding which did not reach statistical significance. It is concluded that the effect of propranolol on heart rate is a predictable function of free drug concentration in man and that the contribution of individual variation in receptor sensitivity to differences in oral dosage requirement is minor compared to that of variations in bioavailability.

Adult↗