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Oral administration of single doses of bopindolol (1-4mg) caused significant reductions in the rises of systolic blood pressure and heart rate produced by exercise; only the reduction in the rise of heart rate was significantly dose-related. Resting heart rate was reduced by bopindolol. There were small effects on resting blood pressure. Bopindolol caused a significant attenuation of the rise in plasma renin activity produced by passive head-up tilting to 75-85 degrees. Bopindolol produced a dose-related attenuation of the increase in pulse rate evoked by passive tilting. All effects 1-4 were maintained for at least 24 h. There was no measurable effect on plasma potassium concentration, peak flow rate or forced expiratory volume (FEV1). [ABSTRACT FROM AUTHOR]

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin-converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose-response and time-course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized 'equiactive' oral doses employed for time-course studies were: SQ 29,852 (1.0), 100 mg kg-1; captopril (3.5), 30 mg kg-1; enalapril (12), 20 mg kg-1; fosinopril (13), 25 mg kg-1; zofenopril (20), 10 mg kg-1; lisinopril (24), 10 mg kg-1; and ramipril (51), 5 mg kg-1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short-lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long-lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia. [ABSTRACT FROM AUTHOR]

1. Two studies of the elimination of mianserin are reported. 2. In the first study, the oral clearance of mianserin was measured in 15 elderly patients at steady state. In a sub-group of eight patients who completed studies at two different doses there was evidence of enhanced oral clearance at the higher dose. 3. In the second study, the elimination half-life was estimated in 12 patients who were observed to have disproportionately high mianserin concentrations with respect to dose. All had half-lives greater than or equal to 2.5 days with a mean of 6 +/- 2.8 (s.d.) days. In six of the patients the profile of elimination was suggestive of saturable elimination. 4. The sparteine oxidation status was measured in seven of the patients showing slow mianserin elimination. Only one was a 'poor oxidiser' of sparteine, suggesting no concordance with this phenotype. 5. It is concluded that there is marked variability in the elimination of mianserin in elderly patients. [ABSTRACT FROM AUTHOR]

1. Heart rate and blood pressure changes following the administration of alinidine 30 mg alone and in combination with atenolol 25 mg, nifedipine retard 20 mg and glyceryl trinitrate 500 micrograms were investigated in three groups of six healthy male volunteers. 2. Concomitant administration of alinidine and atenolol reduced (P less than 0.05) supine, standing and exercise heart rate when compared with alinidine alone. The maximum reduction in exercise heart rate was 116 +/- 2.4 beats min-1 for the combination vs 129.0 +/- 3.1 beats min-1 for alinidine alone. 3. Supine (3, 4, 8 h) and standing (2 h) systolic BP were also reduced (P less than 0.05) with the alinidine and atenolol combination compared with alinidine alone. Little change occurred in diastolic blood pressure. 4. Alinidine and nifedipine in combination reduced (P less than 0.05) the nifedipine induced increase in heart rate in the supine (2, 4 h) and standing (4 h) position and following exercise (2, 4 h). No further decreases in systolic and diastolic blood pressure occurred with the combination. 5. Alinidine administered 2 h before a glyceryl trinitrate challenge reduced (P less than 0.05) the glyceryl trinitrate induced increase in standing heart rate at all time intervals (1 to 6 min); the maximum reduction occurred at 3 min (105.0 +/- 4.3 (glyceryl trinitrate) vs 86.8 +/- 6.7 beats min-1 (combination]. Systolic blood pressure was further reduced at all time intervals with glyceryl trinitrate taken in the presence of alinidine.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The kinetics of metoclopramide and the effects of haemodialysis on metoclopramide kinetics were examined in eight uraemic subjects 1 h and 24 h prior to the onset of dialysis. In spite of the relatively minor contribution of renal clearance to total body clearance in normals, metoclopramide kinetics were substantially altered in uraemia. The total body clearance was decreased by 2-4 fold, terminal elimination half-life proportionately increased, while the volume of distribution appeared to be unaffected compared with that previously demonstrated in normal healthy subjects. Haemodialysis does not appear to be effective in removing metoclopramide from the body and metoclopramide clearance subsequent to dialysis is unaltered. The kinetic parameters in the uraemic subjects are not significantly different between drug administrations 1 or 24 h prior to the time of onset of haemodialysis. Following kidney transplantation, in one subject, there appeared to be a rapid return to apparently normal kinetics from the uraemic state. [ABSTRACT FROM AUTHOR]

The disposition of metoclopramide was studied on a four-way crossover basis in six healthy non-smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/- 0.38 (mean +/- s.d.) from the oral dosage forms examined in this study. [ABSTRACT FROM AUTHOR]

The influence of haematocrit on blood cyclosporin measurements has been studied in 276 paired blood and plasma samples from 21 renal transplant patients. A highly significant correlation was found between blood and plasma cyclosporin concentrations, r = 0.8744, but the correlation between blood or plasma cyclosporin and haematocrit was not significant. The ratio of blood/plasma cyclosporin did not significantly increase with increasing haematocrit. It was concluded that in vivo the influence of haematocrit on the measurement of blood cyclosporin concentrations was negligible. [ABSTRACT FROM AUTHOR]

1. The effects of the acute and chronic administration of the alpha 1- adrenoceptor antagonist alfuzosin (5 mg twice daily for 7 days) on baroreflex function, physiological tremor and sedation (visual analogue scale) were investigated in six healthy volunteers. 2. Phenylephrine- systolic pressure dose-response curves were shifted (P less than 0.05) to the right by alfuzosin compared with placebo on day 1, and on day 8 prior to the administration of alfuzosin indicating significant alpha- adrenoceptor blockade over 24 h with 5 mg twice daily administration. 3. Baroreflex sensitivity (delta R-R ms mmHg-1 systolic arterial pressure) was reduced (P less than 0.05) by alfuzosin compared with placebo on day 1 (13.8 +/- 2.6 vs 20.6 +/- 3.6 ms mmHg-1) and on day 8 (13.4 +/- 1.7 vs 21.1 +/- 2.7 ms mmHg-1). 4. Maximum power (microV2) or frequency (Hz) of physiological tremor did not change 2 h after alfuzosin administration on day 1 (13.7 +/- 4.4 microV2, 9.2 +/- 0.3 Hz) or day 8 (11.5 +/- 4.3 microV2, 10.0 +/- 0.4 Hz) compared with placebo on day 1 (16.9 +/- 7.5 microV2, 10.0 +/- 0.4 Hz) and day 8 (17.3 +/- 5.7 microV2, 10.2 +/- 0.8 Hz). 5. Alfuzosin 5 mg twice daily did not cause sedation on day 1 or day 8. 6. In conclusion the reduction in baroreflex sensitivity with the alpha-adrenoceptor antagonist alfuzosin may contribute to its antihypertensive activity in reducing the reflex tachycardia associated with its hypotensive action. [ABSTRACT FROM AUTHOR]

1. The effect of captopril 12.5 mg three times daily for 14 days on baroreflex sensitivity was investigated in six normotensive salt- replete male subjects. 2. Baroreflex sensitivity [delta R-R interval ms/mmHg systolic blood pressure (SBP)] was assessed following decreases and increases in SBP with glyceryl trinitrate and phenylephrine respectively and during Valsalva's manoeuvre. 3. Captopril had no effect on supine intra-arterial SBP or R-R interval on days 1 and 15 compared with placebo. However decreases (P less than 0.05) which occurred in plasma angiotensin II on day 1 (12.3 +/- 0.8 to 7.6 +/- 1.5 pg ml-1) and on day 15 (14.5 +/- 1.5 to 6.3 +/- 0.5 pg ml-1) and increases (P less than 0.02) in plasma renin activity on day 1 (1.2 +/- 0.7 to 4.8 +/- 0.8 ng A I ml-1 h-1) and on day 15 (1.1 +/- 0.2 to 5.4 +/- 0.9 ng A I ml-1 h-1) compared with placebo, indicated angiotensin- converting enzyme inhibition. 4. Baroreflex sensitivity was unchanged by captopril on day 1 and day 15 compared with placebo following the use of glyceryl trinitrate and phenylephrine to deactivate and activate respectively the baroreceptors, and during the strain and release phases of Valsalva's manoeuvre. [ABSTRACT FROM AUTHOR]

1 Fosinopril sodium is the first phosphorus-containing angiotensin- converting enzyme (ACE) inhibitor to be studied clinically as an antihypertensive agent. It is an ester prodrug that is hydrolysed in vivo to the active diacid ACE inhibitor, SQ 27, 519. 2 In a three-way crossover study, nine healthy male subjects (age range 20-34 years) each received an intravenous 7.5 mg dose of SQ 27, 519-[14C] and two oral 10 mg doses of [14C]-fosinopril sodium, administered as a capsule and in solution. 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a beta- glucuronide conjugate of SQ 27, 519 (15-20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min-1), renal clearance (17 ml min-1), Vss (10 1), and plasma protein binding (approximately 95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites. [ABSTRACT FROM AUTHOR]

Theophylline and antipyrine disposition has been compared in smoking epileptic patients, non-smoking epileptic patients and non-smoking healthy volunteers. Although clear differences in drug clearance and half-life were evident as a result of anticonvulsant drug therapy, no effect of smoking was discernible. Thus, additive effects from induction of the hepatic microsomal monooxygenase system in man by anticonvulsant drugs and polycyclic aromatic hydrocarbons (in cigarette smoke) were not evident. [ABSTRACT FROM AUTHOR]

Eight Sudanese patients with hepatosplenic schistosomiasis and seven Sudanese controls were administered a single oral dose of long acting (LA), propranolol 160 mg; blood propranolol levels were measured at regular intervals for 12 h using g.l.c. In patients with hepatosplenic schistosomiasis, propranolol blood concentrations were greater (P less than 0.05) at all time intervals, Cmax 63.5 (29-143) ng ml-1 (median and range) than controls Cmax 23 (12-37) ng ml-1. Median AUC0-12 was also greater (P less than 0.05) (533 and 218 ng ml-1 h respectively), tmax were not significantly different. In patients and controls prior to treatment, standing heart rate (77.5 (60-110), 72 (68-74) beats min- 1) systolic (120 (105-150), 110 (100-120) mm Hg) and diastolic blood pressure (75 (60-90), 70 (60-80) mm Hg) were not significantly different. However following propranolol administration a reduction (P less than 0.05) occurred in both systolic (median 20 mm Hg) and diastolic (median 12.5 mm Hg) blood pressure in the patients compared with controls. Heart rate was reduced by a median of 10 beats min-1 in both groups. These observations indicate that propranolol bioavailability in patients with hepatosplenic schistosomiasis is increased possibly due to reduced presystemic extraction. [ABSTRACT FROM AUTHOR]

The pharmacokinetic and pharmacodynamic effects of the beta- adrenoceptor antagonist H-I 42 BS were examined in healthy subjects. In an open dose ranging study, H-I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H-I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 +/- 1.0%-mean +/- s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 +/- 7.2%). Seven subjects received in double-blind, randomised order, single oral doses of H-I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H-I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H-I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P less than 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H-I 42 BS 50 mg was 10.9 +/- 7.1%, after 100 mg was 18.7 +/- 5.8%, after 200 mg was 20.6 +/- 6.4% and after 400 mg was 21.9 +/- 8.2%. H-I 42 BS 400 mg still caused 11.0 +/- 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 +/- 6.0% but did not reduce exercise heart rate after 24 h. The mean peak plasma concentrations for all doses of H-I 42 BS occurred at 5.1 +/- 1.5 h. The plasma elimination half-life was 47.6 +/- 8.1 h. There was a linear correlation between the dose and AUC0-infinity (r = 0.97). The cardioselectivity of H-I 42 BS and atenolol was compared. Six subjects received in double-blind random order H-I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min- 1. Dose-response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. There was no difference in the dose-response curves for forearm blood flow or finger tremor after H-I 42 BS 400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P less than 0.01) of the diastolic blood pressure response. These results indicate that H-I 42 BS is a cardioselective beta-adrenoceptor antagonist with a long duration of action in man. [ABSTRACT FROM AUTHOR]

The effects of oral nitrendipine and oral propranolol, alone and in combination, on AV conduction have been examined in 11 patients with essential hypertension in whom arterial pressure was not adequately controlled despite treatment with thiazide diuretics. The study was performed double-blind. After a drug free period of 1 week, the patients received two 7 day courses of drug therapy after initial control measurements. Five of the eleven patients were randomised to receive nitrendipine 20 mg daily, the other six patients received propranolol (Inderal LA 160 mg daily) for the first week of therapy. During week 2, 10 patients received combined therapy. In the 10 patients who completed the study, oral nitrendipine, given either alone or in combination with oral propranolol, had no significant effect on resting PR, QRS, QT intervals nor on AV conduction as assessed by ambulatory electrocardiography. Propranolol did not affect the resting PR interval but significantly increased PR intervals on the ambulatory ECG recordings during single and combined therapy. However the maximum PR intervals remained within normal limits. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The disposition of a low dose (600 mg) of acetylsalicylic acid (ASA) and its metabolites (salicylate, salicyluric acid and salicyl glucuronides) was studied in 25 male and female patients of different ages. Plasma levels of ASA and salicylate were found to be significantly higher in the females (young and elderly), whereas plasma levels of salicyluric acid were found to be significantly higher in the elderly (male and female) groups. The higher plasma levels of ASA and salicylate in the females appear to be due to an intrinsically lower metabolic activity in that sex, while the lower clearance of salicyluric acid leads to the accumulation of that compound in the aged. No age and sex effects were found to influence the volumes of distribution of ASA, salicylate and salicyluric acid. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study. Two hundred and eighty-three patients were excluded, mainly because of recent treatment with beta-adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty-eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The integrated surface abdominal electromyogram (EMG) has been used as a simple measurement of cough intensity which correlates well with the volume, air flow and noise produced in different coughs. Using the integrated abdominal EMG as a measure of cough intensity, dose response curves to inhaled citric acid can be drawn which are highly reproducible. We have studied the effects of codeine (60 mg) on these curves, and have demonstrated a reduction in cough intensity. It is suggested that this method of testing the effects of an antitussive on such a dose-response curve may be a useful one. [ABSTRACT FROM AUTHOR]

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/- 3.0 mm Hg to 104.3 +/- 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/- 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/- 2.6 mm Hg to 57.0 +/- 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, -26.7 mm Hg at 4 h after drug administration; labetalol, -21.3 mm Hg at 2 h; alinidine, -21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The abilities of triprolidine 2.5 mg and pseudoephedrine 60 mg, alone and in combination, to protect against an increase in nasal airway resistance (NAR) after histamine challenge were determined in eighteen individuals with grass pollen allergy. The study was conducted outside the pollen season using a double-blind, placebo controlled crossover design. The prior administration of pseudoephedrine 60 mg and triprolidine 2.5 mg alone or in combination was superior to placebo in reducing the increase in NAR after challenge with 1.0% histamine. However, such NAR measurements did not differentiate between pseudoephedrine 60 mg and triprolidine 2.5 mg administered alone or in combination. Challenge with 0.1% histamine failed to discriminate between any of the test medications. [ABSTRACT FROM AUTHOR]

The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. The three active drugs reduced systolic arterial pressure in the standing position to a similar extent (indoramin, −24 mm Hg; phenoxybenzamine, −23.4 mm Hg; hydralazine, −30.4 mm Hg). The maximum effect of indoramin and phenoxybenzamine was observed at 4 h, and of hydralazine at 2 h after drug administration. The reductions of arterial pressure in the standing position were accompanied by increases in heart rate, plasma NA and PRA. Small increases were observed after indoramin (heart rate, + 9.2 beats min-1; plasma NA, + 126 pg/ml; PRA, + 0.33 ng angiotensin 1 ml-1 h-1), greater increases after phenoxybenzamine (heart rate, + 20; plasma NA, + 210; PRA, + 0.47), and the greatest increases after hydralazine (heart rate, + 26; plasma NA, + 250; PRA, + 1.16). In the supine position, indoramin and phenoxybenzamine produced no effect on arterial pressure, heart rate or plasma NA. Hydralazine produced small reductions in diastolic pressure, which were accompanied by an increase in heart rate of 25.5 beats min-1 (P less than 0.01 when compared to placebo) and in plasma NA of 223 pg ml-1 (P less than 0.05). Plasma NA, PRA and heart rate increased together and may be regarded as three interdependent indices of sympathetic activity. Indoramin reduced the degree of increase of plasma NA, PRA and heart rate per unit fall in pressure, when compared to phenoxybenzamine and hydralazine. The effect of phenoxybenzamine and hydralazine on the degree of increase was similar. The results are consistent with the hypothesis that indoramin produces selective postsynaptic alpha 1-adrenoceptor blockade in man, and therefore produces relatively less tachycardia and NA increase than does a non- selective alpha-adrenoceptor antagonist (phenoxybenzamine) or an arteriolar vasodilator (hydralazine). [ABSTRACT FROM AUTHOR]

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1 The present study compared the effects in healthy volunteers of the acute and chronic administration of placebo, pindolol and propranolol to see if the partial agonist activity of pindolol was reduced by the beta-adrenoceptor blocking activity of pindolol on chronic administration. 2 Five subjects received in random order for 8 days placebo, propranolol 160 mg and pindolol 10 mg; on days 1 and 8 treatments were given twice at 0 and 2 h. Heart rate in supine position and at end of exercise was recorded before dosing and at 2 and 4 h post- dosing on days 1 and 8. 3 Propranolol and pindolol reduced exercise heart rate to the same extent on days 1 and 8. 4 Propranolol reduced supine heart rate more than pindolol on days 1 and 8 but the difference was only significant on day 8. [ABSTRACT FROM AUTHOR]

1 The effect of long-acting (LA) propranolol, LA propranolol and bendrofluazide, and a new combined formulation of LA propranolol/bendrofluazide (Inderex) on exercise tachycardia was studied in ten normal volunteers. 2 The preparations were given in random order, double-blind, on three separate study weeks. Observations were made 0, 1, 3, 6, 8, 24, 33 and 48 h after drug administration. 3 The three preparations produced a significant reduction in exercise tachycardia up to 48 h after drug administration, and the effects of the three preparations were not significantly different from each other. 4 Following LA propranolol, LA propranolol and bendrofluazide, and the combined formulation the mean reductions in exercise heart rate 24 h after drug administration were 16.7 +/- 2.1%, 13.0 +/- 1.8% and 16.2 +/- 1.7% respectively. 5 Plasma levels of propranolol and bendrofluazide were measured at 0, 1, 2, 3, 6, 8, 10, 12, 24, 33 and 48 h after dose administration. 6 There was no significant difference in plasma propranolol levels, Cmax propranolol or AUCo-x following the three preparations. The mean apparent t1/2 beta of propranolol after LA propranolol alone was significantly shorter than following the other two preparations (P less than 0.05), but this was not associated with a different pharmacodynamic response. 7 There was no significant difference in the pharmacokinetic parameters of bendrofluazide following the two preparations containing bendrofluazide. No bendrofluazide was detected in plasma after LA propranolol alone. 8 The new combined formulation produces similar pharmacodynamic and pharmacokinetic responses to LA propranolol and bendrofluazide given separately, and to LA propranolol given alone, and so may be of value in the treatment of hypertension. [ABSTRACT FROM AUTHOR]

1 Prizidilol hydrochloride (SK&F 92657) is a new compound which causes both arteriolar dilatation and beta-adrenoceptor blockade. The effect of a single oral dose on the responses of heart rate and blood pressure to isoprenaline infusion has been studied in healthy volunteers. 2 Isoprenaline heart rate dose-response curves showed parallel shifts to the right after oral prizidilol, indicating antagonism by this compound at beta-adrenoceptors in the heart. 3 Isoprenaline dose-response curves for decreases in diastolic blood pressure also showed shifts to the right after oral prizidilol, providing evidence of beta-adrenoceptor antagonism by this drug in peripheral resistance vessels. 4 The peak effect of a 40 mg dose of propranolol was greater than that of a 200 mg dose of prizidilol but both drugs caused persistent beta-adrenoceptor blockade for at least 7 h after ingestion. [ABSTRACT FROM AUTHOR]

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax - 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC - 1122.9 ng ml-1 h; VdSS - 190.71 and T1/2 - 4.2 h, and after i.v. administration: AUC - 1046.7 ng ml-1 h; VdSS - 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine. [ABSTRACT FROM AUTHOR]