Biomedical subjects
S M MacLeod
Publications and source records attributed to S M MacLeod.
Antihypertensive efficacy of propranolol given twice daily.
The therapeutic efficacy of propranolol in four and two daily doses was compared in 63 treated hypertensive patients in a multicentre trial. After 3 months of a stable diastolic blood pressure while receiving propranolol four times a day the patients were switched to a twice-a-day regimen, the drug being given at 8 am and 8 pm, with the same total daily dose, for 3 more months. Blood pressures and heart rates were measured at 8 am, 12 noon, 4 pm and 8 pm at 4-week intervals. There were no significant changes in mean blood pressure after the change to the twice-a-day regimen, although some patients reported new side effects. Compliance appeared to be unaffected.
Chlordiazepoxide and oxazepam disposition in cirrhosis.
When disease impairs clearance of drugs, multiple-dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy-proven cirrhosis. In the normal subjects, mean (+/- SE) kinetic parameters were: t 1/2 beta, 10.0 (+/- 0.9) hr; Vd, 0.38 (+/- 0.04) l/kg; clearance, 0.54 (+/- 0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = -0.63). Values in cirrhotic patients were: t 1/2 beta, 34.9 (+/- 8.7) hr; Vd, 0.34 (+/- 0.024) 1/kg; and clearance, 0.185 (+/- 0.34) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean t 1/2 beta for oxazepam (7.1 +/- 1.0 hr) was 27% longer than in control subjects (5.6 +/- 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.
Use of the overturn end point in goldfish to measure the interaction of diazepam and ethanol and the effects of the binding of diazepam to bovine serum albumin.
Over the ranges 2.8 X 10(-5) to 8.78 X 10(-5) M diazepam and 4.85 X 10(-2) to 1.22 X 10(-1) M ethanol, addition of the effects of these agents on the overturn end point in goldfish was observed. The addition of bovine serum albumin (1.56 X 10(-5) M) to aqueous solutions of diazepam modifies the diazepam effect by reducing the "free" drug concentrations.
Clinical pharmacology in a paediatric hospital.
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Interaction of disulfiram with benzodiazepines.
The disposition of chlordiazepoxide (50 mg, intravenously), diazepam (0.143 mg/kg, orally), and oxazepam (0.429 mg/kg, orally) were studied in normal and alcoholic men before and after chronic disulfiram administration. Decreases in the plasma clearance of chlordiazepoxide (54%, p less than 0.05), diazepam (41%, p less than 0.05), and their active N-desmethyl metabolites were observed. Oxazepam has no important active metabolites and its net disposition is minimally altered by disulfiram. Oxazepam disposition is unaffected by age and liver disease. These considerations together with that of the short half-life of oxazepam (median, 6.1 hr) suggest that oxazepam may be the drug of choice if benzodiazepine therapy is used for patients taking disulfiram.
Clinical pharmacokinetics of chlordiazepoxide.
Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biotransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (tl/2beta) of chlordiazepoxide following single doses, in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5%. Elimination of the parent compound is mirrored by formation of the first active metabolite. Clearance of chlordiazepoxide is reduced and tl/2beta is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals. A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.