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Biomedical subjects

S Freestone

Publications and source records attributed to S Freestone.

At least 55 records · Page 3Linked to original sources
PubMed1984

Should the acetylator phenotype be determined when prescribing hydralazine for hypertension?

The role of acetylator phenotype in determining the response to hydralazine when it was added to diuretic and beta-blocker at doses not exceeding 200 mg daily was examined in 57 hypertensive patients. 81% of rapid acetylators needed 200 mg hydralazine daily compared to 38% of slow acetylators (p less than 0.01). Despite higher doses of hydralazine the blood pressure was controlled in only 27% of rapid acetylators compared to 65% of slow acetylators (p less than 0.02). The relation of acetylator phenotype to blood pressure response was statistically independent of initial blood pressure, age, sex, body weight and serum creatinine (p less than 0.005). Current recommendations on hydralazine dosage are unsatisfactory for the 40% of hypertensive patients who are rapid acetylators. We suggest measurement of the acetylator phenotype in patients who respond incompletely to 200 mg hydralazine daily. About 70% of these patients will be rapid acetylators in whom the dose of hydralazine can be increased safely.

Acetylation↗
PubMed1984

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of propranolol.

The pharmacokinetics and pharmacodynamics of propranolol (80 mg by mouth) were studied in seven extensive and four poor metabolisers of debrisoquine. Evidence for impairment of the 4'-hydroxylation of propranolol was found in poor metabolisers. However, no significant difference was detected in the oral clearance of unchanged drug between the two groups of debrisoquine oxidation phenotypes. Poor metabolisers of debrisoquine did not experience more intense or more prolonged beta-adrenoceptor blockade than extensive metabolisers of debrisoquine.

Adult↗
PubMed1984

Xipamide: no advantage over bendrofluazide in hypertension.

In patients with uncontrolled hypertension addition of xipamide 20 mg daily to bendrofluazide 5 mg daily produced no significant additive antihypertensive effect, and the 95% confidence limits excluded a clinically important response. Xipamide treatment worsened hypokalaemia and increased the blood urea concentration significantly.

Bendroflumethiazide↗
PubMed1983

Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers.

The hypothesis that variability in metoprolol metabolism stereoselectivity is related to debrisoquin oxidation phenotype was tested in six extensive (EM) and six poor (PM) debrisoquin metabolizers. In EM, plasma AUCs for (S)-metoprolol were 35% higher than for (R)-metoprolol, whereas in PM, AUCs for (S)-metoprolol were lower than for (R)-metoprolol. AUCs for total metoprolol correlated with the ratio of (S)- to (R)-metoprolol AUC. The renal clearance of metoprolol was also stereoselective but to the same extent in both EM and PM. Findings suggest that the enzyme system responsible for polymorphic oxidation of the debrisoquin-type is stereoselective. The relation between log total metoprolol plasma concentration and response (beta-blockade) was shifted to the right in PM relative to EM, which is compatible with a difference in pharmacologic activity of metoprolol enantiomers. Kinetic predictions based on total drug measurements will tend to overestimate dynamic differences between EM and PM, but the magnitude of the error is relatively small, and, in absolute terms, there is a large difference in pharmacologic activity between the phenotypes (beta-blockade at 24 hr: EM = 5.3 +/- 5.6%; PM = 18.9 +/- 3.8%).

Adult↗
PubMed1983

Preliminary evaluation of pinacidil in hypertension.

In a balanced single-blind placebo controlled study in six hypertensive patients treated with diuretic and beta-adrenoceptor blocker, a single oral dose of 10 mg pinacidil lowered blood pressure significantly, by a maximum of 26/13 mm Hg lying and 15/12 mm Hg standing at 3 h. The duration of action was less than 6 h. Chronic treatment of four patients (mean dose 20 mg twice daily for 3--7 weeks) lowered blood pressure by only 15/7 mm Hg. All four patients experienced side-effects of the type often observed during treatment with potent vasodilators. In the formulation studied pinacidil is unlikely to offer any advantage over the antihypertensive drugs currently available.

Antihypertensive Agents↗
PubMed1983

Duration of beta-blockade with metoprolol and atenolol: influence of drug oxidation.

The beta-blocking activity of two slow-release formulations of metoprolol was compared to conventional metoprolol and atenolol which were each given once daily for one week to 8 healthy volunteers in a balanced crossover study. Plasma levels of metoprolol were also measured. Only metoprolol SA (Astra) produced plasma concentrations significantly higher than those for conventional metoprolol 24 hours after dosing. Mean reduction in exercise tachycardia at 24 hours after dosing was significantly greater with atenolol and metoprolol SA than with metoprolol SR and conventional metoprolol. Beta-adrenoceptor blocking activity at 24 hr was more variable with all formulations of metoprolol than with atenolol, which was explained by differences in metoprolol metabolism. Subjects who were found to be "poor metabolizers" when tested with debrisoquine had much greater bioavailability, half-life and response to metoprolol. These subjects had maintained beta-blocking activity at 24 hr following metoprolol whereas extensive metabolizers did not, even with sustained-release formulations. The response to atenolol did not depend on oxidation phenotype.

Atenolol↗
PubMed1982

Hydralazine once daily in hypertension.

The effects of hydralazine formulation and dose interval were assessed in 20 patients with hypertension well controlled on conventional hydralazine tablets, 100 mg twice daily, in addition to atenolol and a diuretic. The double-blind study used four regimens crossed over in random order at five-week intervals; placebo; conventional hydralazine 100 mg twice daily; conventional hydralazine 200 mg once daily; and slow-release hydralazine 200 mg once daily. Blood pressure and pulse rate were assessed soon after (2.5 +/- 0.9 h) and immediately before taking hydralazine (previous dose: once daily, 26.5 +/- 0.9 h; twice daily, 13.6 +/- 2.0 h). Seventeen patients completed the study. All hydralazine regimens were associated with significant falls in blood pressure. Once-daily treatment with conventional hydralazine was unsatisfactory, as its hypotensive effect waned at 24 h; there was a significant difference between the peak and trough effects on blood pressure and pulse in rapid acetylators. Compared with placebo twice-daily conventional hydralazine and once-daily slow-release hydralazine gave satisfactory control for 24 hours in both rapid and slow acetylators, though the hypotensive effect was larger in the slow acetylators. It is concluded that there is no need to administer hydralazine more than twice daily.

Adult↗
PubMed1982

Sample size for short-term trials of antihypertensive drugs.

1 Controlled trials of antihypertensive drugs published in the British Journal of Clinical Pharmacology during 1979 and 1980 were examined. Studies comparing two or more active drugs or dosage regimens nearly always failed to separate and treatments significantly. The sample size (mean 19 patients) and power of these studies were too low. 2 When planning such studies the aims should be a power of at least 0.8; significance 0.05 or less; and to detect a difference between treatments of 10/5 mmHg, or 6.7 mmHg mean arterial pressure (MAP). The sample size needed can be derived readily from a nomogram if the standard deviation of differences (SDD) between BP measurements under trial conditions is known. 3 In five studies the SDDs were fairly constant despite different observers, patient groups and measuring devices, at approximately 14 mmHg systolic, 9 mmHg diastolic, and 9 mmHg MAP. Use of three BP measurements at each visit reduced the SDD by about 1 mmHg, and would reduce the sample size required by about 20%. Replicate BP measurements at separate visits would be expected to have a larger effect on the power of the study. 4 Published studies with negative results should give an estimate of the power of the study.

Antihypertensive Agents↗
PubMed1982

Defective metabolism of metoprolol in poor hydroxylators of debrisoquine.

Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of beta-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and beta-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.

Adrenergic beta-Antagonists↗
PubMed1982

Comparison of two long-acting preparations of metoprolol with conventional metoprolol and atenolol in healthy men during chronic dosing.

1 Eight healthy men received two long-acting formulations of metoprolol 200 mg (SA Astra, SR Geigy), conventional metoprolol 200 mg and atenolol 100 mg once daily for 1 week each in balanced, crossover fashion. There was a washout period of at least a week between each phase. 2 On the last day of each phase, post-exercise heart rate was recorded at intervals and compared to pretreatment values. Plasma metoprolol concentrations were measured. 3 The mean AUC was similar after each of the three formulations of metoprolol (relative bioavailability of SA and SR v conventional was 97%) but with SA and SR metoprolol the time to peak was significantly delayed by about 2 h. 4 In comparison to conventional metoprolol only metoprolol SA was associated with significantly higher plasma metoprolol concentrations at the end of a dosing interval (mean values: conventional, 25 ng/ml, SR 37 ng/ml, SA 51 ng/ml). 5 Mean (+/- s.d.) reduction in exercise tachycardia at the end of a dosing interval was significantly greater with atenolol (14.8 +/- 4.5%) and metoprolol SA (13.7 +/- 10.3%) than with metoprolol SR (10 +/- 8.4%) and conventional metoprolol (8.2 +/- 7.1%). 6 The variability in beta-adrenoceptor blockade at 24 h was much greater with each of the three metoprolol formulations than that with atenolol. This was explained by the variability in metoprolol metabolism. 7 Oxidation phenotype testing with debrisoquine showed there were six extensive metabolisers and two poor metabolisers. The AUC, half-life and response to metoprolol at 24 h were much greater in poor metabolisers. Response to atenolol was not influenced by phenotype.

Adult↗
PubMed1982

Drug-related acute medical admissions.

1 A survey of urgent admissions to a general medical unit in Sheffield in 1978 showed that about 25% of admissions were caused by drug-related illness; 18% by self-poisoning, 3.1% by definite or probable adverse reactions, 3.1% by possible adverse reactions, and 1.4% by non-compliance with drug treatment. These patients accounted for 10.8% of the bed use by patients admitted urgently. 2 Drug-related admissions to the unit did not increase between 1974 and 1980. 3 The use of barbiturates for self-poisoning declined sharply, while that of paracetamol increased steadily. Self-poisoning with dextropropoxyphene appeared to peak in 1978, and then decline. 4 While drug-related illness caused the admission of 81% of all patients under the age of 30 years, they rarely came to harm. Self-poisoning had a high mortality in older patients, and they were also the principal sufferers from adverse drug reactions.

Adult↗
PubMed1982

Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic-treated hypertensive patients.

Patients with mild hypertension who habitually smoked cigarettes and consumed caffeine were examined after they abstained from caffeine and cigarettes overnight. Their mean blood pressure (147/89 mm Hg) was substantially lower than values recorded in the clinic (164/102 mm Hg) and remained so when they continued to abstain (149/94 mm Hg at two hours). Smoking two cigarettes (3.4 mg nicotine) elevated blood pressure by 10/8 mm Hg, but for only 15 minutes. Drinking coffee (200 mg caffeine) elevated blood pressure by up to 10/7 mm Hg between one and two hours. Combined coffee ingestion and cigarette smoking caused a sustained rise in blood pressure from 5 to 120 minutes to levels similar to those measured in the clinic (162/102 mm Hg at two hours). Similar results were obtained in thiazide-treated patients. The interaction of coffee and cigarettes on blood pressure, but not on pulse rate, was significant. The pressor effect of cigarette smoking and caffeine ingestion in combination may be important in the evaluation of patients with mild hypertension.

Adult↗
PubMed1981

A clinical and pharmacokinetic evaluation of tolmesoxide in hypertensive patients.

The pharmacokinetics, hypotensive effect and tolerability of a new vasodilator, tolmesoxide (T), have been studied in 6 uncontrolled hypertensive patients receiving atenolol and diuretic. After a 50 mg oral dose mean (+/- SD) peak plasma concentration of T was 1.13 +/- 0.29 micrograms/ml-1 and occurred 0.79 +/- 0.40 h after the dose; mean peak plasma concentration of its sulphone metabolite (M) was 0.37 +/- 0.09 micrograms/ml-1 at 1.92 +/- 1.32 h after the dose. Following peak plasma concentrations there was a monoexponential decline in T and M concentrations with half-lives of 2.78 +/- 0.77 h and 10.78 +/- 7.85 h respectively. There was a linear increase in plasma concentration of T and M during incremental dosing with 50--200 mg t.i.d. During in-patient administration of 600--900 mg T daily (n = 6) there was no significant change in blood pressure, pulse rate or body weight. Out-patient administration of 900 mg T daily (n = 4) was associated with a significant fall in mean systolic but not diastolic by (lying -15/+1 mm Hg. standing -25/-8 mm Hg). A further fall was observed in 2 subjects receiving 1200 mg and 1500 mg daily. Supine pulse rate increased (mean +/- SD) significantly from 55 +/- 5/min to 66 +/- 8/min following 900--1500 mg T in 4 out-patients. Severe nausea and other gastro-intestinal side-effects in all subjects receiving 600--900 mg daily eventually necessitated drug withdrawal. In its present form T is not recommended for the treatment of hypertension.

Adult↗