Search PubMed⌕ Search

Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 199 records · Page 11Linked to original sources
PubMed1984

A species difference in the presystemic metabolism of carbazeran in dog and man.

The bioavailability of carbazeran and the metabolism of carbon-14 labelled drug have been studied in the dog and man following oral administration. The drug was moderately well absorbed in both species, but there was a marked difference in bioavailability and in routes of metabolism. In the dog, systemic bioavailability was approx. 68% and biotransformation involved mainly O-demethylation. In man, bioavailability was not measurable and carbazeran was almost completely cleared via 4-hydroxylation of the phthalazine moiety. Thus the lack of detectable pharmacological effect in man following oral administration of the drug appears to be due to presystemic metabolism by a particularly active pathway not found in the dog.

Adult↗
PubMed1984

Clinical pharmacological studies with the vasodilator endralazine in normotensive subjects and essential hypertensives.

Endralazine is a peripherally-acting vasodilator with chemical and pharmacological similarities to hydralazine. In both normotensive volunteers and essential hypertensives, single oral doses of 10 mg endralazine (in combination with a beta-adrenoceptor antagonist) led to substantial falls in blood pressure, with no significant additional orthostatic effect. Maintenance treatment of hypertensive patients with the addition of 5 or 10 mg B.D. endralazine significantly improved blood pressure control: the mean supine blood pressure improved from 197/107 mmHg, on baseline treatment with a thiazide and beta blocker, to 160/86 after one week and 161/91 mmHg after one year with endralazine as third drug therapy. Apart from facial flushing and mild headache following the early doses, no significant side-effects were observed or reported. In the long term, there was no weight gain to suggest fluid retention and in all patients treated with endralazine for at least one year the anti-nuclear factor remained negative. Following acute administration the terminal elimination half-life of endralazine was approximately 2.5 h and the oral bioavailability was 75%. During chronic dosing with endralazine the terminal elimination half-life significantly increased to a mean of 7.5 h, but there was no accumulation of drug. There were no significant differences related to acetylator phenotype either for the dosage, the pharmacokinetics or the hypotensive effect.

Adult↗
PubMed1984

Pharmacodynamic and pharmacokinetic studies with the vasodilator endralazine.

Endralazine is a peripherally-acting vasodilator similar to hydralazine. In normotensive subjects and essential hypertensive and renal patients, single oral doses of 10 mg endralazine led to substantial falls in blood pressure, with no significant additional orthostatic effect. Maintenance endralazine treatment (5 or 10 mg b.d.) of essential hypertensive patients significantly improved blood pressure control: the mean supine blood pressure improved from 197/107 mmHg on baseline treatment with a thiazide and beta-blocker to 160/86 mmHg after one week and 161/91 mmHg after one year. There was no evidence of fluid retention and in all patients treated for at least one year the anti-nuclear factor remained negative. Following acute administration the terminal elimination half-life of endralazine was approximately 2.5 h and the oral bioavailability was 75%. During chronic treatment the elimination half-life significantly increased to about 7.5 h. The elimination half-life following the first dose was only significantly prolonged in the renal dialysis group. There were no significant differences related to acetylator phenotype.

Adult↗
PubMed1983

Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients.

The concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central alpha 2 receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an alpha receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting anti-hypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.

Aged↗
PubMed1983

Pharmacokinetic and pharmacodynamic modelling of trimazosin and its major metabolite.

The pharmacokinetic and pharmacodynamic profiles of intravenous trimazosin, a postsynaptic alpha 1 antagonist, were analyzed empirically by integrated modelling techniques. The mean terminal elimination half-life for trimazosin was 186 +/- 80 min and the mean elimination half-life of its alkyl hydroxylated metabolite (CP 23445) was 93 +/- 29 min. The placebo-corrected fall in systolic blood pressure after 5 min standing was most appropriately characterized in all subjects by a model that incorporated "effect" compartments for both parent drug and its metabolite.

Adult↗
PubMed1983

Pharmacokinetics and pharmacodynamics of trimazosin in man.

In this study the pharmacokinetics of trimazosin and its major metabolite, CP 23445, were determined, as were also the effects on blood pressure, heart rate, and peripheral vascular alpha-1 receptors. Trimazosin was administered intravenously (100 mg) and orally (200 mg) to six healthy volunteer subjects (24 to 39 years of age). Blood samples were withdrawn from an indwelling intravenous cannula, and supine and erect blood pressure and heart rate recordings were made at frequent intervals over 12 hours. Concentrations of trimazosin and CP 23445 in whole blood were measured by a sensitive and specific high-pressure liquid chromatography-fluorescence assay developed in our laboratory. Both drug and metabolite could be measured after oral and intravenous administration. Pharmacokinetic parameters were obtained by computer-assisted, nonlinear, least-squares-fitting regression analysis. The pharmacokinetic profile of trimazosin was best described by a two-compartment model. The mean (+/- SD) terminal elimination half-life of trimazosin was 2.73 (+/- 0.90) hours. The metabolite concentrations were then incorporated into the model and a simultaneous fit of drug and metabolite carried out. This did not alter the pharmacokinetic profile of the parent drug but did allow the elimination half-life of the metabolite to be calculated as 1.47 +/- 0.65 hours. The bioavailability of oral trimazosin was 61 +/- 28%. Erect blood pressure was reduced for at least 6 hours after both oral and intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

Evidence for postjunctional vascular alpha 2-adrenoceptors in peripheral vascular regulation in man.

Preliminary studies in healthy normotensive subjects with a selective alpha 2-adrenoceptor antagonist 2-[2-(1,4-benzodioxanyl)]-2-imidazoline (RX781094) in a dose of 0.2 microgram/kg intravenously are described. There was a transient increase in blood pressure, and plasma noradrenaline, 10-20 min after dosing and an associated reduction in heart rate. These observations are consistent with blockade of peripheral presynaptic alpha 2-adrenoceptors in man. The pressor responses to alpha-methylnoradrenaline, which has relatively selective agonist effects on alpha 2-adrenoceptors, were markedly attenuated between 0.5 and 3.0 h after dosing (dose ratio greater than 20). The pressor responsiveness to intravenous phenylephrine, a selective alpha 1-adrenoceptor agonist, was only slightly reduced (dose ratio 1.7 +/- 0.8), as was the blood pressure rise after intravenous noradrenaline (dose ratio 1.7 +/- 0.7). The differential effects on the agonist pressor responses are consistent with antagonism by RX781094 of post-junctional alpha 2-adrenoceptors on vascular smooth muscle.

Adrenergic alpha-Antagonists↗
PubMed1983

Doxazosin, an alpha 1-adrenoceptor antagonist: pharmacokinetics and concentration-effect relationships in man.

The effects of single doses of doxazosin, a quinazoline derivative similar to prazosin, were studied in six normotensive volunteers. Both 1 mg (i.v.) or 2 mg (oral) doxazosin caused a fall in blood pressure which was most apparent in the erect posture at 5-6 h following drug administration. The maximum fall in blood pressure following i.v. doxazosin was from 123/81 to 106/69 mm Hg associated with a rise in heart rate from 81 to 107 beats/min. The terminal elimination half-life following oral and intravenous doxazosin was about 9 h. Pressor responsiveness to the alpha 1-adrenoceptor agonist, phenylephrine, showed no significant difference between oral and i.v. doxazosin suggesting that the route of administration did not influence alpha 1-adrenoceptor antagonism at the doses used. Using a pharmacodynamic modelling technique in individual subjects, there was a significant correlation between the change in doxazosin concentration in the effect compartment and its hypotensive effect. With the modelling technique it was possible to show a significant correlation between the pressor responsiveness to the alpha 1-adrenoceptor agonist phenylephrine and the concentration of doxazosin in the effect compartment. This is consistent with the concept that the hypotensive effect of doxazosin is mediated by alpha 1-adrenoceptor blockade.

Adrenergic alpha-Antagonists↗
PubMed1983

The pharmacokinetics of endralazine in essential hypertensives and in normotensive subjects.

The direct-acting vasodilator, endralazine, in combination with a beta-adrenoceptor blocker significantly reduced the blood pressures of normotensive volunteers and of patients with essential hypertension. The mean terminal elimination half-life for endralazine of 136 min in hypertensive patients did not differ significantly from the 155 min in normotensive subjects. In normal subjects the mean oral bioavailability for endralazine was 75% and the mean clearance was 780 ml/min. There were no significant pharmacokinetic differences between fast and slow acetylators. The administration of endralazine to steady state in the hypertensive patients was associated with an increase in terminal elimination half-life and a decrease in the rate of absorption. However, there was no accumulation of endralazine with chronic dosing.

Acetylation↗
PubMed1983

The pharmacokinetics of mianserin.

1 The pharmacokinetics of mianserin hydrochloride have been determined in eight normal healthy volunteers, mean age 27, and 14 elderly patients, mean age 76. 2 Mianserin was administered to volunteers by intravenous infusion (0.011 mg/kg/min for 15 min) and, on another occasion, by mouth, in a single dose of 30 mg. Elderly patients received a single oral dose of 40-60 mg. 3 The terminal elimination half-life was significantly prolonged in the elderly. In young subjects it was 9.6 +/- 1.9 (s.d.) h. In the elderly it was 27 +/- 13.1 (s.d.) h. 4 Apparent oral clearance was significantly reduced in the elderly. In young subjects it was 87.1 +/- 32 (s.d.) h. In the elderly, it was 38.1 +/- 14.8 (s.d.) h. 5 These kinetic differences may have an important bearing on the sedative effects of mianserin.

Administration, Oral↗
PubMed1983

Assessment of the interaction between mianserin and centrally-acting antihypertensive drugs.

1 The interaction between mianserin and centrally-acting antihypertensive drugs was evaluated in normal volunteers and in patients with essential hypertension receiving either clonidine or methyldopa. 2 The administration of the first dose of 20 mg mianserin to the normal volunteers was associated with a significant sedative effect and transient postural hypotension. 3 In the normal volunteers, the blood pressure responses to a single oral dose of 300 micrograms clonidine were not modified by pretreatment with mianserin. The bradycardia associated with clonidine alone, however, was significantly attenuated. 4 In the patient study, no significant changes in blood pressure control were observed, either after the first dose of 30 mg mianserin or after one and two weeks' continued treatment with mianserin. 5 There is no evidence from these studies that the addition of mianserin therapy results in a clinically significant impairment of the antihypertensive effects of clonidine or methyldopa.

Adult↗
PubMed1983

Peripheral pre and postjunctional alpha 2-adrenoceptors in man: studies with RX781094, a selective alpha 2 antagonist.

The imidazoline derivative RX781094 has been shown in animal studies to be a potent selective alpha 2-adrenoceptor antagonist. The alpha 2 antagonist activity of RX781094 was confirmed in this study by in vitro human platelet aggregation studies in which RX781094 was five times more potent than alpha-yohimbine. Within the first 20 min after intravenous administration of RX781094 to eight normotensive men there was a short-lived increase in blood pressure (mean maximum change 9/7 mmHg) and decrease in heart rate (mean maximum change 15 beats/min) associated with slight increases in plasma noradrenaline concentration and renin activity. These findings are consistent with an effect at prejunctional alpha 2-adrenoceptors. The pressor dose-response analysis for three agonists of varying selectivities for alpha 1 and alpha 2-adrenoceptors showed only modest changes with phenylephrine and noradrenaline with dose ratios less than 2, in contrast to the marked antagonism by RX781094 of the pressor response to the alpha 2 agonist, alphamethylnoradrenaline, dose ratio greater than 20. These results provide evidence that adrenoceptors of the alpha 2 subtype are located postjunctionally on resistance vessels in man and that RX781094 is a selective antagonist at human alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗