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Biomedical subjects

R G Shanks

Publications and source records attributed to R G Shanks.

At least 55 records · Page 3Linked to original sources
PubMed1986

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.

Adrenergic beta-Antagonists↗
PubMed1986

Dose independent pharmacokinetics of mexiletine in healthy volunteers.

In 12 healthy volunteers who received orally 100, 200, 300, 400 and 600 mg mexiletine at weekly intervals, the maximum plasma concentration of mexiletine and AUC increased linearly with the dose of mexiletine. Between doses there were no significant differences in the values for clearance and volume of distribution of mexiletine but there were for plasma elimination half-life. These results indicate that the kinetics of mexiletine are linear.

Administration, Oral↗
PubMed1985

Prophylactic lidocaine in the early phase of suspected myocardial infarction.

Four hundred two patients with suspected myocardial infarction seen within 6 hours of the onset of symptoms entered a double-blind randomized trial of lidocaine vs placebo. During the 1 hour after administration of the drug the incidence of ventricular fibrillation or sustained ventricular tachycardia among the 204 patients with acute myocardial infarction was low, 1.5%. Lidocaine, given in a 300 mg dose intramuscularly followed by 100 mg intravenously, did not prevent sustained ventricular tachycardia, although there was a significant reduction in the number of patients with warning arrhythmias between 15 and 45 minutes after the administration of lidocaine (p less than 0.05). The average plasma lidocaine level 10 minutes after administration for patients without a myocardial infarction was significantly higher than that for patients with an acute infarction. The mean plasma lidocaine level of patients on beta-blocking agents was no different from that in patients not on beta blocking agents. During the 1-hour study period, the incidence of central nervous system side effects was significantly greater in the lidocaine group, hypotension occurred in 11 patients, nine of whom had received lidocaine, and four patients died from asystole, three of whom had had lidocaine. We cannot advocate the administration of lidocaine prophylactically in the early hours of suspected myocardial infarction.

Adult↗
PubMed1985

Effects of betaxolol, propranolol, and atenolol on isoproterenol-induced beta-adrenoceptor responses.

Five healthy young men received, in a double-blind fashion, single oral doses of 10 mg betaxolol, 40 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and placebo. After the dose each received serial 12-minute infusions of isoproterenol sulfate through the dose range 0.5 to 32 micrograms/min until the heart rate rose by 40 bpm or the subject could not tolerate the effects of the infusion. Heart rate, finger tremor, blood pressure, and forearm blood flow were measured after each infusion. Dose-response curves were constructed for the changes in these parameters with increasing doses of isoproterenol. The ascending order of potency of the drugs in preventing the changes in heart rate, finger tremor, diastolic blood pressure, forearm blood flow, and forearm vascular resistance induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg betaxolol, and 40 mg propranolol. The ascending order of potency of the drugs in preventing the change in systolic blood pressure induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and 40 mg betaxolol. Betaxolol, 10 mg, is equally cardioselective to 50 mg atenolol and at a dose of 40 mg betaxolol also exhibits cardioselectivity.

Adrenergic beta-Antagonists↗
PubMed1985

Very early intervention with metoprolol in suspected acute myocardial infarction.

A double blind randomized study of 800 patients was carried out to determine if very early intervention with metoprolol (15 mg I.V. followed by oral administration) in suspected acute myocardial infarction affected overall mortality in selected subgroups, (age, site of infarct, delay to intervention). Sudden death occurred less frequently in patients allocated to metoprolol but there was no significant difference in total mortality on discharge, at three months and at twelve months. Ventricular fibrillation after intervention was not significantly reduced. Adverse reactions did not occur significantly more frequently in patients assigned to metoprolol.

Aged↗
PubMed1985

Effects of ranitidine on the disposition of metoprolol.

The effects of ranitidine on the pharmacokinetics of metoprolol were examined in two studies. In the first study, pharmacokinetics of single doses of metoprolol were examined in six subjects before, during and after ranitidine administration for 1 week. Peak concentrations of metoprolol were increased on ranitidine but its half-life and clearance were unaltered. In the second study, 12 subjects received metoprolol twice daily for 1 week; once with ranitidine and once with placebo. Ranitidine had no effects on the chronic-dose pharmacokinetics or pharmacodynamics of metoprolol. The chronic dose study suggests no inhibition of the metabolism of metoprolol by ranitidine. The single dose study suggests, however, that some interaction of an as yet unknown nature, cannot be excluded.

Adult↗
PubMed1985

Indoramin-prolongation of repolarization time, a mechanism of bradycardia in man?

The effect of indoramin, a selective alpha 1-adrenoceptor antagonist, on ECG time intervals in normal man was studied. Significant prolongation of QTc was observed after indoramin 100 mg, with no change in QRS duration. In addition, the slope of the RR/QT relationship was changed by indoramin 100 mg. These results suggest that indoramin may have Class III antiarrhythmic activity. If such activity were to affect the SA node, it may explain at least in part the observed lack of reflex tachycardia after indoramin administration.

Adult↗
PubMed1985

Human pharmacokinetic and pharmacodynamic studies on Ro31-1118, a new beta-adrenoceptor antagonist.

The pharmacokinetic and pharmacodynamic effects of Ro31-1118 were examined in groups of healthy volunteers. In three subjects given 10 mg of [14C]-Ro31-1118 orally, peak levels of radioactivity (84 +/- 5 ng/ml) were 16 times those of the parent drug (approximately 5 ng/ml). Very little parent drug was recovered in the urine, although recovery of total radioactivity was nearly 80% in the urine by day 5. In five subjects studied after both oral and intravenous administration of 20 mg Ro31-1118 the average bioavailability was 57% (range 41-73%). Following intravenous infusion the apparent volume of distribution for the five subjects averaged 590 1 (range 510-700 1). The elimination half-life averaged 18 h (range 17-26 h). In eight subjects who received 40, 80, 160 and 320 mg of Ro31-1118 orally there was a linear relationship between dose and plasma concentration (r = 0.999) and between dose and AUC (r = 0.996). Ro31-1118 had no effect on resting heart rate whereas atenolol reduced resting heart rate up to 6 h after all doses. The maximum reduction of an exercise tachycardia after Ro31-1118 (320 mg) was 23.13 +/- 0.7% and compared with atenolol (100 mg) was 28.2 +/- 1.25%. At 24 h the percentage reduction after Ro31-1118 was 21.5 +/- 1.7%, while after atenolol the percentage inhibition had decreased to 11.1 +/- 1.6%. In three subjects Ro31-1118 (160 mg) orally had no effect on resting heart rate, forearm blood flow and systolic blood pressure, while atenolol (50 mg) reduced all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Comparative effects of adimolol, labetalol and propranolol on heart rate and blood pressure in man.

The cardiovascular effects of adimolol, a new, potent, long acting beta-adrenoceptor blocking drug were investigated in three studies. In the first study blood pressure and heart rate were measured in five male volunteers before and at 2, 4, 6, 8, 24, 32, 48, 72 and 96 h after single oral doses of adimolol. All doses of adimolol reduced supine, standing and exercise heart rates in a dose dependent manner. The maximum effect ranged from 18% following 25 mg to 29% following 600 mg and all doses showed an effect at 96 h (range 3.5-17.2%). In the second study the effects of adimolol, 25 and 400 mg, labetalol, 200 and 800 mg, propranolol 40 mg and placebo were compared on supine and standing heart rate and blood pressure and on exercise heart rate before and at 2, 4, 6 and 8 h after single oral doses. The exercise heart rate was significantly reduced at all times following adimolol 25 and 400 mg, labetalol 800 mg and propranolol 40 mg. At 2 h all the drugs significantly reduced standing systolic blood pressure. In the third study, 4 h after single oral doses of adimolol 400 mg, labetalol 400 mg and propranolol 40 mg six subjects received serial 4 min infusions of phenylephrine. The blood pressure was measured after each infusion. Labetalol 400 mg significantly shifted the blood pressure dose-response curve to the right. There was no difference between propranolol 40 mg and adimolol 400 mg. These studies show that adimolol is a potent, long acting beta-adrenoceptor blocking drug without evidence of alpha-adrenoceptor blockade in man.

Adrenergic beta-Antagonists↗
PubMed1985

Effects of the beta 2-adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline-induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2-adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2-adrenoceptors in man.

Adrenergic beta-Antagonists↗
PubMed1985

Effects of azepexole and clonidine on baroreceptor mediated reflex bradycardia and physiological tremor in man.

The effects of oral administration of azepexole 10 mg, clonidine 300 micrograms and placebo on baroreceptor mediated reflex bradycardia and physiological tremor were investigated in six healthy volunteers. Both azepexole and clonidine reduced (P less than 0.05) systolic (120.5 +/-2.5 to 105.0 +/- 3.3 mm Hg; 115.8 +/- 2.6 to 104.7 +/- 2.8 mm Hg respectively) and diastolic (52.5 +/- 2.6 to 47.2 +/- 1.4 mmHg; 53.7 +/- 1.6 to 49.0 +/- 1.5 mmHg respectively) pressure when compared to placebo and to pre-treatment values. This reduction in pressure was not accompanied by a change in heart rate. Both azepexole and clonidine enhanced (P less than 0.05) baroreflex sensitivity to increases in systolic arterial pressure with phenylephrine. Clonidine facilitated (P less than 0.05) baroreflex sensitivity during the strain phase of the Valsalva manoeuvre, whereas azepexole reduced it (P less than 0.05). Neither clonidine nor azepexole altered finger tremor when compared to placebo or pre-treatment values. Azepexole produced (P less than 0.05) sedation compared to placebo but not when compared to pre-treatment values. Clonidine caused significant increases in sedation when compared to both placebo and to pre-treatment values. The differences between azepexole and clonidine may be due to the greater specificity of azepexole for the alpha 2-adrenoceptor than clonidine.

Adrenergic alpha-Agonists↗
PubMed1985

A comparison of the cardiovascular effects of (+)-sotalol and (+/-)-sotalol following intravenous administration in normal volunteers.

In a placebo controlled open study in six healthy male volunteers (+)-sotalol in the dose range 0.125 mg kg-1-2.0 mg kg-1 intravenously, was found to have little or no beta-adrenoceptor blocking activity in comparison to the racemic mixture (+/-)-sotalol. The repolarization effects of (+)- and (+/-)-sotalol on the QTc interval however were comparable over the same dose range. The beta-adrenoceptor blocking activity and repolarization effects of sotalol appear to be unrelated.

Adolescent↗
PubMed1985

Comparison of the haemodynamic effects of bucindolol, propranolol and pindolol in healthy volunteers.

The effects of single oral doses of bucindolol (50, 100, 200 and 400 mg), pindolol (10 mg), propranolol (160 mg) and placebo on arterial pressure and heart rate in the supine and standing positions and exercise heart rate were compared in 12 healthy male volunteers. Supine heart rate was significantly greater after all four doses of bucindolol and pindolol in comparison to propranolol. Bucindolol had no significant effect on standing heart rate which was significantly reduced by pindolol and propranolol. Bucindolol, pindolol and propranolol significantly reduced an exercise tachycardia for at least 24 h after drug administration. Supine systolic pressure was not affected by any treatment but supine diastolic pressure was significantly reduced by bucindolol (200 and 400 mg) and by pindolol. All doses of bucindolol, propranolol and pindolol significantly reduced standing systolic blood pressure. There was a significant linear trend for reductions in standing systolic blood pressure and increasing doses of bucindolol. Standing diastolic blood pressure was significantly reduced by bucindolol 200 and 400 mg. Faintness and light headedness occurred in 6 of 12 subjects after 200 mg bucindolol and in 8 of 10 subjects after 400 bucindolol. After bucindolol, analysis of plasma samples demonstrated the presence of bucindolol, 5-hydroxy and 6-hydroxy bucindolol and indolyl-t-butylamine. These observations indicate that in man, bucindolol is a beta-adrenoceptor blocking drug with hypotensive activity and probably partial agonist activity. It is unlikely that the hypotensive effects result from blockade of beta-adrenoceptors or from the drug's partial agonist activity.

Adrenergic beta-Antagonists↗
PubMed1985

[Acute and long-term antiarrhythmia effect of encainide in chronic atrial extrasystole].

The antiarrhythmic effects of Encainide in acute intravenous and long-term oral therapy were investigated in 10 patients suffering from chronic atrial ectopic beats previously non-responsive to conventional therapy. The efficacy of Encainide was assessed by 24-hour ECG monitoring during the acute i.v. application and in 4 week intervals over a period of 4 to 6 months. Plasma concentrations of Encainide and the O-demethyl- (ODE) and 3-methoxy-O-demethyl metabolites (3-MODE) were determined after i.v. administration and during oral therapy. A significant reduction of arrhythmias by 76% was found after 1.0 mg/kg Encainide given intravenously. Atrial ectopic beats with bundle branch block QRS-morphology were reduced by more than 90% after only 0.5 mg/kg. During long-term oral therapy 6 of the 9 patients were treated successfully. Following i.v. administration Encainide-plasma concentrations rapidly decreased with a half life of approximately 75 min in the final distribution phase. During oral therapy Encainide levels were not detectable under steady state conditions 4 to 6 hours after the last dose, or they were only minimal, but the average concentrations of ODE and 3-MODE were 71.3 +/- 21.3 and 75.6 +/- 13.5 ng/ml. Encainide increased PR interval and QRS duration significantly. QT-interval changed as a result of the QRS-prolongation. Encainide was well tolerated during acute and chronic therapy. No severe side effects were seen, except in one case, in which dose reduction by 50% was necessary because of blurred vision.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Effect of 8-(3-diethylaminopropyl)-6,6-dimethyl-(2-phenyl-1 H-imidazo(4,5 h))isoquinoline-7,9-(6H)-dione dihydrochloride (AR-LH31) on experimental cardiac arrhythmias in dogs.

The effects of intravenously administered 8-(3-diethylaminopropyl)-6,6-dimethyl-(2-phenyl-1H-imidazo (4,5H))-isoquinoline-7,9-(6H)-dione dihydrochloride (AR-LH31) on experimentally induced ventricular tachycardia were studied in dogs. Ventricular tachycardia was produced in 6 anaesthetised dogs by the intravenous injection of ouabain (66.7 +/- 4.9 mg/kg). AR-LH31 administered by increasing bolus injections every 5 min completely suppressed the ventricular tachycardia with a return to sinus rhythm in 1 out of 6 dogs, with a partial return of sinus beats in a second dog. There was no return to sinus rhythm in the 4 remaining dogs after doses ranging from 1.75 to 15.75 mg/kg. Observations were made in 9 conscious dogs 22-24 hours after ligation of the anterior descending branch of the left coronary artery when a ventricular tachycardia was present. The administration of AR-LH31 by bolus intravenous injection in 4 dogs did not abolish the arrhythmia in any dog but increased the number of sinus beats. In 3 out of 4 dogs after a cumulative dose of 7.75 mg/kg, 60% of ventricular beats were of sinus origin. The effects of larger doses could not be studied be cause of adverse effects. In 5 dogs the administration of AR-LH31 by constant intravenous infusion at 16 mg/kg/h restored sinus rhythm in all dogs after a mean dose of 9.9 +/- 0.9 mg/kg. These studies indicate that AR-LH31 has anti-arrhythmic activity in dogs and highlight the importance of the method of administration in determining the effects of a drug.

Animals↗
PubMed1984

Hemodynamic effects of mexiletine.

A review of studies of mexiletine, a class I antiarrhythmic drug, supports its use in patients with ventricular arrhythmias or in sinus rhythm. Studies include patients likely to receive the drug in clinical use--patients with and without coronary disease and patients who have suffered acute myocardial infarction. Some studies are open and others are controlled to compare mexiletine to placebo or to lidocaine. Mexiletine in therapeutic ranges was shown not to affect arterial pressure; to prolong aortic ball travel time, indicating depression of myocardial contractility; and not to adversely affect cardiac function. Adverse effects occurred as often in patients taking placebo as in mexiletine-treated patients, even in those with impaired cardiac function. Studies bear out early reports of mexiletine as an effective antiarrhythmic drug nearly devoid of adverse hemodynamic effects when administered intravenously or orally in a dosage to maintain a therapeutic plasma concentration.

Animals↗