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Biomedical subjects

K McLean

Publications and source records attributed to K McLean.

53 records · Page 3Linked to original sources
PubMed1982

A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist, doxazosin (UK33274) in normotensive subjects.

1 Doxazosin is a quinazoline derivative, related to prazosin, recently developed for the treatment of hypertension. 2 The intravenous administration of doxazosin (12 micrograms/kg) to six healthy normotensive subjects resulted in significant fall in erect blood pressure, with a corresponding increase in heart rate, but there were no significant changes in supine blood pressure or heart rate. 3 The changes in blood pressure and heart rate were maximal at 6 h after intravenous dosing. With prazosin the maximum effects occurred within the first hours. 4 Pressor response studies with phenylephrine confirmed that doxazosin is a relatively selective postsynaptic alpha-adrenoceptor antagonist. 5 The mean elimination half-life of doxazosin was 11 h. This compared with a T1/2 of 2.5 h for prazosin.

Adrenergic alpha-Antagonists↗
PubMed1982

Noradrenaline release and clearance in relation to age and blood pressure in man.

Plasma noradrenaline concentration increases with age. This study was designed to investigate whether an increased rate of noradrenaline release into the circulation or a decrease in clearance is primarily responsible for this age related change in concentration. Sixteen healthy male subjects were studied, eight young (21-36 years) and eight old (65-78 years). Clearance was calculated from steady state noradrenaline concentrations during constant rate infusions of unlabelled noradrenaline. Clearance did not differ between the two groups: young 4.8 l/min (range 2.7-6.1), old 4.1 (range 2.6-8.2). The old subjects had significantly greater rates of release. Supine: young 10.3 nmol/min (range 5.3-17.6), old 19.7 (range 10.1-30), P less than 0.05. Standing: young 17.2 (range 11-36.4), old 29.2 (range 21.8-47.9), P less than 0.01. No significant relationship was found in either supine or standing position between rate of noradrenaline release and either systolic or diastolic blood pressure. These results indicate that plasma noradrenaline concentration rises with age because of an increased rate of release, but that this increased release is not responsible for the higher blood pressure seen in the elderly.

Adult↗
PubMed1982

Lead in the water supply alters swimming-maze behavior in adult mice.

After about two weeks of exposure to either 20 ppm or approximately 2000 ppm of lead in the drinking water or tap water only and under an ad libitum or restricted food regime, albino male and female mice (N = 48) were tested for three consecutive days (3 blocks of 3 trials per day) in a swimming maze. Body weights were not altered by lead treatments significantly. The mice treated with the lead displayed longer escape latencies and more errors than the controls on tap water. Statistically significant interactions of lead treatment by test day by test block were also apparent.

Animals↗
PubMed1982

Clinical evaluation of endralazine (BO22708), a new vasodilator, in essential hypertension.

In the treatment of severe hypertension the choice of vasodilator is limited by side-effects, of which the lupus erythematosus syndrome induced by hydralazine is potentially the most serious, particularly in patients with the slow acetylator phenotype. This study describes the clinical evaluation of a new vasodilator, endralazine, which is related to hydralazine but which is not metabolised to any great extent by acetylation. In 6 essential hypertensives not adequately controlled by combined beta-blocker and diuretic therapy the additional administration of the first dose of 10 mg endralazine resulted in a significant reduction in blood pressure, without orthostatic symptoms, but associated with significant increases in heart rate and plasma noradrenaline concentration. These 6 patients and a further 9 similar hypertensive patients were then prescribed twice daily endralazine for 4 weeks with significant improvement in blood pressure control. During this short period of maintenance treatment with endralazine the single dose observations were repeated and no significant changes in heart rate or plasma noradrenaline concentration were observed. In summary, endralazine is an effective vasodilator/antihypertensive which was well tolerated in a triple therapy regimen in this study.

Adult↗
PubMed1981

Pharmacodynamic studies on mianserin and its interaction with clonidine.

There is evidence that clonidine's hypotensive effect is reduced by the concurrent administration of tricyclic antidepressants. It has been proposed that this results from an interaction at alpha 2-receptors in the brain stem where clonidine acts as a relatively selective agonist and the tricyclic antidepressants as antagonists. Mianserin is an antidepressant with a tetracyclic structure and, although it has been reported to cause less cardiovascular disturbance, there is evidence that it also has alpha-adrenoceptor blocking effects. This study in 6 normotensive healthy male volunteers was designed to investigate a possible interaction between clonidine and the antidepressant mianserin. Administration of the first dose of 20 mg mianserin was associated with acute cardiovascular effects, notably transient postural hypotension, but no significant disturbance of heart rate or blood pressure was detected after 3 days continuous treatment with mianserin 20 mg tid. Following pre-treatment with mianserin or placebo the responses to a single oral dose of 300 micrograms clonidine were then assessed. The combination of mianserin and clonidine was not associated with any attenuation of clonidine's hypotensive effect, erect or supine, but there was significant attenuation of clonidine's supine bradycardic effect. There was no evidence that mianserin interfered with the ability of clonidine to diminish salivary flow, cause sedation, and reduce catecholamine output, but it was noted that mianserin itself had a very pronounced sedative effect. Mianserin alone had no significant effect on salivary flow. This short term study demonstrates that mianserin does not significantly interfere with the responses to a single oral dose of clonidine.

Adult↗
PubMed1981

Immediate cardiovascular responses to oral prazosin--effects of concurrent beta-blockers.

Initiation of prazosin therapy may be complicated by the first-dose response of acute postural hypotension and tachycardia. The effects of beta-blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 +/- 7 mm Hg (mean +/- SD), associated with a tachycardia of 117 +/- 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 +/- 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective beta-blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 +/- 7 and 75 +/- 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent beta-adrenergic blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial dose of prazosin.

Administration, Oral↗
PubMed1981

Calcium antagonists decrease adrenal and vascular responsiveness to angiotensin II in normal man.

1. The effect of the calcium antagonist nifedipine on the pressor and aldosterone responses to angiotensin II was studied in six normal subjects. 2. Blood pressure, pulse rate and plasma aldosterone, potassium and cortisol were measured during paired consecutive infusions of angiotensin II (5, 10 and 20 ng min-1 kg-1) on two separate occasions. Nifedipine (20 mg by mouth) was given, 30 min before the second set of infusions. 3. After nifedipine there were reciprocal changes in supine resting blood pressure (-7 mmHg) and pulse rate (+18 min-1) and a significant decrease in the pressor response to angiotensin II (P less than 0.05; Wilcoxon signed rank test). 4. Basal levels of aldosterone were not changed by nifedipine, but the response to angiotensin II was significantly attenuated (P less than 0.05). Nifedipine had no effect on plasma potassium or cortisol. 5. Transmembrane movement of calcium is involved in the aldosterone response to angiotensin II in man. Calcium antagonists may lower blood pressure via decreased adrenal responsiveness to angiotensin II as well as by peripheral vasodilatation.

Adrenal Glands↗
PubMed1980

A comparative study of automated blood pressure recorders.

Four automated blood pressure machines (Arteriosonde 1225, Bosomat 11D, Elag Koln BE 237R and Omron HEM 3) have been compared with each other and with the Hawksley Random Zero Sphygmomanometer in 18 subjects with a wide range of BP. Each form of measurement provided a high degree of internal consistency. The Arteriosonde 1225 consistently recorded systolic and diastolic pressures which were below the values obtained with the Random Zero instrument (P=0.001). The other 3 automated machines recorded BPs which did not differ significantly from the Random Zero or from each other. Heart rate readings did not differ significantly for any of the machines compared to manual recording. The disparity attributable to the Arterisonde could result from its being the only form of measurement to use an ultrasonic rather than a microphonic recording technique. However, the cheaper and more portable automated machines produce results which closely reflect those obtained by using a mercury sphygmomanometer.

Blood Pressure Determination↗
PubMedDate not supplied

Drug therapy in multiple sclerosis: a study of Nova Scotia senior citizens.

We conducted a study to determine the types and costs of drugs used by Nova Scotia senior citizens with multiple sclerosis (MS) compared with the types and costs of drugs used by all senior citizens in Nova Scotia. Administrative claims databases from the Nova Scotia Seniors Pharmacare program for persons aged 65 years or older were linked to the Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinical database (1980-1994). Analyses compared persons with MS aged 65 years or older who attended the DMSRU at least once with the general population of senior citizens. Not all persons with MS attended the DMSRU. In aggregate, Pharmacare costs in 1993-1994 for patients with MS aged 65 years or older (N = 52) were $975.00 Canadian per capita compared with $590.00 Canadian for all senior citizens in Nova Scotia (N = 108,646). Thus average drug costs for the senior citizens with MS were 65% greater than those for all senior citizens covered by Nova Scotia's comprehensive, publicly funded Pharmacare program. Compared with other senior citizens, those with MS more frequently received alpha-blockers, anticholinergics, cholinergics, tricyclic antidepressants, anticonvulsants, antifatigue agents, antispasticity agents, and antibiotics for bladder infections.

Aged↗
PubMedDate not supplied

Effect of age on the responsiveness of vascular alpha-adrenoceptors in man.

Aging has been reported to alter the responsiveness of beta-receptors, but there have been few comparable studies of alpha-receptors. This study compares in six young and six healthy elderly subjects the haemodynamic effects of the alpha 1 -antagonist prazosin and the pressor responses to the alpha 1-agonist phenylephrine. Prazosin orally lowered erect (but not supine) blood pressure in both groups by a similar amount between 2 and 6 h after dosing. Maximal falls in systolic pressure were 19.5 +/- 15.7 and 29.3 +/- 11.4 mm Hg (mean +/- SD) in young and old, respectively. There was a significant difference in the associated heart rate response: in the young group mean heart rate increased to 103 beats/min, but there was no corresponding increase in the elderly group, which has a mean heart rate of 80 beats/min. Following the intravenous infusion of increasing doses of phenylephrine, log dose-response curves were deprived, and the dose required to raise mean arterial pressure by 20 mm Hg (PD20) was compared. The mean PD20 was significantly different in the two groups: 2.5 +/- 1.6 in the young, compared to 4.6 +/- 2.3 micrograms/kg/min in the elderly. However, no significant difference was apparent when pressor responsiveness was determined following the administration of prazosin. Thus, while there is no evidence of an age-related increase in the sensitivity of alpha-adrenoceptor-mediated vasoconstriction, the data are not inconsistent with an age-related reduction in responsiveness to alpha-adrenoceptor activation.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Pharmacodynamic studies with a specific alpha 2-adrenoceptor agonist (BHT-933) in man.

We conducted pharmacodynamic studies in man with a specific alpha 2-adrenoceptor agonist BHT-933. The study involved nine male normotensive volunteers each of whom received BHT-933 5 mg or placebo in random order. BHT-933 significantly lowered systolic and diastolic blood pressure (BP) in supine and standing positions, the greatest effect occurring 3-4 h following drug administration. Supine values: placebo 116/73; BHT-933 99/64. Standing values: placebo 114/79; BHT-933 92/67. Heart rate was uninfluenced by BHT-933 even at the time of maximum fall in BP. Plasma noradrenaline concentration in the supine position was significantly reduced: placebo 2.5 +/- 0.8 nmol/L; BHT-933 1.7 +/- 0.6. The haemodynamic changes accompanying Valsalva's manoeuvre and cold pressor test were uninfluenced by BHT-933. All subjects experienced sedation and dry mouth following BHT-933 with a time course similar to that of the fall in BP. These results are consistent with an effect of BHT-933 on BP control through an action on alpha 2-receptors at the level of the brainstem.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Endogenous opioids and baroreflex control in humans.

We describe two studies designed to elucidate the role of endogenous opioids in blood pressure control in humans. In the first study, nine normal subjects received infusions of DAMME (a metenkephalin analog), naloxone, or saline, and blood pressure, heart rate, and plasma norepinephrine concentration were determined supine and following 5 minutes of 70 degrees head-up tilt at intervals for 6 hours. Blood pressure following tilt was significantly decreased by DAMME but not influenced by naloxone, the effect being most marked at 3 hours (placebo = 110 +/- 6/78 +/- 7 mm Hg; naloxone = 106 +/- 10/79 +/- 5 mm Hg; DAMME = 96 +/- 16/67 +/- 8 mm Hg (p less than 0.01). However, heart rate and plasma norepinephrine did not rise in response to this hypotension. Heart rates at 3 hours were: placebo = 87 +/- 16 bpm; naloxone = 88 +/- 19 bpm; DAMME = 89 +/- 23 bpm. Plasma norepinephrine levels (nmol/liter) at 3 hours were: placebo = 6.0 +/- 2.2; naloxone = 5.8 +/- 1.9; DAMME = 6.0 +/- 1.9. In the second study, seven normal subjects had blood pressure reduced by incremental infusions of sodium nitroprusside, and the effects of placebo, naloxone, and DAMME on the slope of the heart period/blood pressure relationship investigated. Naloxone significantly increased the slope by 90% and DAMME significantly reduced the slope by 30%. It is concluded that endogenous opioids modulate the baroreflex control of blood pressure in normal humans.

Adolescent↗
PubMedDate not supplied

A randomized clinical trial of agents to reduce sensitivity after crown cementation.

Three desensitizing agents were evaluated for the control of sensitivity after cementation of 77 crowns. Information was collected on pain in response to hot, cold, or bite preoperatively; and postoperatively with temporary crowns at one week and at one month after cementation of crowns. No medicament was clearly better than the placebo.

Adult↗