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Biomedical subjects

K R Lees

Publications and source records attributed to K R Lees.

At least 163 records · Page 9Linked to original sources
PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half life of over 30 hours associated with sustained inhibition of ACE. During repeated dosing there is little accumulation of drug, and no evidence of increased haemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: binding of perindoprilat to ACE prolongs the haemodynamic effect, giving the option of once daily administration; despite the long terminal elimination half life of the drug, significant accumulation is not a problem during chronic treatment; increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used; further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adolescent↗
PubMed1989

Pharmacokinetics of perindopril: therapeutic consequences.

Perindopril has been studied in groups of normal young and elderly subjects, in patients with hepatic cirrhosis and in hypertensive patients. Plasma concentrations of perindoprilat are increased and renal clearance reduced in elderly subjects, resulting in an increase in the acute pharmacodynamic effect of perindopril. Compensated hepatic cirrhosis does not have any independent effect on the pharmacokinetics of perindopril. After intravenous administration, perindoprilat concentrations show multiexponential decay with a terminal half-life of over 30 hours, associated with sustained inhibition of ACE. During repeated dosing, there is little accumulation of the drug and no evidence of increased hemodynamic effect after chronic treatment in hypertensives. The therapeutic consequences of these findings are: (1) Binding of perindoprilat to ACE prolongs the hemodynamic effect, giving the option of once daily administration. (2) Despite the long terminal elimination half-life of the drug, significant accumulation is not a problem during chronic treatment. (3) Increased plasma concentrations of active metabolite in the elderly and reduced renal elimination may require reduced doses to be used. (4) Further dose adjustment in compensated hepatic cirrhosis is not routinely necessary.

Adult↗
PubMed1989

Captopril versus perindopril: a double blind study in essential hypertension.

This was a double blind, parallel group, multicentre comparison of the therapeutic efficacy and acceptability of perindopril and captopril in essential hypertension. After one month of placebo, 165 patients with supine diastolic blood pressure (DBP) between 95 and 125 mmHg were randomised to perindopril 4 mg once daily or captopril 25 mg twice daily orally. The perindopril group (n = 82) had significantly higher pretreatment DBP (105.4 +/- 0.8 mmHg vs 102.3 +/- 0.6 mmHg) but other demographic variables were similar. Assessment was monthly for three months: 'uncontrolled' patients (DBP greater than 90 mmHg) had the dose doubled and then hydrochlorothiazide added. Two of the six withdrawals were attributed to drug side effects and were in the captopril group. There was no significant difference in the number of withdrawals or incidence of side effects between the drugs. The final titrated treatments were similar and monotherapy normalised DBP in 49% of each group. The final 'control' rate was higher with perindopril than captopril: 75% vs 57%, P = 0.016. The overall fall in DBP was greater in the perindopril group: 26.5 +/- 1.9 mmHg vs 18.9 +/- 1.9 mmHg, P = 0.005. The doses of diuretic were similar in the two groups. The DBP of patients who received only monotherapy for three months also fell more in the perindopril group (-17.5 +/- 1.4 mmHg vs -13.9 +/- 1.0 mmHg, P less than 0.01). At the doses studied, perindopril was more effective than captopril in lowering DBP, either as monotherapy or in combination with a diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Overnight clonidine suppression test in the diagnosis and exclusion of pheochromocytoma.

In a prospective study designed to differentiate pheochromocytoma from other forms of hypertension, urinary catecholamines were measured after sleep and clonidine administration in 12 patients with pheochromocytoma, 19 hypertensive patients in whom pheochromocytoma was suspected but later excluded, and 31 hypertensive patients in whom pheochromocytoma was never suspected. The test correctly identified all 12 patients in whom pheochromocytoma was present. Four of these had equivocal plasma levels of both norepinephrine and epinephrine, suggesting that overnight clonidine suppression may be of particular value when tumor secretion is intermittent or low. When pheochromocytoma was not present, urinary norepinephrine and epinephrine levels were suppressed below 60 and 20 nmol/mmol creatinine, respectively, after sleep and clonidine, the two in combination giving better suppression than sleep alone. Since urinary catecholamines can be determined relatively easily by high-pressure liquid chromatography with electrochemical detection, this test may be more widely applicable than suppression tests based on plasma measurements.

Adrenal Gland Neoplasms↗
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

Exercise and platelet intracellular free calcium concentration.

1. A positive correlation between blood pressure and platelet intracellular free calcium concentration ([Ca2+]i) has been reported. We examined the effect of acute changes in blood pressure associated with exercise on platelet [Ca2+]i. 2. Twenty-one subjects had blood pressure and heart rate readings taken after 60 min rest, and subjects were then exercised on a bicycle ergometer at 120 W for 30 min. Blood pressure and heart rate readings were repeated immediately after exercise, 30 min after exercise, and then after a further hour. Blood samples were taken after each set of blood pressure and heart rate readings for catecholamine, lactate and platelet [Ca2+]i estimations. 3. There were significant increases in systolic and diastolic blood pressure, heart rate, and plasma lactate and catecholamine levels during the course of the study. There were no significant changes in platelet [Ca2+]i. 4. These results suggest that the acute blood pressure changes related to exercise are not associated with a change in platelet [Ca2+]i.

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

Indirect assessment of tissue angiotensin II converting enzyme inhibition in vivo in man.

The pharmacokinetics of long-acting angiotensin converting enzyme (ACE) inhibitors show features which are consistent with saturable binding of the drugs to ACE. Their pharmacokinetics may thus be used to assess the extent and affinity of plasma and tissue binding of the drug. For 16 subjects, a hierarchy of pharmacokinetic models was fitted by weighted, least squares, non-linear regression analysis to the concentration-time profile during and after an intravenous infusion of S-9780. A one-compartment model which included saturable tissue and plasma binding gave the best description of the data. The median parameter estimates from this model suggested that total binding capacity for drug was 333 micrograms, of which 62% was in tissue sites, and that the total plasma concentration of drug at half maximum saturation was 6.3 ng/ml. Thus the extent and affinity of ACE inhibitor binding to tissue ACE may be estimated from appropriate analysis of pharmacokinetic data in man.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients.

We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred. Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA). Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration. After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng X ml-1 following the first dose to 5.5 ng X ml-1 after one month.

Adolescent↗
PubMed1987

The influence of beta-adrenoceptor antagonists with and without partial agonist activity on exercise tolerance and muscle lactate production.

Epanolol is a beta-adrenoceptor antagonist with partial agonist activity, a property which could be useful in reducing the fatigue associated with beta blockers. In a double-blind, randomized, crossover study we have investigated the effects of metoprolol 100 mg b.d., epanolol 100 mg b.d., and epanolol 200 mg b.d. on blood pressure, heart rate, and exercise-induced fatigue in 10 hypertensive men. Fatigue was measured subjectively by the Borg rating scale and objectively by blood lactate concentrations. Resting and exercise heart rates were lower with metoprolol than with either dose of epanolol. Preexercise standing diastolic blood pressure was lowered by metoprolol, but there were no other treatment effects on blood pressure. Exercise-induced fatigue was not altered by any treatment, whether measured subjectively or objectively. These results do not support the hypothesis that partial agonist activity improves exercise tolerance in hypertensive patients treated with beta-adrenoceptor antagonists.

Adolescent↗
PubMed1987

Age and the pharmacokinetics and pharmacodynamics of chronic enalapril treatment.

Enalapril clearance after single doses is reduced in the elderly. The influence of age on the pharmacokinetics and pharmacodynamics of chronic enalapril treatment was examined in six young (22 to 31 years) and six elderly (65 to 78 years) healthy subjects who took enalapril, 10 mg, daily for 8 days. The blood pressure fall was greater in the elderly even with chronic administration. Plasma angiotensin-converting enzyme inhibition was similar in both groups. Steady-state serum enalaprilat concentrations were achieved more slowly in the elderly subjects and were correspondingly higher for all subjects. Clearance/bioavailability and volume of distribution/bioavailability diminished with repeated administration. Repeated exposure also led to a reduction in sensitivity of plasma angiotensin-converting enzyme to the inhibitor. Prolonged inhibition probably induces synthesis of new angiotensin-converting enzyme.

Adult↗
PubMed1987

Effects of intravenous S-9780, an angiotensin-converting enzyme inhibitor, in normotensive subjects.

S-9780 is the active diacid metabolite of the new angiotensin-converting enzyme (ACE) inhibitor perindopril. In a double-blind, randomised, crossover study, the effects of 1, 2, and 4 mg of S-9780 administered intravenously (i.v.) were compared with placebo in eight normotensive subjects. All active doses caused immediate, maximal, and similar inhibition of plasma ACE with 40% inhibition persisting after 48 h. Plasma renin activity was elevated 4 and 8 h after dosing, but no effect on plasma aldosterone, adrenaline or noradrenaline levels was detected. Diastolic blood pressure was lowered by 4 mg of S-9780 until 24 h after dosing. Heart rate did not change. The pharmacokinetics of S-9780 fitted a three-compartment model with a terminal half-life (t1/2) of 31 h. Inhibition of plasma ACE was closely related to observed drug concentration, with 1.8 +/- 0.9 ng/ml (mean +/- S.D.) producing 50% inhibition of the enzyme. S-9780 caused predictable effects on the cardiovascular and renin angiotensin systems.

Adolescent↗
PubMed1987

Haemodynamic and humoral effects of oral perindopril, an angiotensin converting enzyme inhibitor, in man.

The tolerance to and dynamic effects of 1 week's oral treatment with the angiotensin converting enzyme inhibitor, perindopril, were assessed in a placebo controlled, parallel group study in 36 normotensive males. The daily dose of perindopril was 1, 2, 4, 8 or 16 mg. The drug was well tolerated and produced no change in routine haematology or serum biochemistry tests. Dose related inhibition of plasma angiotensin converting enzyme was observed. Perindopril 16 mg produced 90% inhibition 4 h after dosing and 60% after 24 h. A dose related rise in plasma renin activity followed doses of 4 mg and over. The renin remained above the normal range for 24 h. Perindopril caused a modest lowering of plasma aldosterone levels but had no effect on plasma adrenaline or noradrenaline levels. Standing diastolic blood pressure was lowered, particularly with 16 mg daily of perindopril but only a slight rise in heart rate occurred. Perindopril appears to be a well tolerated inhibitor of plasma angiotensin converting enzyme, with predictable effects on the renin angiotensin system and blood pressure. An appropriate dose range for further study would appear to be 4 to 16 mg daily.

Adolescent↗
PubMed1987

Ethanol and platelet intracellular free calcium concentrations.

The effect of 0.8 g kg-1 absolute ethanol orally on platelet intracellular free calcium was assessed in a random order study in 24 normotensive subjects with an isocaloric control. Platelet calcium was measured 90 min and 12 h after treatment by the Quin 2 method. The study had 90% power of detecting a 16.5% change. After 90 min, breath ethanol was 37 +/- 9 micrograms 100 ml-1, blood pressure was unchanged and heart rate rose slightly. Platelet calcium was unchanged by ethanol after 90 min or 12 h.

Adult↗
PubMed1987

Perindopril, a new angiotensin converting enzyme inhibitor--clinical pharmacological studies in healthy subjects.

Perindopril is a new angiotensin converting enzyme (ACE) inhibitor which is activated after hydrolysis in vivo to a diacid (S9780). Oral administration of perindopril (1-16 mg) to groups of 6 healthy males led to a long lasting and dose-elated inhibition of plasma ACE and rises in plasma renin activity with no evidence of accumulation of drug or effect. At higher doses there was a modest fall in blood pressure. S9780 given intravenously in doses of 1,2 or 4 mg caused an immediate inhibition of plasma ACE. The concentration of S9780 in plasma which led to 50% inhibition of plasma ACE was 1.55 +/- 1.14 ng/ml (mean +/- S.D.). Clinical trials with 2-8 mg once daily in essential hypertension are currently in progress.

Administration, Oral↗
PubMed1987

A clinical pharmacological study of nifedipine and lisinopril alone and in combination.

A double-blind, randomised, placebo-controlled, latin square design study of nifedipine, 20 mg, and lisinopril, 20 mg, alone and in combination was performed in 12 healthy male volunteers. Blood pressure, heart rate, lisinopril and nifedipine levels, plasma catecholamines, renin, aldosterone, and angiotensin converting enzyme activity were measured for 96 h after each acute dose. Both drugs lowered blood pressure (p less than 0.001), but the combination showed only additive effects. Heart rate rose over the first 4 h following the combination. Side effects were also additive. There was no effect of nifedipine on plasma ACE, renin, or aldosterone and no effect of either drug on plasma catecholamines. The pharmacokinetics of both drugs were unaltered in combination. Thus, nifedipine and lisinopril have additive dynamic effects with no pharmacokinetic interaction.

Adult↗