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Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 235 records · Page 13Linked to original sources
PubMed1988

In vivo and in vitro studies of the site of inhibitory action of omeprazole on adrenocortical steroidogenesis.

The site of omeprazole inhibition of adrenal steroidogenesis has been sought in vivo by analyzing the patterns of urinary steroid metabolite excretion after 6 days of treatment with placebo/omeprazole. Excretion rates of androsterone, aetiocholanolone, dehydroepiandrosterone, 11 beta hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol and alpha cortolone were reduced, indicating a block at an early step in steroidogenesis, possibly cholesterol side-chain cleavage. In vitro studies have confirmed this finding by measuring conversion of added precursors to cortisol in isolated bovine adrenocortical cells. Cortisol synthesis from added 20 alpha hydroxycholesterol was inhibited by 83% in the presence of 100 micrograms omeprazole/ml. Conversion from pregnenolone and progesterone and their 17 alpha hydroxylated derivatives was inhibited by 20-40% whereas cortisol production from added 11 deoxycortisol was not affected. These data suggest that omeprazole primarily inhibits cholesterol cleavage and does not inhibit 3 beta hydroxysteroid dehydrogenase, 17 alpha hydroxylase or 11 beta hydroxylation; 21 hydroxylase activity may be marginally attenuated.

Adrenal Cortex↗
PubMed1988

Optimal features of a new beta-blocker.

Therapeutics involves the careful balance between treatment disadvantages and advantages--the so-called risk-benefit ratio. Even after 20 years beta-blockers must be selected carefully to suit the patient's needs. This review examines several problems associated with beta-blockade. Generally, beta1-cardioselectivity is considered advantageous, but properties such as partial agonist activity, which limits receptor up-regulation, might be of greater value in reducing the adverse effects associated with abrupt drug withdrawal. Beta-Blockers, either lipophilic or hydrophilic agents, have specific problems: lipophilic drugs provoke adverse central nervous system effects and need careful dose titration; variable gastrointestinal absorption is common with hydrophilic agents, whereas extra care is needed in patients with renal impairment. For most patients, especially those with asymptomatic conditions, once-daily dosing is preferred. For many, the quality of life is of overriding clinical importance. Despite significant pharmacokinetic and pharmacodynamic advances, the final criteria depend largely on a clinical assessment, improvement in the quality of life, and patient preference. We still await the discovery of an ideal beta-adrenoceptor blocking agent; some of the newer beta-blockers, however have many of the properties that clinicians value.

Adrenergic beta-Agonists↗
PubMed1988

Influence of lead exposure on catecholamine metabolism in discrete rat brain nuclei.

1. Using the rat exposed both acutely and chronically to lead as a model of lead neurotoxicity, various parameters of catecholamine metabolism were investigated. 2. The steady-state concentrations of noradrenaline, adrenaline and dopamine together with the activities of tyrosine hydroxylase and phenylethanolamine N-methyl transferase were measured in discrete brain nuclei--periventricular, paraventricular, median eminence, posterior and anterior hypothalamus, caudate putamen and globus pallidus. 3. Lead exposure resulted in significant fall in the activity of the rate-limiting enzyme of catecholamine synthesis, tyrosine hydroxylase which was associated with alterations in concentrations of catecholamines in the median eminence, periventricular nucleus and anterior hypothalamus. 4. No other brain nuclei investigated exhibited any effect of lead on the catecholaminergic nervous system and, therefore, the effect of lead on rat brain can be considered to be regionally specific.

Animals↗
PubMed1988

Effects of lead exposure on rat brain catecholaminergic neurochemistry.

1. The effects of lead on catecholaminergic neurotransmission have been investigated. 2. Using the rat as a model, animals were exposed both acutely and chronically to lead. The levels of catecholamines, noradrenaline, adrenaline, and dopamine along with the activities of tyrosine hydroxylase and phenylethanolamine-N-methyl transferase were measured in 5 brain regions--cerebral cortex, brainstem, hippocampus, anterior and posterior hypothalamus. 3. A lead related reduction in the activity of tyrosine hydroxylase was observed in association with alterations in steady-state levels of the catecholamines in the posterior and anterior hypothalamus. 4. Thus, lead exposure, known to result in behavioural changes, is associated with localised neurochemical effects on the hypothalamus.

Animals↗
PubMed1988

Influence of age on the pharmacokinetics and pharmacodynamics of perindopril.

Perindopril is the ester prodrug of the angiotensin converting enzyme inhibitor S-9780. The influence of age on the pharmacokinetics and pharmacodynamics of S-9780 (1 mg administered intravenously) and perindopril (8 mg administered orally) was examined in a double-blind, crossover, acute study in eight young (29 +/- 3 years) and eight elderly (71 +/- 3 years) healthy subjects. Mild headache and light-headedness were the only adverse effects and were more common in the younger subjects. Blood pressure fall was greater in the elderly even after correction for starting blood pressure. Bioavailability of S-9780 was increased in the elderly (35% +/- 17% compared with 19% +/- 7%; p less than 0.025) mainly because of increased conversion rather than absorption. Renal clearance of S-9780 was lower in the elderly (67 +/- 31 ml/min compared with 110 +/- 39 ml/min; p less than 0.03). Dose reduction of approximately 50% is suggested for elderly patients with further adjustment proportional to any preexisting diminished renal function.

Adult↗
PubMed1988

The combination of prazosin and verapamil in the treatment of essential hypertension.

An exaggerated fall in blood pressure has been reported with the combination of an alpha 1-blocker and a calcium antagonist. This study investigated, in a placebo-controlled, randomized crossover trial, the clinical usefulness of the combination of prazosin (2 mg b.i.d.) and verapamil (160 mg b.i.d.). Therapeutic efficacy was monitored at regular outpatient visits: average supine and erect blood pressures were, respectively, 175/99 and 176/103 mm Hg with placebo, 160/91 and 164/96 mm Hg with single drug treatment, and 152/84 and 152/89 mm Hg with combination therapy. This significant and clinically useful reduction in blood pressure had an overall magnitude of approximately 28/18 mm Hg (supine) and 29/19 mm Hg (erect). Further measurements were made during a series of intensive study days, and the most important additional finding was a pharmacokinetic interaction that resulted in increased peak concentrations and bioavailability of prazosin. In conclusion, the combination of prazosin and verapamil proved effective in the treatment of 12 patients with essential hypertension who had been poorly responsive to conventional treatment with a beta-blocker and thiazide diuretic.

Adult↗
PubMed1988

Relationship between plasma prazosin concentration and alpha-antagonism in humans: comparison of conventional and rate-controlled (Oros) formulations.

A single-dose comparative evaluation in young normotensive men of the plasma concentrations and alpha-adrenoceptor antagonism after conventional prazosin and a new slow-release formulation (Oros) is described. Whereas conventional prazosin (2 mg) produced a maximum reduction in erect blood pressure at 3 hours (80/46 mm Hg compared with 110/65 mm Hg with placebo), the lowest blood pressure of 94/48 mm Hg with Oros prazosin (5.5 mg) was not observed until 8 hours after administration. Twenty-four hours after Oros prazosin, prazosin was still detectable in plasma and erect blood pressure was reduced to 107/58 mm Hg compared with 110/71 mm Hg after placebo. alpha 1-Antagonism (assessed by the pressor responses to intravenous phenylephrine) was maximal, with a 4.8-fold shift in dose-response 24 hours after Oros prazosin, and persisted at least until 30 hours after administration, with a 2.3-fold shift. There were significant correlations between alpha 1-antagonism and plasma prazosin concentrations for both Oros and conventional prazosin. The slopes of these relationships were significantly different, but this is thought to be consistent with the differences in the rates of drug release from the two formulations. Overall this study provides further evidence in humans that the duration and extent of the alpha 1-antagonism and the blood pressure response reflect the plasma prazosin concentrations. Additionally these data suggest the potential suitability of this type of a slow-release formulation for single daily administration.

Adult↗
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

The effects of chronic administration of adrenaline on the function and number of adrenoceptors in the rabbit.

Chronic (10-day) intravenous infusions of adrenaline (0.05 mumol/kg/h) were given to rabbits via osmotic minipumps implanted at the femoral vein. Blood pressure, heart rate, and plasma catecholamine concentrations were measured five times during the period of infusion. Tenfold elevations in circulating adrenaline levels were achieved within 24 h of commencing infusion and maintained throughout the study. This increase in plasma adrenaline was not accompanied by significant changes in blood pressure or heart rate. Rabbits were killed after 10 days: blood was withdrawn for platelet aggregation studies. Kidney, heart, and lung were also collected and alpha 2-adrenoceptor number on platelets and kidney measured using [3H]yohimbine. Beta adrenoceptors on platelets, lymphocytes, heart, and lung were quantified using [125I]iodocyanopindolol. Adrenaline infusion led to a significant reduction in platelet aggregation responses to adrenaline (0.001-100 microM), together with a decrease in alpha 2-adrenoceptor number on platelets, but no significant decrease in kidney alpha 2-adrenoceptors. A significant decrease in the density of beta adrenoceptors on heart and lung membranes was observed with no reduction in platelet and lymphocyte beta-adrenoceptor number. Thus adrenaline-induced down-regulation of adrenoceptors in the rabbit was dependent on the location and subtype of adrenoceptor.

Adenosine Diphosphate↗
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

Lisinopril and nifedipine: no acute interaction in normotensives.

1. A double-blind, four period crossover study was undertaken to test for an interaction between single oral doses of nifedipine retard (20 mg) and lisinopril (20 mg) in normal subjects. 2. Side effects with both drugs were mild and the incidence was additive. 3. Blood pressure (BP) was lowered by nifedipine for 4 h, by lisinopril for 48 h and the combination showed simply additive effects. Standing heart rate was higher after the combination than after single treatment. 4. Plasma angiotensin converting enzyme (ACE) and renin activity (PRA), aldosterone, noradrenaline and adrenaline levels showed no evidence of an interaction. 5. The pharmacokinetics of lisinopril were unaltered by nifedipine and vice versa. 6. There is no evidence of a pharmacokinetic or pharmacodynamic interaction between single oral doses of nifedipine and lisinopril.

Adult↗
PubMed1988

Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline.

1. We have previously shown that salbutamol induced hypokalaemia, like adrenaline induced hypokalaemia, is the result of stimulation of a membrane bound beta 2-adrenoreceptor linked to Na+/K+ ATPase. We have also demonstrated that adrenaline induced hypokalaemia is potentiated by therapeutic concentrations of theophylline. 2. In a single-blind study of 14 normal volunteers, we infused salbutamol in doses used in clinical practice and examined the effects of the addition of theophylline alone or combined with (-)-adrenaline on plasma potassium levels, heart rate and blood pressure. The combinations studied were (i) salbutamol + vehicle control adrenaline infusion + placebo theophylline; (ii) salbutamol + vehicle control adrenaline infusion + theophylline; (iii) salbutamol + adrenaline + theophylline. 3. In a randomised, balanced placebo controlled design oral slow release theophylline or placebo was given for 9 days. Subjects were studied twice on the active limb (days 7 and 9) and once on the placebo limb (day 9) and the procedure was identical on each of the 3 study days except for the solutions administered. 4. Theophylline increased salbutamol induced hypokalaemia and in some individuals profound hypokalaemia (less than 2.5 mmol l-1) was observed with these relatively low doses of salbutamol and theophylline. Adrenaline did not further increase the magnitude of the fall in potassium observed. Combining theophylline with salbutamol increased the tachycardia resulting from the salbutamol infusion. Salbutamol infusion caused a fall in diastolic and rise in systolic blood pressure on all 3 study days and this was not altered by either theophylline or adrenaline alone or together.(ABSTRACT TRUNCATED AT 250 WORDS)

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

The pharmacokinetics, antihistamine and concentration-effect relationship of ebastine in healthy subjects.

1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal elimination half-life was 10.6 +/- 2.6 and 12.5 +/- 1.9 h respectively after 10 and 50 mg of ebastine. 4. Antihistamine (H1-receptor) activity was examined with intradermal histamine (2 micrograms). Oral ebastine reduced the histamine wheal area for up to 24 h and also reduced subjective local pain. 5. Antihistamine activity correlated well with plasma levels of carebastine in individual subjects. 6. Ebastine appears to have potential as an antihistamine for once a day dosing.

Adult↗
PubMed1988

Ebastine: the effect of a new antihistamine on psychomotor performance and autonomic responses in healthy subjects.

1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1-receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long-lasting antihistamine effects can be demonstrated.

Adult↗