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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 217 records · Page 12Linked to original sources

The influence of protein binding on disopyramide clearance.

Individual disopyramide clearance is not constant and previous studies have suggested that this may be time and/or concentration dependent. Steady state disopyramide concentrations were achieved in six volunteer subjects at each of three infusion rates. Drug analysis was by HPLC and protein binding was determined by ultrafiltration. The disopyramide free fraction was concentration dependent and marked interindividual variability was observed. Disopyramide clearance was independent of time but dependent on total plasma concentration. This can be completely explained by non-linear protein binding since free disopyramide clearance was observed to be independent of free concentration.

Adult↗

The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide in essential hypertensives.

Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined beta-blocker and diuretic therapy (average supine blood pressure 178/103 mmHg) the addition of tolmesoxide (300-900mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). the effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 microgram/ml compared to 2.97 microgram/ml) and a significant increase in the time to reach peak plasma tolmesoxide concentration (2.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.

Aged↗

Protein binding of piretanide in normal and uraemic serum.

The protein binding of piretanide was assessed by continuous ultrafiltration of sera from six normal subjects and seven uraemic subjects (samples taken immediately pre-dialysis). Throughout the range of piretanide concentrations studied (0.5-4.5mM), the mean protein binding for uraemic serum was less than that for normal serum. This difference was significant (p less than 0.05) at piretanide concentrations of 1.5 mM and above, but not at 1mM where mean protein binding for uraemic serum was 88.1% compared to 94.2% for normal serum. Analysis of piretanide protein binding characteristics using the Rosenthal plot showed no significant differences between uraemic and normal serum with respect to primary or secondary binding sites. Parallel assessment by the Scatchard method suggests, as expected, that albumin is the principle protein moiety responsible for binding piretanide.

Blood Proteins↗

Analysis of the pressor dose response.

(1) When incremental infusions of drugs that increase blood pressure are given to human subjects to assess "pressor responsiveness," only the lower part of the sigmoid dose-response curve can be obtained. (2) Fitting a quadratic function does not involve discarding data points, which is usually the case with a linear fit, and it provides a more satisfactory fit to the lower part of a sigmoid dose-response curve. (3) In the presence of a competitive antagonist, a pressor dose-response curve will be shifted to the right. In this situation the dose-response curves obtained before and after treatment with antagonist should be fitted simultaneously to a quadratic model in which the parallel shift is one of the parameters. (4) The use of quadratic fitting is illustrated by reference to clinical experiments to obtain the following three curves for drugs that modify peripheral alpha adrenoceptors: norepinephrine pressor response curves after placebo and doxazosin, an alpha 1 antagonist; norepinephrine pressor response curves after placebo, labetalol, and medroxalol (drugs with combined alpha 1 and beta blocking properties); and phenylephrine pressor response curves before and after prazosin. (5) Fitting a quadratic function is the appropriate initial step in the analysis of pressor dose-response curves in man.

Blood Pressure↗

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↗

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↗

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↗

The determination of labetalol in plasma by high-performance liquid chromatography using fluorescence detection.

A sensitive and specific assay for labetalol is described. The method employed is reverse phase high-performance liquid chromatography (HPLC) with fluorescence detection. Using 1 ml of plasma, the limit of detection of the assay was 8 ng/ml and the coefficient of variation over a typical calibration range is 5.5%. Various drugs that might be coadministered with labetalol are shown not to interfere in the assay. The method has been employed to study the pharmacokinetics of labetalol following intravenous and oral administration.

Administration, Oral↗

Lead exposure and renal failure: does renal insufficiency influence lead kinetics?

Blood and urine lead concentrations have been measured in 40 subjects with normal and impaired renal function. Derived renal lead clearance varied widely, but was not influenced by the degree of renal impairment. Lead, however, appeared to reduce its own clearance. These findings provide additional evidence of nephrotoxicity from sub-clinical lead exposure.

Adolescent↗

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↗

Effect of iron poly (sorbitolgluconic acid) complex on urinary cellular excretion.

The intramuscular injection of 250 mg iron poly (sorbitol-gluconic acid) complex caused no increase in urinary cellular or bacterial excretion in 8 patients with chronic pyelonephritis, 4 patients with non-infective renal disease, and 4 controls. However, in 4 patients with chronic infective disease of the renal tract given 500 g there was a significant increase in cellular excretion. This response was not seen in 2 control patients, nor in 2 patients with non-infective renal disease. Using a differential staining technique, this increase in urinary cellular excretion was found to be due, not to leucocytes, but to renal tubular cells. The precise significance of this is unclear, but there would be concern that the high concentration of excreted iron was providing a 'toxic' insult to susceptible, infection-damaged cells.

Gluconates↗

Changes in blood pressure, heart rate, and sympathetic activity on abrupt withdrawal of tiamenidine (HOE 440) in essential hypertension.

A limitation of clonidine therapy is the syndrome of rebound hypertension and sympathetic overactivity after withdrawal. Ten patients, four male, six female, aged 28--64 years, with essential hypertension, were treated for one year with an imidazoline derivative, tiamenidine. Blood pressure fell from an average of 178/108 mm Hg pretreatment to 152/86 mm Hg after 1 year. Tiamenidine was then withdrawn in hospital, replaced by identical placebo under single blind conditions and observations made over 96 h. The study was interrupted in five patients (4 patients within 36 h) because blood pressure rose to greater than 30 mm Hg (systolic) or greater than 20 mm Hg (diastolic) above pretreatment values. For the group, blood pressure was maximal at 194/112 mm Hg, 18 h post withdrawal, significantly higher than pretreatment (p less than 0.005). Headache, tremor, flushing and insomnia were noted. Saliva production rose 100% at 24 h. Plasma noradrenaline rose within 24 h with an accompanying rise in urinary metanephrine and catecholamine excretion. Tiamenidine appears to share with other imidazolines rebound cardiovascular and autonomic effects following abrupt withdrawal.

Adult↗

The clinical pharmacology of a herbal asthma cigarette.

1 Herbal preparations containing atropine-like alkaloids are marketed as proprietory asthma remedies, typically in the form of cigarettes. 2 This randomised, cross-over study compares in six healthy volunteers the pharmacological effects caused by smoking a standard, medium tar, tobacco cigarette or a herbal cigarette. 3 Smoking a herbal cigarette is associated with a significant fall in heart rate consistent with the systemic response to atropine-like alkaloids and a significant increase in peak expiratory flow rate consistent with the bronchodilator effect of reduced cholinergic activity. 4 Smoking a herbal cigarette seems analogous to the inhalation of ipratropium by aerosol for a local bronchodilator effect.

Adult↗

Thrombophlebitis migrans: a further systemic complication of ulcerative colitis.

Thrombophlebitis migrans complicating ulcerative colitis has been reported only once previously when it occurred in a patient with chronic and extensive bowel disease. This report describes the occurrence of thrombophlebitis before any bowel upset in a patient who proved to have only a mild colitis, and no laboratory evidence of hypercoagulability. It seems that thrombophlebitis migrans is a further systemic complication of ulcerative colitis, and that its occurrence may precede overt bowel disease.

Adult↗

Whole body aluminium in chronic renal failure and dialysis encephalopathy.

Whole body calcium, phosphorus and nitrogen have been measured by in vivo neutron activation analysis in patients with chronic renal failure, including 9 with dialysis encephalopathy. Aluminium was also activated by this procedure, but to the same radioactive product as that from phosphorus: its presence was therefore detected as an increase in the apparent total body phosphorus above that expected for a person with the same calcium content. Patients with dialysis encephalopathy had slightly more apparent phosphorus than others with chronic renal failure, although the difference was not statistically significant. This difference corresponded to an excess of aluminium not greater than 3.3 g(95% confidence limit) which places an upper limit on excess aluminium accumulation in this condition.

Adult↗