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Biomedical subjects

S M MacLeod

Publications and source records attributed to S M MacLeod.

At least 37 records · Page 2Linked to original sources
PubMed1991

Clinical pharmacology and optimal therapeutics in developing countries: aspirations and hopes of the Pediatric Clinical Pharmacology Subcommittee.

By the year 2000 the world's population will exceed 6 billion people, of whom one-half will be under the age of 15. Many of these children will die unnecessarily from diseases readily treatable with pharmaceutical agents. The discipline of pediatric clinical pharmacology has the potential to provide significant benefit to the world's children. Critical to the recognition of this potential is the blending of the expertise to be found in the disciplines of pediatrics, toxicology, clinical pharmacology, pharmacogenetics and clinical epidemiology. Through a marriage of these disciplines and an appropriate admixture of social sciences we may create a strong discipline focused on the encouragement of optimal drug therapy for children and for their protection from inappropriate drug exposure in utero. Such a development is the prime objective of the Pediatric Clinical Pharmacology Subcommittee: International Union of Pharmacology, Section of Clinical Pharmacology.

Child↗
PubMed1991

Adverse drug reactions: an integrated approach.

The need for early detection and a better understanding of adverse drug reactions (ADRs) is well recognized today. This paper describes an approach to the study of ADRs characterized by the integration of pharmacoepidemiology, clinical pharmacology and molecular/cellular biology (pharmacogenetics). Merging of these disciplines would greatly enhance our approach to unanticipated drug toxicity and would narrow the risk/benefit margin of pharmacotherapeutic interventions. Such an integrative strategy is a key element in any initiative directed toward the promotion of optimal drug therapy. (Ref. 16.)

Adverse Drug Reaction Reporting Systems↗
PubMed1989

Determinants of recall and recall bias in studying drug and chemical exposure in pregnancy.

Case-control studies on effects of drugs in pregnancy rely heavily on maternal recall. At the Motherisk Program in Toronto we counsel women during early pregnancy on the risk of drug and chemical exposure; subsequently, we follow up the outcome of pregnancy after birth. This cohort has given us an opportunity to assess the magnitude of recall of early pregnancy exposure and determinants likely to affect it in 145 consecutive cases. The mean recall of exposure identity was 62%, while accurate recall of timing of exposure was 37% and of dosage 24%. Exposures that prompted the clinic visit, chronic therapeutic exposures, environmental agents, and known teratogens were recalled significantly better than were other exposures. Accurate report of smoking was significantly higher than of alcohol use (79.4% vs. 59%, respectively, P = .0002). The number of agents consumed by the pregnant woman negatively correlated with her recall; mean recall of 1 agent was 85% vs. only 40% recall of 4 agents. Women greater than or equal to 30 years of age recalled significantly worse (mean +/- SEM, 52 +/- 4%) than women younger than 30 (70 +/- 4%), P = .002) despite a similar mean number of exposures. No difference in mean recall was found between women having normal (n = 112) or adverse pregnancy outcome (n = 33). There was a recall bias in reporting alcohol consumption; postnatally, women with adverse outcome tended to report significantly less than the amount initially reported by them.

Abnormalities, Drug-Induced↗
PubMed1989

The McMaster M.D. program: a case study of renewal in medical education.

This paper presents four aspects of health professions education at McMaster University: (1) a review of the key elements of the history and distinctive approach of the Doctor of Medicine (M.D.) program; (2) a description of the process and substance of curriculum change over the past decade, focusing on a major revision of the M.D. program that began in 1983; (3) a summary of the findings of follow-up studies of McMaster M.D. program graduates; and (4) an analysis of the current context within which the Faculty of Health Sciences (of which the M.D. program is a part) is operating and a description of strategies for renewal that are being implemented. The evidence and experience to date support the assertion that satisfactory--and in some ways special--physicians can be prepared using the "McMaster approach" to medical education, but that continuous review and periodic major revisions of the educational program are both necessary and possible; they must occur in concert with developments in other sectors of Faculty of Health Sciences activities.

Attitude of Health Personnel↗
PubMed1989

Anti-allergy and anti-asthma drugs. Disposition in infancy and childhood.

Six classes of drug may be prescribed in the treatment of airway hyperreactivity and allergy. Use of the methylxanthine theophylline requires that plasma drug concentrations be monitored because of its pharmacokinetic properties and narrow therapeutic range. beta 2-Selective adrenergic agonists, glucocorticoids, sodium cromoglycate and the quaternary antimuscarinic ipratopium achieve specificity of drug action on the bronchi with minimal side effects by local delivery as aerosols or 'microfine' powders. Glucocorticoids, sodium cromoglycate and ipratropium bromide may also be applied locally to the nasal mucosa in allergic rhinitis, and sodium cromoglycate (cromolyn sodium) may be applied to the eye. The 'antihistamines'--H1-receptor antagonists--are not used to treat bronchial hyperreactivity but are frequently used systemically for treating allergic conditions. Two new agents, terfenadine and astemizole, appear to be specific for H1-receptors and represent a new 'generation' of antihistamines that produce sedation only infrequently. Terfenadine exhibits a bimodal elimination phase (slow component +/- 22 hours) and astemizole has an active metabolite with a half-life of 12 days. The half-lives of most other antihistamines lie in the 4- to 8-hour range (except chlorpheniramine, which has a longer half-life). However, data reflecting disposition of these drugs in children are scanty. There is a need for more powerfully predictive pharmacokinetic approaches, which is discouraged by the widely used modelling approach combining patient and drug characteristics in single variables. Separation of these could improve extrapolation from drugs for which data are available to those for which they are not.

Adolescent↗
PubMed1988

The dissociation between aminoglycoside serum concentrations and nephrotoxicity.

Using newborn and adult rats we tested the correlation between aminoglycoside dose, resultant serum and renal cortical concentrations and nephrotoxicity evidenced by creatinine in serum and urine, N-acetylglucosaminidase and beta 2 microglobulins in urine and sphingomyelinase in renal cortical tissue. Our data reveal that aminoglycoside nephrotoxicity is clearly more evident in adult rats despite significantly lower drug serum concentrations and in the presence of substantially higher renal cortical concentrations. These data indicate that high aminoglycoside serum concentrations are not causing nephrotoxicity but rather reflect secondary body accumulation of the drug associated renal damage.

Acetylglucosaminidase↗
PubMed1988

Pharmacokinetics and adverse effects of amphotericin B in infants and children.

The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.

Adolescent↗
PubMed1988

Cystic fibrosis: enhanced theophylline metabolism may be linked to the disease.

Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p less than 0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhanced N-demethylation and 8-hydroxylation of theophylline, pathways that appear to be mediated by two different families of P-450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.

Adolescent↗
PubMed1988

Endogenous digoxin-like substance(s) associated with uneventful and high-risk pregnancies.

We assessed the existence of endogenous digoxin-like substance(s) (EDLS) in mother-neonate pairs using a routine radioimmunoassay for digoxin. None of those studied had been treated with cardiac glycosides during or before pregnancy. In uneventful pregnancies, cord EDLS levels (0.31 +/- 0.02 ng/ml mean +/- SEM) were significantly higher (p less than 0.001) than both antepartum and postpartum maternal levels (0.14 +/- 0.02 and 0.17 +/- 0.02 mg/ml, respectively). This observation was in contrast with findings in high-risk pregnancies. In general, EDLS levels in the high-risk group were significantly higher than in normal pregnancies (cord 0.94 +/- 0.38 ng/ml; antepartum 1.63 +/- 0.54 ng/ml; postpartum 0.89 +/- 0.73 ng/ml). In the high-risk group there was a remarkably wide range of maternal and cord EDLS concentrations. The present studies suggest that following pregnancies of high risk for a variety of reasons, EDLS determination may be commonly high in the perinatal period and may affect the determination of 'true' digoxin. Consequently, digoxin dosing based on monitoring drug concentration may be futile.

Blood Proteins↗
PubMed1987

The influence of hypothermia on the disposition of fentanyl--human and animal studies.

The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 degrees C-25 degrees C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100-140 min later; p greater than 0.1). In subsequent experiments, the effect of hypothermia on the pharmacokinetics of fentanyl was studied in 4 piglets serving as their own controls. Both distribution volume (Vz) and total body clearance (CL) were significantly smaller during hypothermia. Our studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion. In addition, TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.

Adolescent↗
PubMed1987

Comparative bioavailability study of three sustained release quinidine formulations.

The absorption characteristics of 3 sustained release quinidine formulations were assessed in 12 healthy male volunteers in a randomised 3-way crossover trial. Each formulation ('Quinidex' 300mg, 'Biquin Durules' 250mg and 'Quinaglute Dura-Tabs' 324mg) was administered as a single tablet every 12 hours for 5 days. Peak quinidine serum concentrations of 2.7 +/- 0.8 mg/L occurred 2.5 +/- 1.1 hour after 'Quinaglute' administration, significantly higher (p less than 0.01) than concentrations of 1.6 +/- 0.4 mg/L achieved 4.2 +/- 1.1 hours following 'Biquin' dosing and 1.7 +/- 0.6 mg/L attained 3.9 +/- 2.7 hours after 'Quinidex' ingestion. The extent of absorption based on AUC infinity and normalised for the anhydrous quinidine content was similar for the 3 products. Following multiple dosing, the mean steady-state trough concentration of quinidine was 2.06 +/- 0.56 mg/L for 'Quinidex', significantly greater (p less than 0.05) than that of 'Biquin' (1.18 +/- 0.67 mg/L) or 'Quinaglute' (1.58 +/- 0.58 mg/L). The rate of absorption was found to be much slower for 'Quinidex' than for the other 2 sustained release quinidine formulations. Comparison of the residual sums of squares from simple linear regression of Wagner-Nelson plots did not demonstrate a preference for a zero- or first-order absorption model. Nevertheless, the absorption of 'Quinidex' was twice as prolonged as that of 'Biquin' and 'Quinaglute' regardless of model; first-order absorption half-lives were 2.83 +/- 1.02 hours, 1.25 +/- 0.6 hours and 1.43 +/- 0.88 hours, respectively. The data also suggest that 'Quinidex' absorption may continue beyond 12 hours in some subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial.

In a randomized, double-blind, crossover trial, nabilone was compared to prochlorperazine for control of cancer chemotherapy-induced emesis in 30 children 3.5 to 17.8 years of age. All subjects received two consecutive identical cycles of chemotherapy with the trial antiemetics given in accordance to a body weight-based dosage schedule beginning eight to 12 hours before treatment. The overall rate of improvement of retching and emesis was 70% during the nabilone and 30% during the prochlorperazine treatment cycles (P = .003, chi 2 test). On completion of the trial, 66% of the children stated that they preferred nabilone, 17% preferred prochlorperazine, and 17% had no preference (P = .015, chi 2 test). Major side effects (dizziness, drowsiness, and mood alteration) were more common (11% v 3%) during the nabilone treatment cycles. CNS side effects appeared to be dose related and were most likely to occur when the nabilone dosage exceeded 60 micrograms/kg/d, but individual tolerance to nabilone varied considerably. Lower dosages of nabilone were associated with equivalent efficacy and no major side effects. Nabilone appears to be a safe, effective, and well-tolerated antiemetic drug for children receiving cancer chemotherapy. Although major side effects may occur at higher dosages, nabilone is preferable to prochlorperazine because of improved efficacy.

Adolescent↗
PubMed1986

Absence of tachyphylaxis in gastric acid secretion during pentagastrin infusion.

Tachyphylaxis to stimulation of gastric juice secretion during intravenous pentagastrin (PG) infusion has been reported in animal studies. We assessed the course of gastric response to PG 2 micrograms/kg/hr over eight hours in eight healthy subjects. Peak H+, pepsin, and volume secretions occurred during the second half hour of stimulation. Peak H+ output was 11.6 +/- 1.3 mmol/0.5 hr or 7.6 +/- 0.8% of the total eight-hour secretion. During subsequent half-hour collection intervals, there was no significant decline in response, and the average output was 10.3 +/- 0.4 mmol/0.5 hr (6.5 +/- 0.1%). Peak pepsin and volume secretions were respectively 10.0 +/- 1.4% (74.8 +/- 11.6 mg/0.5 hr) and 8.8 +/- 1.1% (146.3 +/- 17.4 mL/0.5 hr) of the total eight-hour secretion. Although there was a significant decline in pepsin and volume response subsequent to the peak output, the decline was not continuous, and pepsin and volume secretions were maintained, respectively, at 6.0 +/- 0.2% (46.1 +/- 2.5 mg/0.5 hr) and 6.2 +/- 0.1% (107.5 +/- 3.0 mL/0.5 hr) of the total eight-hour secretion. Our study did not demonstrate any tachyphylaxis in H+ response to continuous PG stimulation. This model appears to be a valid tool for the assessment of histamine-H2 antagonist effects on stimulated gastric juice secretion over 8 hours in humans.

Adult↗