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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 163 records · Page 9Linked to original sources
PubMed1987

A pragmatic approach to the pressor dose-response as an index of vascular reactivity and adrenoceptor function in man.

In clinical pharmacological studies, where it is not possible to describe the full dose-response curve, the construction of dose-response relationships ideally depends upon achieving a reproducible and readily measurable response for each dose administered. This study investigates in normotensive males the technique of dose-response analysis for the blood pressure and heart rate increases with constant infusions of incremental doses of vasoactive drugs, particularly catecholamines. Steady state responses could be adequately obtained using 5 min infusion periods (at each dose level) for noradrenaline and alpha-methyl noradrenaline. At least 7 min was required for phenylephrine and 8 min for isoprenaline. There was an approximate correlation between the time to achieve the steady state response and the half-life of the offset of the agonist effect. For interindividual comparisons it is desirable to compare steady state responses and so the time at each dose level will vary according to which agonist is being used. For intraindividual comparisons it may not be essential that steady state responses are achieved. For example, assessment of the effect of prazosin on the responses to phenylephrine, by calculation of dose ratios, indicated that 5 min dose intervals were adequate.

Adult↗
PubMed1987

Adimolol, a long acting beta-adrenoceptor blocker in man.

A comparative study in eight healthy normotensive males of the effects on blood pressure, heart rate and beta-adrenoceptor function following single oral doses of adimolol (600 mg), propranolol (240 mg) and placebo. Both active treatments produced small but significant reductions in blood pressure and heart rate, supine and erect. These effects persisted for up to 7 days after adimolol. The heart rate increases following both dynamic exercise and intravenous isoprenaline were attenuated by both propranolol and adimolol. With adimolol evidence of functional beta-adrenoceptor antagonism was sustained for up to 7 days. Lymphocyte beta-adrenoceptor binding studies showed that both adimolol and propranolol significantly reduced affinity for beta-adrenoceptors. In addition, adimolol significantly reduced receptor number and even by 3 days after dosing Bmax had only returned to half the control value. In a small sub-group of subjects there was no evidence to suggest that adimolol had additional alpha-adrenoceptor antagonist properties. Adimolol was detected in plasma for up to 3 days after dosing. The mean terminal elimination half-life was 14 h, compared to 3 h for propranolol. This study confirms that adimolol has prolonged beta-adrenoceptor antagonist activity with effects persisting for up to 7 days after a single dose. The reduction in beta-adrenoceptor number following adimolol suggests that this prolonged effect may not be solely due to competitive antagonism but may additionally depend upon non-competitive antagonism at beta-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1987

Acute and chronic ketanserin in essential hypertension: antihypertensive mechanisms and pharmacokinetics.

1. In nine patients with essential hypertension, following single and multiple doses of ketanserin, assessments were made of blood pressure and heart rate, QT interval, and pressor responses to phenylephrine and angiotensin II. 2. Significant reductions in blood pressure occurred for 6 h after the first dose, on average 23/14 mm Hg supine, and there was a comparable antihypertensive effect after 1 month's treatment. 3. There were small but significant rightward shifts (1.5 to 2-fold) in the phenylephrine pressor-response curves but no changes in the responsiveness to angiotensin II. 4. The QT interval (QTc) was significantly increased after 1 month's treatment: at 1 h after dosing 334 +/- 32 ms after 1 month of ketanserin compared with 302 +/- 31 ms after placebo. 5. The elimination half-life and AUC for ketanserin were both significantly increased at steady state compared with the first dose: respectively 13.4 vs 4.3 h for half-life and 830 vs 437 ng ml-1 h for AUC. 6. Ketanserin had no significant effects on baroreflex function, plasma renin activity, aldosterone, catecholamines and 24 h urinary excretion.

Adult↗
PubMed1987

Enalapril in essential hypertension: the comparative effects of additional placebo, nicardipine and chlorthalidone.

The effect of adding placebo, a calcium antagonist, nicardipine and a thiazide diuretic, chlorthalidone, each for 2 weeks, to ongoing treatment with the ACE inhibitor, enalapril was evaluated in seven patients with essential hypertension. Compared with placebo, nicardipine and chlorthalidone both significantly enhanced the antihypertensive effect of enalapril: average blood pressure reductions over 8 h were respectively 26/16 and 33/17 mm Hg (supine) but the time-course of these augmented effects was significantly different. In particular, blood pressure control with the addition of nicardipine, despite apparently being at steady state, was significantly attenuated during the latter part of the dosage interval and therefore was less well sustained at 24 h. In contrast, an effect throughout 24 h appeared possible with the chlorthalidone-enalapril combination.

Acetylcholinesterase↗
PubMed1987

Verapamil and prazosin in essential hypertension: evidence of a synergistic combination?

An enhanced hypotensive effect has been observed in short-term studies of the combination of an alpha-adrenoceptor antagonist and a calcium channel blocker. This study further evaluates combined treatment with prazosin and verapamil in 12 essential hypertensives who had not responded satisfactorily to standard beta-blocker and thiazide diuretic regimens. After placebo treatment, patients received monotherapy with either prazosin or verapamil. The appropriate second drug was then added, and combination treatment was continued for 4 weeks. A series of 8 h study days was undertaken at the end of each treatment phase to assess blood pressure, heart rate, and pharmacokinetics. Both monotherapies caused significant reductions in blood pressure. For the prazosin group the average blood pressure on monotherapy was 146/81 mm Hg (supine) and 151/88 mm Hg (erect), and for the verapamil group the corresponding figures were 149/81 and 156/92 mm Hg. In both groups significant further reductions in blood pressure were observed during combination treatment: on average, 133/74 mm Hg (supine) and 130/77 mm Hg (erect) for the prazosin group and, respectively, 137/75 and 141/85 mm Hg for the verapamil group. The pharmacokinetics of verapamil were not altered by the coadministration of prazosin, but there were changes in the pharmacokinetics of prazosin, with significant increases in peak plasma concentrations and bioavailability. Prazosin and verapamil form a useful antihypertensive drug combination. The overall effect is partly due to an increase in the apparent bioavailability of prazosin but may also reflect a synergistic effect on reducing peripheral vascular resistance.

Adult↗
PubMed1987

Risk factor modification in hypertension--success and failure.

A group of 175 patients have attended for four years a microcomputer based, nurse practitioner managed clinic for the long term care of hypertension. Improvement in blood pressure (BP) control was seen initially and has been maintained. Drug treatment has been with a beta blocker followed if necessary by a diuretic and/or a vasodilator. Despite individual dietary and 'stop smoking' advice, there was no marked change in body weight while only males reduced smoking. A significant increase in non fasting serum cholesterol (6.4 +/- 1.3 to 6.6 +/- 1.3 mmol/l) and glucose (5.5 +/- to 6.1 +/- 2.5 mmol/l) was seen overall, but was restricted to those patients taking a thiazide diuretic (with or without other drugs). These findings indicate the need for a more systematic collection of information on effects of long term treatment and for the development of better strategies for improving lifestyle.

Adrenergic beta-Antagonists↗
PubMed1986

Disopyramide in acute myocardial infarction: problems with changing pharmacokinetics.

In the acute phase of myocardial infarction it is recognized that serum disopyramide concentrations may be lower than expected. This has generally been attributed to reduced oral bioavailability. This report describes data obtained routinely from 6 patients with acute myocardial infarction and cardiac dysrhythmias treated initially with intravenous disopyramide. Serum disopyramide concentrations were consistently lower than expected, on average by 2.6 micrograms/ml. This was interpreted as being due to relatively high drug clearance, calculated as 6.7 +/- 1.5 l/h, compared to expected values of 3-4 l/h. Dosage schedules determined on the basis of the acute phase pharmacokinetics subsequently produced higher than predicted concentrations at later times on average by 2.8 micrograms/ml. Clearance at this time was calculated to be 3.1 +/- 0.6 l/h. Thus even with intravenous disopyramide therapy there are problems with changing pharmacokinetic parameters after myocardial infarction.

Aged↗
PubMed1986

Desensitization of platelet alpha 2-adrenoceptors after short term infusions of adrenoceptor agonist in man.

The effect of intravenous infusion of catecholamines and related drugs on human platelet alpha 2-adrenoceptor number and function was investigated. Short (60-120 min) infusions of catecholamines with alpha 2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. Acute infusions of alpha 2-adrenoceptor agonists may alter the coupling of the platelet alpha 2-adrenoceptor to adenylate cyclase.

Adolescent↗
PubMed1986

The pharmacokinetics of doxazosin in elderly normotensives.

The pharmacokinetics of doxazosin were studied in 12 normotensive elderly volunteers aged 62-89 years. There was marked inter-individual variability in all the parameters derived but the disposition of doxazosin was similar in both sexes. These results were compared to those of a group of young normotensive volunteers aged 23-39 years studied previously under comparable conditions. The volume of distribution increased significantly with age although the bioavailability and clearance were not significantly different in the two groups. These results suggest that age is unlikely to influence the disposition of doxazosin to a clinically significant extent.

Administration, Oral↗
PubMed1986

Clinical pharmacological studies with doxazosin.

The clinical pharmacology of doxazosin is reviewed from studies in normotensive young (21-39 years) and elderly (62-89 years) subjects following oral (2 mg) and intravenous (1 mg) administration. In young subjects the mean bioavailability was 65% and the mean terminal elimination half-lives were 9.5 and 10.5 h following acute intravenous and oral administration respectively. These parameters were similar in the elderly with bioavailability of 69% and half-lives of 8.8 and 11.9 h. The apparent volume of distribution and clearance were significantly higher in elderly (1.7 1 kg-1 and 140 ml min-1) than in young subjects (1.01 kg-1 and 83 ml min-1). In both groups blood pressure reductions were most marked in the standing position and the maximum effect did not occur until 5-6 h, even after intravenous administration. The blood pressure reduction produced by doxazosin was associated in the young with a significant increase in heart rate to 108 beats min-1 (placebo, 82 beats min-1) but this increase was significantly attenuated in the elderly at 91 beats min-1 (placebo, 77 beats min-1). Pressor response studies in the young subjects confirmed the alpha 1-adrenoceptor antagonist activity of doxazosin with significant rightward shifts of the dose-response curves for the selective alpha 1-adrenoceptor agonist phenylephrine. Using the technique of concentration-effect analysis, both the degree of alpha 1-adrenoceptor antagonism and the hypotensive effect can be correlated with the concentration of doxazosin in the 'effect compartment'.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1986

Racial differences in drug responses--a comparative study of trimazosin and alpha 1-adrenoceptor responses in normotensive Caucasians and West Africans.

The possible racial differences in alpha 1-adrenoceptor responsiveness and the blood pressure and heart rate responses following alpha 1-adrenoceptor antagonism with trimazosin have been investigated in matched groups of six Caucasians and six Nigerians. There were no significant differences between the racial groups in the blood pressure and heart rate responses to oral (200 mg) and intravenous (100 mg) trimazosin. alpha 1-adrenoceptor responsiveness was similar in both groups after placebo and following both active treatments. There were only minor pharmacokinetic differences with the Caucasians having a larger volume of distribution, and a longer terminal elimination half-life for the metabolite, 1-hydroxy-trimazosin. These results suggest a similarity in peripheral vascular alpha 1-adrenoceptor mechanisms and show no major significant racial differences in the pharmacokinetics and pharmacodynamics of trimazosin.

Adult↗
PubMed1986

The pharmacodynamics and dose-response relationships of the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.

In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94-96% at 2-3 h. At 24 h residual inhibition of ACE was 49-54%. Plasma renin activity increased in a dose-dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.

Adult↗
PubMed1985

The effect of cimetidine on the pharmacokinetics, pharmacodynamics and alpha 1-adrenoceptor responsiveness of trimazosin in man.

The effect of cimetidine treatment on the pharmacokinetics and pharmacodynamics of single doses of trimazosin was studied in 6 normotensive volunteers. Co-administration of cimetidine did not significantly affect the overall magnitude of the hypotensive effect of trimazosin. However, the time profile of the blood pressure response was significantly modified particularly with attenuation of the delayed component. Co-administration of cimetidine did not alter alpha 1-adrenoceptor antagonism by trimazosin. There was no significant change in the clearance and volume of distribution of trimazosin but there was a significant reduction in the area under the concentration-time curve for the metabolite, 1-hydroxy-trimazosin. The reduction in the AUC of 1-hydroxy-trimazosin corresponds in time with the attenuation of the delayed hypotensive response. This is consistent with the suggestion that the delayed hypotensive response is related to an active metabolite, probably 1-hydroxytrimazosin.

Adult↗
PubMed1985

Acute and chronic regulation of alpha 2-adrenoceptor number and function in man.

Agonist regulation of platelet alpha 2-adrenoceptors was examined in human volunteers after acute elevations of adrenoceptor agonist and during chronic elevation of plasma catecholamines in two patients with phaeochromocytoma. Platelet alpha 2-adrenoceptor number was measured by radioligand binding [( 3H]yohimbine) and alpha 2-adrenoceptor function measured by turbidimetric platelet aggregation. Short term infusion of adrenoceptor agonists with alpha 2 activity caused reductions in the platelet response to adrenaline in vitro; conversely an increase in activity was observed postoperatively in two patients after removal of phaeochromocytoma. The changes in platelet response were not accompanied by changes in alpha 2-adrenoceptor number. It is proposed that a process of receptor inactivation occurs during desensitization and this is responsible for the dynamic regulation of platelet responses.

Adolescent↗
PubMed1985

Clinical pharmacological studies on the interaction between alpha-adrenoceptors and calcium antagonists.

On the basis of animal studies, it has been proposed that calcium antagonists selectively interfere with the pressor response to alpha 2-adrenoceptor antagonists and have less direct action on alpha 1-adrenoceptor mechanisms. In placebo-controlled randomized studies in healthy normotensives, we have found that verapamil 160 mg significantly increases the fall in blood pressure after prazosin 1 mg orally. In part, this appears to be related to the cardioinhibitory and negative chronotropic action of verapamil, but it is also likely to depend on increases in bioavailability of prazosin and higher plasma levels when the drug is given with verapamil. Interactions of calcium antagonists with alpha-receptors were further explored in a study in which the pressor responses to intravenous angiotensin II were compared with those after phenylephrine (alpha 1-agonist) or alpha-methylnoradrenaline (alpha 2-agonist) in subjects treated with verapamil or nisoldipine, a new dihydropyridine related to nifedipine. Both calcium antagonists attenuated the pressor response to all three pressor substances to a similar degree. There was no evidence that pressor responses to alpha-methylnoradrenaline were selectively or more extensively reduced. Calcium antagonists can modify responses to both alpha 1- and alpha 2-receptors. Calcium antagonists in combination with drugs modifying adrenoceptor activity may have useful additional antihypertensive activity.

Angiotensin II↗