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S M MacLeod

Publications and source records attributed to S M MacLeod.

113 records · Page 7Linked to original sources
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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.

Administration, Oral↗
PubMedDate not supplied

Pemoline pharmacokinetics and long term therapy in children with attention deficit disorder and hyperactivity.

The pharmacokinetic behaviour of pemoline was studied in 28 children, aged 5 to 12 years, diagnosed as having the attention deficit disorder with hyperactivity. The mean elimination half-life of pemoline in these children was approximately 7 hours, which is considerably shorter than the half-life of 11 to 13 hours previously reported in adults. The tendency of the half-life to increase with age may be explained by the statistically significant decrease in total body clearance with age. The increasing half-life of pemoline with age should be considered during long term drug therapy. In this study no tolerance to the beneficial effects of pemoline was observed over 6 months. The apparent therapeutic serum concentration range for these children was attained after doses of 37.5 to 131.25 mg pemoline daily. Since the optimum serum concentration shows wide variation, the dosing regimen must be determined individually. Routine monitoring of the pemoline serum concentrations is not useful because of this apparent variation in optimum serum concentration and because of the linear relationship between dose and concentration.

Aging↗
PubMedDate not supplied

Impact of antibiotic administrative restrictions on trends in antibiotic resistance.

CONTEXT: In March 2001, in response to concerns about increasing resistance to fluoroquinolone (FQ) antibiotics, the Ontario Drug Benefit (ODB) program limited reimbursement of FQs to ODB beneficiaries defined as high risk or in whom other therapies are not tolerated. OBJECTIVE: To analyze the impact of the limited use (LU) policy changes on antibiotic resistance rates in Ontario, focussing on community-acquired pathogens. DESIGN: Ontario data submitted to the Canadian Bacterial Surveillance Network (CBSN) between January 1, 1998 and June 30, 2002 were analyzed for rates of resistance in various pathogen-antibiotic combinations. The effect of the LU policy on the level and rate of change of antibiotic resistance was estimated using time series models. RESULTS: Resistance rates for S. pneumoniae were 10-12% for penicillin, erythromycin and trimethoprim sulfamethoxazole (TMP/SMX) and less than 3% for amoxicillin and all three FQs tested. There was a statistically significant increasing trend in resistance rates of S. pneumoniae to amoxicillin and levofloxacin throughout the study period. Antibiotic resistance of S. pneumoniae to ciprofloxacin indicated a statistically significant decreasing trend over the study period with a statistically significant increase in the level of antibiotic resistance at the time of the LU policy implementation. No other indication of any statistically significant decrease in resistance rates associated with the LU policy was found. CONCLUSIONS: Although no direct cause and effect can be proven with these observational data, there is no evidence that the limited use policy to restrict fluoroquinolones decreased antibiotic resistance in any of the pathogen-antibiotic combinations tested.

Amoxicillin↗
PubMedDate not supplied

Digoxin-verapamil interaction: in vitro studies in rat tissue.

Recent studies have shown a significant increase in plasma digoxin concentration during verapamil treatment. This phenomenon has been attributed in part to reduced renal clearance of digoxin owing to inhibition of the digoxin tubular secretory process. We studied the influence of digoxin-verapamil interaction on [125I]digoxin uptake by various rat tissues in vitro, employing the tissue slice technique. Slice/medium digoxin ratios (mean +/- SD) were: kidney, 4.09 +/- 0.60; heart, 3.63 +/- 0.41; liver, 3.93 +/- 0.39; and muscle, 3.55 +/- 0.55. Addition of verapamil to the incubation medium resulted in a 15.6% reduction of digoxin uptake by kidney tissue, to 3.38 +/- 0.49 (p less than 0.0005). Verapamil failed to reduce digoxin uptake in liver, heart, or striated muscle. We conclude that the renal cortical transport mechanism of digoxin may be inhibited by verapamil. In contrast, the unaffected uptake of digoxin in heart or muscle indicates that the increase in serum digoxin concentration in the presence of verapamil is not caused or accompanied by redistribution of digoxin from the heart or striated muscle.

Animals↗