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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 145 records · Page 8Linked to original sources
PubMed1988

Kinetic-dynamic relationships and antihypertensive mechanisms of ketanserin in essential hypertension.

This study of ketanserin illustrates the use of concentration-effect analysis in clinical investigations of antihypertensive mechanisms and the factors responsible for interindividual differences in blood pressure response. Using an integrated kinetic-dynamic model the acute and chronic responses to ketanserin were characterized for each individual patient in terms of blood pressure fall per unit drug concentration. Two principal findings were obtained from this approach. (1) There was a significant reduction in responsiveness to ketanserin during chronic treatment: on average, -0.47 after the first dose compared with -0.25 mmHg/ng per ml after 1 month. (2) There was a significant change in the parameter keq, which characterizes the temporal discrepancy between the time profiles for plasma drug concentration and effect: from a mean value of 0.49 (first dose) to 1.86/h (1 month). There was no significant relationship between the responsiveness to ketanserin and patient age, peripheral alpha 1-adrenoceptor blockade or initial blood pressure. These results suggest that there is a change in the relative contributions of the component antihypertensive mechanisms during continued treatment with ketanserin. Furthermore, there is no clear relationship between patient age and responsiveness to ketanserin.

Dose-Response Relationship, Drug↗
PubMed1988

Factors determining the response to calcium antagonists in hypertension.

Pharmacokinetic and pharmacodynamic variability account for the large interindividual differences in the antihypertensive response to treatment with a calcium antagonist. Using an integrated kinetic-dynamic model, the acute and chronic (4-6 weeks) responses to nifedipine (n = 14) and verapamil (n = 14) were characterized for individual hypertensive patients in terms of fall in blood pressure per unit drug concentration. The responsiveness to nifedipine, as the mean of the group, was -0.48 mm Hg/ng/ml following the first dose and -0.49 mm Hg/ng/ml after chronic dosing. The corresponding values for verapamil were -0.13 and -0.12 mm Hg/ng/ml, respectively. For nifedipine and verapamil, the responsiveness to the first dose was significantly correlated both with the height of the pretreatment blood pressure (p less than 0.001) and the responsiveness after 4-6 weeks of treatment (p less than 0.001). Parameters derived from an individual approach to concentration-effect analysis are useful for evaluating the determinants of response to calcium antagonists and form a potential basis for optimizing drug therapy in individual patients.

Adult↗
PubMed1988

Pharmacokinetics of calcium antagonists.

Calcium antagonists are a biochemically heterogeneous group of drugs that share the property of blocking the entry of calcium into cells by voltage-operated channels in cardiac and smooth muscle. They are useful in the management of angina pectoris and hypertension. The drugs available at present include nifedipine, verapamil, and diltiazem. All three drugs have similar pharmacokinetic properties of low and variable bioavailability, high first-pass metabolism, short elimination half-life, and active metabolites. The pharmacokinetics of calcium antagonists are relevant, because in individual patients the intensity and duration of the pharmacological effect is related to the level of drug in plasma. Amlodipine is a new dihydropyridine calcium antagonist in advanced clinical development. It has a completely different pharmacokinetic profile. It is water soluble and photostable, and has a long half-life of 35-50 h. Amlodipine is slowly absorbed, its absolute bioavailability is high, and it is extensively metabolized in the liver. The long half-life is associated with a prolonged (greater than 24 h) duration of pharmacodynamic action. Amlodipine, because of its novel pharmacokinetics, may offer practical advantages over existing calcium antagonists in the long-term treatment of cardiovascular disease.

Calcium Channel Blockers↗
PubMed1988

A comparison of the disposition of single oral doses of amlodipine in young and elderly subjects.

The potential use of calcium antagonists in the treatment of hypertension and ischemic heart disease in elderly patients creates a requirement for pharmacokinetic information that is specific for that age group. This study describes the pharmacokinetics of amlodipine after single oral doses of 5 mg in 16 elderly subjects, mean age 72 years, age range 65-85 years. The principal findings were that the mean elimination half-life was 48 h and that peak plasma drug concentrations were not observed until 7 h after dosing. In comparison with data obtained from a group of young subjects, mean age 26 years, there were significant differences in pharmacokinetics. The terminal elimination half-life of 48 h in the elderly was significantly longer than that of 35 h in the young subjects and there was a correspondingly greater area under the curve in the elderly, by approximately 50%. These findings are consistent with an age-related reduction in drug clearance.

Adult↗
PubMed1988

Ketanserin concentration-effect relationships in individual hypertensive patients.

1. This study further investigates the relationship between ketanserin concentration and the fall in BP in individual hypertensive patients. 2. An integrated kinetic-dynamic model was used to characterise the response to ketanserin for each individual in terms of BP reduction per unit drug concentration and to describe the temporal discrepancy for the plasma concentration-effect relationship (keq). 3. Using the linear effect model ketanserin concentrations were well correlated with the fall in BP in individual patients. There was a significant reduction in the responsiveness to ketanserin (m) after 1 month: -0.25 mm Hg ng-1 ml-1, compared with -0.47 following the 1st dose. 4. There was a significant increase in keq from 0.49 (1st dose) to 1.86 h-1 (1 month). 5. There was no relationship between the responsiveness to ketanserin and patient age, starting BP or peripheral alpha-adrenoceptor blockade.

Aging↗
PubMed1988

Initial blood pressure as a predictor of the response to antihypertensive therapy.

1. The relationship between fall in systolic blood pressure and initial systolic blood pressure has been investigated in 255 mixed normotensive and hypertensive subjects given placebo or one of five types of antihypertensive drug (ACE inhibitors, calcium antagonists, direct vasodilators, alpha-adrenoceptor blocker, beta-adrenoceptor blocker). 2. In all cases there was a significant correlation between the change in blood pressure and initial blood pressure. When Oldham's transformation was used (replacing the initial blood pressure by the mean of the initial and minimum pressures) the correlation coefficients were all reduced, although five out of six were still statistically significant. 3. In a subset of 43 hypertensive subjects given four antihypertensive agents, concentration-effect analysis was carried out. For three of the agents a linear model was used to relate effect to concentration; for the remaining agent a Langmuir type model was used. 4. For all four sets of data for which concentration-effect analysis was carried out, there was a significant correlation between the sensitivity of response and the initial blood pressure. 5. The observed relationships between initial blood pressure, change in blood pressure and sensitivity of response can be qualitatively explained by postulating a general form of dose-response relationship for all antihypertensive agents.

Antihypertensive Agents↗
PubMed1988

Risk-benefit of specific antihypertensive regimens: relevance of metabolic and haemodynamic effects of alpha 1-blockers.

1. Existing strategies for the control of high blood pressure have had a disappointing impact on coronary heart disease--the major cause of death in hypertension. 2. There is a need for more work to identify the relationship between blood pressure, atheroma and other risk factors. 3. A more aggressive approach to treatment may be indicated, especially in high risk groups. 4. In addition to treatment of blood pressure, other major risk factors (lipids and smoking) must be tackled. 5. Alternative treatment regimens with different mechanisms of action and/or effects on lipids should be evaluated in practice. 6. Selective alpha 1-blockers have potential haemodynamic advantages, improve the lipid profile and are well tolerated as first or second line therapy.

Adrenergic beta-Antagonists↗
PubMed1988

Nifedipine: individual responses and concentration-effect relationships.

Dynamic and kinetic variability account for the large intersubject differences in the antihypertensive response to nifedipine, and a clear concentration-effect relationship has not been established. The effects of placebo, first dose, and chronic (1 and 6 weeks) treatment with nifedipine were studied in 14 subjects with essential hypertension using an integrated kinetic-dynamic model to calculate individual subject responsiveness in terms of fall in blood pressure per unit change in drug concentration. Nifedipine concentrations were well correlated with the fall in systolic blood pressure in individual subjects, and the mean responsiveness was -0.48 mm Hg/ng/ml after the first dose, -0.45 mm Hg/ng/ml after 1 week, and -0.49 mm Hg/ng/ml after 6 weeks. The responsiveness to the first dose of nifedipine was significantly correlated with the responsiveness after 1 (r = 0.83) and 6 weeks (r = 0.78) of therapy and with the height of the pretreatment blood pressure (r = 0.6). This study incorporated kinetic as well as dynamic information to characterize the antihypertensive response to nifedipine and identify nifedipine concentration-effect relationships in individual hypertensive subjects.

Adult↗
PubMed1988

Pharmacokinetic and pharmacodynamic modelling of the alpha adrenoceptor antagonist doxazosin.

1. The pharmacokinetic and pharmacodynamic profiles of intravenous and oral doxazosin were investigated in 6 normotensive volunteers. 2. The pharmacokinetics of i.v. and oral doxazosin were fitted simultaneously and independently. The parameters derived were in good agreement with a mean elimination half-life of 539 +/- 75 min, bioavailability of 0.65 +/- 0.11 and clearance of 140 +/- 26 ml/min. 3. Pharmacokinetic-pharmacodynamic modelling indicated that the sensitivities to oral and i.v. doxazosin in individual subjects were in good agreement. 4. Based on these findings it is unlikely that doxazosin metabolites contribute significantly to the pharmacodynamic profile of doxazosin.

Administration, Oral↗
PubMed1988

Effects of ketanserin on peripheral vascular pressor mechanisms in essential hypertension.

The principal aim of this study was to investigate the effects of ketanserin on peripheral vascular pressor mechanisms in nine patients with essential hypertension, including an assessment of the responsiveness to intravenous infusions of the alpha 1-adrenergic agonist, phenylephrine, and the nonadrenergic vasoconstrictor, angiotensin II. There were small but significant rightward shifts in the phenylephrine pressor dose-response curves (by 1.5- to twofold) following ketanserin but no shifts for angiotensin II. This modest shift in phenylephrine responsiveness contrasted with the fivefold shift obtained with a single oral dose (1 mg) of prazosin. The relationship between the phenylephrine-induced increase in blood pressure and the reduction in heart rate was used as an index of baroreflex responsiveness: there were no significant effects attributable to ketanserin. There were no significant differences in plasma aldosterone or renin activity, nor in 24-h urinary volume or electrolytes, following ketanserin. The principal mechanism underlying the antihypertensive effect of ketanserin is unlikely to involve peripheral vascular alpha 1-adrenoceptor antagonism, altered baroreflex responsiveness, or perturbation of the renin-angiotensin-aldosterone system.

Aldosterone↗
PubMed1988

Alpha 1-adrenoceptor responsiveness: the influence of age.

The association between increasing age and increasing blood pressure is the principal factor that has compromised the interpretation of many studies attempting to evaluate the effects of age alone on alpha-adrenergic mechanisms and the antihypertensive response to alpha 1-adrenoceptor antagonists. In clinical studies of antihypertensive response, difficulties of interpretation have been created by the failure to take into account the statistical association between the initial blood pressure and magnitude of the blood pressure fall and also the potential influence of age-related alterations in pharmacokinetics and drug disposition. Only a few studies have integrated pharmacokinetic and pharmacodynamic information to quantify more accurately responsiveness to alpha-antagonist drugs. These studies have failed to show any independent age-related differential effect but have confirmed that the pretreatment blood pressure, irrespective of age, is a significant determinant of the antihypertensive response.

Adrenergic alpha-Antagonists↗
PubMed1987

Pharmacokinetic overview of doxazosin.

After both oral and intravenous administration, doxazosin is extensively metabolized, with only about 5% of the administered dose excreted unchanged in urine. For single doses, oral bioavailability has been calculated to be about 65%; terminal elimination half-life is approximately 10 to 12 hours. In later multiple-dose studies in which doxazosin concentrations were measured beyond 24 hours after administration, the terminal elimination half-life was 22 hours. Clearance of doxazosin, presumably in the liver, involves the production of mainly O-demethylated and C-hydroxylated metabolites, and is low in comparison with hepatic blood flow. Protein binding is reported to be 98.3% in humans. Relatively low clearance (1.0 to 2.0 ml/min/kg) in association with a moderate volume of distribution (1.0 to 1.9 liters/kg) is responsible for doxazosin's relatively long plasma half-life. There is no evidence to suggest that active metabolites contribute significantly to the pharmacologic activity of doxazosin; both hypotensive effect and alpha-adrenoceptor inhibitor activity have been directly related to the concentration of doxazosin in blood. During long-term treatment, no significant changes in the disposition of doxazosin have been reported; with dosages up to the maximum clinically used dosage of 16 mg daily, there is no evidence of dose-dependent pharmacokinetics. Studies in elderly patients have shown no major pharmacokinetic differences. Overall, these pharmacokinetic results suggest that doxazosin is suitable for once-daily administration in the long-term treatment of patients with essential hypertension.

Administration, Oral↗
PubMed1987

Clinical pharmacology of selective alpha blockers. Hemodynamics and effects on lipid levels.

Selective alpha 1 antagonists decrease blood pressure by reducing elevated peripheral resistance and preserving normal cardiac reflexes. They have also been reported to usually decrease total cholesterol and low-density lipoprotein cholesterol levels, and, in some studies, to increase high-density lipoprotein cholesterol levels. Prazosin, a quinazoline derivative, is well tolerated and is not associated with chronic toxicity. Prazosin has been successfully used in the treatment of hypertension for more than 10 years. Its short plasma half-life requires twice-daily dosing. Although the hypotensive response to an initial dose of prazosin is usually greater than to subsequent doses during long-term therapy, the initial response is an accurate predictor of the hypotensive response in patients during long-term therapy. The vasodilatory action of prazosin is largely due to its blockade of vascular postjunctional alpha 1 receptors. The mechanism involved in its effect on lipid levels is currently under investigation and is an important consideration since hypercholesterolemia, as well as hypertension, is an independent risk factor for stroke and coronary heart disease. Reduction of blood pressure with conventional agents, such as beta blockers or diuretics, has not had the expected impact on coronary heart disease. However, since alpha 1 blockers may influence both hemodynamics and lipids, they warrant evaluation as first-line treatment of hypertension to confirm that they also have an effect on coronary heart disease.

Hemodynamics↗
PubMed1987

Experimental central nervous system phaeohyphomycosis following intranasal inoculation of Xylohypha bantiana in cortisone-treated mice.

Experimental central nervous system (CNS) phaeohyphomycosis was established in cortisone-treated mice following intranasal exposure to conidia of Xylohypha bantiana (Cladosporium bantianum, C. trichoides). X. bantiana was recovered from the lungs of 78% of intranasally inoculated normal mice sacrificed within the first 3 days of infection and from 15% at day 28. The fungus was not recovered from the brains of normal mice. In contrast, X. bantiana was recovered from only 33% of the lungs of cortisone-treated mice within the first 3 days of infection. However, the fungus was recovered from the brain of 11% of cortisone-treated mice sacrificed or dying over a 28 day period. Histologically and temporally the CNS disease in cortisone-treated, intranasally inoculated mice was consistent with hematogenous dissemination from a primary pulmonary focus.

Animals↗
PubMed1987

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects.

Lignocaine clearance declines during continuous intravenous infusion in man and in vitro studies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine. MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120 mg, MEGX HCl 120 mg, lignocaine HCl 120 mg + MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (Vss), and half-life values were calculated and compared by paired t-test. Systolic time intervals and QT interval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58 +/- 18 to 48 +/- 13 L hr-1 (p less than 0.02). The Vss was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QT interval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.

Adult↗
PubMed1987

An evaluation of the pharmacodynamics and pharmacokinetics of nicardipine combined with enalapril in essential hypertension.

Recent observations suggest that calcium antagonists may enhance the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors. Twelve essential hypertensives who had blood pressures greater than 160/90 after a minimum of 6 weeks of monotherapy with the ACE inhibitor enalapril 20 mg daily received additional treatment with nicardipine 30 mg t.i.d. and placebo, each for 2 weeks, in a double-blind crossover study. The combination of nicardipine with enalapril was well tolerated. The addition of the first dose of nicardipine was associated with significant reductions (p less than 0.05) in blood pressure during the first 4 h: from a baseline of 165/99 to 128/80 (supine) at 2 h after nicardipine as compared with 167/101-146/90 following placebo. Two weeks of combined treatment with nicardipine and enalapril significantly reduced the predosing blood pressure, 12 h after the last dose of nicardipine (158/96 as compared with 172/106 with placebo), and there were further significant reductions in blood pressure during the subsequent dosage interval. The profile of plasma ACE inhibition and the pharmacokinetics of enalaprilat were unaffected by the addition of nicardipine. These results suggest that nicardipine and enalapril are an effective and well-tolerated antihypertensive combination.

Adult↗