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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

248 records · Page 14Linked to original sources
PubMedDate not supplied

An assessment of the pharmacokinetics and pharmacodynamics of single doses of amlodipine in elderly normotensives.

This study characterizes the single dose pharmacokinetic characteristics of the dihydropyridine calcium antagonist drug amlodipine in a group of 16 elderly subjects, aged 65 to 86 years (8 M:8 F). The most notable pharmacokinetic features were a prolonged terminal elimination half life of 48 +/- 16 hours and a delayed tmax of 7.3 +/- 1.3 hours. Consistent with the time to achieve peak plasma drug concentrations, there was a modest but significant reduction in blood pressure at 6-8 hours after dosing. Comparison of these results with those of published data for young subjects indicate not only a greater degree of intersubject variability but also a longer half life in the elderly, suggestive of reduced drug clearance, which may lead to higher plasma drug concentrations particularly at steady state.

Aged↗
PubMedDate not supplied

Occupational lead exposure and renin release.

Hypertension may result from chronic lead exposure. Lead poisoning arising from "moonshine whiskey" drinking has been associated with a rise in plasma renin activity. In the present study, plasma renin concentration following intravenous administration of frusemide was measured in eleven subjects with moderate or severe lead poisoning of industrial origin. The results were compared with those obtained for seven normal, control subjects. There was no significant difference in response obtained in the two groups. Industrial lead poisoning does not appear to affect renin release. The combined insult of lead and alcohol may explain the findings in the previous study.

Adolescent↗
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 in normal volunteers with MDL-899, a new arteriolar vasodilator.

We conducted pharmacodynamic studies with a new vasodilator, MDL-899. Following initial dose-ranging studies we studied eight male normotensive volunteers, each of whom received, orally, 10 mg MDL-899 or placebo in double-blind random order. MDL-899 significantly lowered standing blood pressure, the maximal effect occurring 3-6 h following drug administration. There was a significant increase in heart rate in both supine and standing positions, maximal 6-8 h postdose. Supine plasma noradrenaline concentrations were greater following MDL-899, with the greatest difference present 4 h after drug administration. Plasma renin concentrations were greater following MDL-899. Six of our subjects were also given 10 mg MDL-899 together with 100 mg atenolol, in an additional study. Atenolol increased the hypotensive effect and attenuated the tachycardia following MDL-899 alone. Side effects following MDL-899 administration included headache, lightheadedness, and tachycardia. These were reduced following atenolol coadministration. The haemodynamic profile of MDL-899 suggests that this drug acts as a direct arteriolar vasodilator in man. The observed increase in heart rate is likely mediated by reflex activation of the sympathetic nervous system.

Adolescent↗
PubMedDate not supplied

Application of pharmacokinetic-pharmacodynamic modelling for the comparison of quinazoline alpha-adrenoceptor agonists in normotensive volunteers.

Prazosin, doxazosin, and trimazosin are structural analogues with relatively selective peripheral alpha 1-adrenoceptor antagonist properties. The relationships between the pharmacokinetics and pharmacodynamics for these three drugs have been studied following acute intravenous administration in normotensive subjects. The mean terminal elimination half-life (+/- SD) for prazosin was 2.0 +/- 0.4 h, and that for trimazosin was comparable at 3.1 +/- 0.3 h, whilst the mean terminal elimination half-life for doxazosin was significantly longer at 9.4 +/- 1.5 h. The clearance of prazosin (mean, 327 +/- 78 ml/min) was greater than that of both doxazosin (139 +/- 30 ml/min) and trimazosin (67 +/- 29 ml/min). The hypotensive effects of prazosin and doxazosin were fitted to an integrated pharmacokinetic-pharmacodynamic model with similar resulting values for the parameter describing responsiveness. The pharmacodynamic profile of trimazosin was subjected to similar analysis and was most appropriately fitted to a model incorporating an effect compartment associated with both parent drug and its major metabolite 1-hydroxy trimazosin.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Trimazosin: relationships between hypotensive effect, vascular responsiveness, and drug and metabolite concentrations.

The relationships between the effects on blood pressure and vascular responsiveness, and the whole blood concentration of the antihypertensive drug trimazosin and its major metabolite were investigated in six normotensive male volunteers following 100 mg i.v. and 200 mg p.o. administration. Pressor responses to intravenous phenylephrine and angiotensin II were evaluated 1-3 (early) and 5-7 h (late) after drug or vehicle administration. There was a fall in blood pressure in the erect position (maximum between 4 and 8 h) associated with a modest increase in heart rate. Following treatment with trimazosin, blood pressure fell to 100/63 mm Hg with intravenous administration and 92/63 mm Hg with oral treatment, compared with the placebo value of 114/83 mm Hg. Both oral and intravenous trimazosin caused a significant rightward shift of the phenylephrine pressor dose-response curve (p less than 0.05). There was no significant shift of the angiotensin II pressor dose responses. Using linear regression analysis, the concentration of trimazosin in whole blood showed a significant correlation with the dose ratios from the phenylephrine pressor dose responses following treatment with both intravenous (r = 0.73, p less than 0.02) and oral (r = 0.57, p less than 0.05) trimazosin. There was no such correlation using dose ratios from angiotensin II pressor dose responses. There was no correlation between the concentration of the metabolite 1-hydroxytrimazosin and dose ratios from either phenylephrine or angiotensin II pressor dose responses. These observations suggest that the predominant mechanism of action of trimazosin, at doses that reduce blood pressure in humans, is through blockade of peripheral postjunctional alpha 1-adrenoceptors.

Adult↗
PubMedDate not supplied

Clinical evaluation of the vasodilator MDL-899 in patients with essential hypertension.

In this study of 10 patients with essential hypertension inadequately controlled by standard beta-blocker-diuretic combination therapy, the addition of 5 mg of MDL-899, a peripheral arteriolar vasodilator, resulted in significant reductions in blood pressure, both supine and standing, which was maximal 4-8 h after dosing, with no additional orthostatic component. There were associated small rises in heart rate but no evidence of significant activation of the sympathetic or renin-angiotensin systems. Six patients continued for 4 weeks receiving MDL-899 twice daily with significant improvement in their blood pressure control--from a mean of 182/95 to 146/77 mm Hg (supine) and from 161/93 to 138/79 mm Hg (erect). These six patients experienced no significant side effects, but four patients were unable to proceed with the study as a result of adverse effects, particularly headache, following the first few doses. It seems likely that these side effects are dose related. In a combined drug regimen, MDL-899 is an effective vasodilator drug that significantly improved the blood pressure control of patients with essential hypertension.

Aged↗
PubMedDate not supplied

Effect of calcium channel blockers on adrenergic and nonadrenergic vascular responses in man.

There is evidence that responses mediated via alpha adrenoceptors are dependent on calcium fluxes and it has been suggested that the alpha 2 adrenoceptor is particularly associated with the increased entry of extracellular calcium ions, which is preferentially antagonised by calcium channel blocking drugs. This study investigates in normotensive men the effects of calcium antagonism with verapamil and the dihydropyridine nisoldipine on the pressor responses to adrenergic and nonadrenergic vasoconstriction. Phenylephrine and alphamethylnoradrenaline were intravenously infused to assess respectively alpha 1 and alpha 2 adrenoceptor-mediated peripheral vascular responsiveness and angiotensin II was used to assess nonadrenergic responsiveness. After 4 days oral treatment, both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the mean pressor dose-response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine but with alphamethylnoradrenaline, although the overall trend was similar, only nisoldipine caused a significant twofold rightward shift. These data demontrate, in humans, that peripheral vascular adrenergic responses mediated via both alpha 1 and alpha 2 adrenoceptors are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the alpha 2 adrenoceptor.

Adult↗
PubMedDate not supplied

Vascular and aldosterone responses to angiotensin II in normal humans: effects of nicardipine.

The effects of the dihydropyridine calcium antagonist nicardipine on pressor responsiveness and hormone release were investigated in healthy normotensive men following both acute intravenous administration and 1 week of oral treatment. There were no significant changes in baseline supine blood pressures but the pressor responsiveness to the intravenous infusion of angiotensin II was significantly attenuated by both intravenous and oral nicardipine. This reduction tended to be greater following intravenous nicardipine, which achieved the highest mean plasma nicardipine concentrations. Neither intravenous nor oral nicardipine caused any significant differences in the aldosterone response to the angiotensin II infusion and there were no significant differences attributable to nicardipine in the levels of plasma renin activity. However, the progressive increase in the aldosterone/renin ratio observed during placebo was significantly attenuated by both nicardipine treatments. There were no significant effects on plasma cortisol, adrenocorticotropic hormone, or noradrenaline. This study has shown that nicardipine acutely and chronically reduces vascular responsiveness to the pressor effect of angiotensin II. There was no significant effect on the aldosterone response to angiotensin and no evidence of clinically significant interference with the release of other hormones to suggest that this mechanism contributes to the antihypertensive effect of nicardipine.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease.

1. Metabolic disorders, such as obesity and non-insulin-dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2. Significant increases in limb blood flow occur in response to systemic hyperinsulinaemia, although there is marked variation in the results due to a number of confounding factors, including activation of the sympathetic nervous system. Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by co-infusing D-glucose. 3. Insulin may stimulate endothelial nitric oxide production or may act directly on vascular smooth muscle via stimulation of the Na+-H+ exchanger and Na+/K+-ATPase, leading to hyperpolarization of the cell membrane and consequent closure of voltage-gated Ca2+ channels. 4. There is evidence both for and against the existence of a functional relationship between insulin-mediated glucose uptake (insulin sensitivity) and insulin-mediated vasodilation (which can be regarded as a surrogate measure for endothelial function). 5. If substrate delivery is the rate-limiting step for insulin-mediated glucose uptake (in other words, if skeletal muscle blood flow is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inability of mediators, including insulin, to stimulate muscle blood flow, may be the underlying mechanism accounting for the association of atherosclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood flow via stimulation of ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre type and capillary density, distribution of adiposity and endogenous corticosteroid production. 8. A complex interaction between endothelial dysfunction, abnormal skeletal muscle blood flow and reduced insulin-mediated glucose uptake may be central to the link between insulin resistance, blood pressure, impaired glucose tolerance and the risk of cardiovascular disease. An understanding of the primary mechanisms resulting in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.

Cardiovascular Diseases↗
PubMedDate not supplied

Clinical pharmacokinetics of prazosin--1985.

Prazosin is a selective alpha 1-adrenoceptor antagonist which is useful alone or in combination for the treatment of hypertension and heart failure. Unlike many other antihypertensive drugs, the action of prazosin appears to be closely related to its concentration in plasma or whole blood. Prazosin is variably absorbed, is subject to first-pass metabolism, and is eliminated almost entirely as metabolites of much lower hypotensive activity than the parent drug. Prazosin is highly bound to plasma and tissue proteins. The influences of renal, hepatic and cardiac disease on the disposition of prazosin are reviewed, as are the effects of pregnancy and ageing. The optimum use of prazosin in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

Aging↗
PubMedDate not supplied

Cardiac and vascular abnormalities in renal transplant patients: differential effects of cyclosporin and azathioprine.

Renal transplant patients die prematurely of cardiovascular disease and LV hypertrophy is now recognised as an important adverse prognostic indicator. This study investigated the factors implicated in the development of echocardiographic abnormalities (including LV hypertrophy) and the possible differential effects of treatment with cyclosporin and azathioprine. A cross-sectional study was undertaken in 46 patients randomly assigned to immunosuppressant treatment with either cyclosporin or azathioprine at 1 year post-transplantation: patients were studied not less than 5 years after assignment to cyclosporin (CyA) - or azathioprine (Aza)-based treatment regimens. Although clinic blood pressure control was not different in the two treatment groups, 24 hour ambulatory BP (ABP), particularly night-time BP, was significantly higher in the CyA group. There was a trend for both left ventricular hypertrophy (61 vs. 43%) and carotid wall thickening (43 vs. 26%) to be more common in the CyA group though this failed to achieve statistical significance. Left ventricular mass was determined by ABP, rather than clinic BP, and was also associated with increased QT dispersion. Multivariate analysis identified that 24 hour ambulatory systolic blood pressure (ASBP) and time on renal replacement therapy (RRT) were the major determinants of LV mass. Thus, despite the absence of differences in clinic BP measurements, CyA treatment was associated with higher rates of cardiovascular functional and structural abnormalities. This small scale study has identified cardiovascular functional and structural abnormalities in renal transplant patients, particularly in those receiving CyA-based immunosuppressive therapy. However, rather than reflecting a direct effect of CyA they are related to increased 24 ABP (but not clinic BP). These data suggest that ABP should be used to monitor and target antihypertensive therapy in this high risk patient group. Moreover, the future use of non-calcineurin inhibitor immunosuppressant therapy may have benefits on blood pressure control and LV mass.

Adult↗