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Biomedical subjects

S M MacLeod

Publications and source records attributed to S M MacLeod.

At least 109 records · Page 6Linked to original sources
PubMed1979

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.

Adult↗
PubMed1979

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.

Animals↗
PubMed1978

Adverse biochemical and clinical consequences of furosemide administration.

Nurse monitors collected clinical and laboratory data from 204 hospitalized patients receiving furosemide (122 men and 82 women; mean age 69.6 years). Biochemical abnormalities and clinical problems definitely or probably induced by any drug occurred in 70.6% and 49.0% respectively of the patients, and were attributed to furosemide in 81.3% and 13.0% respectively of these patients. The most important clinical events were dehydration and hypotension. Furosemide-induced hypochloremia, hypokalemia and hyponatremia occurred in 35.8%, 25.0% and 24.5% of the patients respectively. Most of the biochemical changes were slight, and only 3.9% of the patients had a furosemide-induced decrease in the serum potassium concentration to less than 3.0 mmol/L. Surprisingly, 24.5% of the patients also manifested drug-induced hyperkalemia. Administration potassium supplements or spironolactone, or both, concurrently with furosemide was responsible in most cases for the development of hyperkalemia. The occurrence of drug-induced adverse effects after 2 weeks of hospitalization was significantly associated (P less than 0.05) with subsequent prolongation of hospitalization. The high frequency of drug-induced events warrants careful monitoring of all patients receiving furosemide in spite of the low frequency of serious toxic effects produced by the drug.

Adult↗
PubMed1978

Influence of age and previous use of diazepam dosage required for endoscopy.

In 19 patients (10 men and 9 women) a 22-fold variation was observed in the intravenous dose of diazepam necessary as preparation for endoscopy (median dose, 20 mg; range, 5 to 110 mg). Analysis of plasma samples for diazepam and N-desmethyldiazepam revealed that the clinical response did not relate to the rate or character of initial drug distribution. There was a high correlation (r = 0.96) between the dose and the plasma concentration 10 minutes after administration. Users of diazepam displayed tolerance to its pharmacologic effects, requiring a significantly larger (P less than 0.05) dose than nonusers (median doses, 35.0 mg and 14.5 mg respectively). Older patients required less than younger patients (r = -0.54, P less than 0.05). The variation between individuals in the dose of diazepam required as preparation for endoscopy cannot be explained by variation in drug disposition but instead reflects previous diazepam use, age and probably differences in sensitivity at the site or sites of drug action.

Adult↗
PubMed1978

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.

Adult↗
PubMed1977

Diazepam actions and plasma concentrations following ethanol ingestion.

In eight normal volunteers, the combination of ethanol (0.5 g/kg) and diazepam (10 mg) administered orally produced a greater decrease in motor performance on a pursuit rotor than diazepam alone. The pharmacologic effect of diazepam was enhanced by 73% and this potentiation was associated with significantly greater diazepam concentrations (p less than 0.01) than after diazepam alone. The failure to observe any increase in the concentrations of the principal metabolite, N-desmethyl diazepam, during the period of enhanced pharmacologic effect precludes any change in the demethylating metabolic process as being responsible. The data suggest (0.10 greater than p greater than 0.05) a trend to a smaller volume of distribution of diazepam when ethanol is administered prior to diazepam ingestion. The subjects showed acute tolerance to the effects of diazepam. Lower plasma concentrations on the ascending side of the plasma diazepam concentration versus time profile were linked with the same pharmacologic responses associated with a greater drug concentration on the descending portion, of the same curve.

Adolescent↗
PubMed1976

Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants.

Many drugs alter the anticoagulant effect of oral coumarins. It is essential that physicians be aware of interactions leading to increased or decreased anticoagulation or to erratic control. Interacting drugs can be classified as influencing the pharmacodynamics (pharmacological actions) or the pharmacokinetics (absorption, biotransformation, binding to plasma proteins, excretion) of oral coumarin anticoagulants. Significant pharmacodynamic interactions include those with vitamin K, salicylates, oestrogens, anabolic steroids, phenylbutazone and other anticoagulants. Significant pharmacokinetic interactions include those with cholestyramine, barbiturates, phenylbutazone, rifampicin and chloramphenicol. When prescribing coumarins, the physician should be fully aware of a patient's other drug therapy and the patient should be cautioned against adding new drugs without consultation. If changes in drug therapy are necessary, close monitoring of prothrombin time after the change is essential.

Anticoagulants↗
PubMed1974

Hepatic microsomal drug oxidation and electron transport in newborn infants.

Many drugs require oxidative metabolism for termination of action and/or for elimination from the body. Many oxidative reactions are catalyzed by hepatic microsomal enzymes. The activities of various drug-metabolizing enzymes, namely, NADPH cytochrome c reductase, NADPH oxidase, aminopyrine-N-demethylase, and analine P-hydroxylase, and the content of cytochrome P-450, were measured in hepatic microsomes obtained from seven newborn infants and four adult patients. The results in the newborn infant show increasing activities of these enzymes (except aminopyrine-N-demethylase) related to advancing age. Good correlation between three components of the hepatic microsomal mixed function oxidase system and aniline p-hydroxylase was established, whereas only NADPH oxidation correlated with aminopyrine N-demethylation. The rate of substrate or drug oxidation and the activities of the components of the microsomal electron transport pathway were lower than comparable values in the adult. The data demonstrate a possible biochemical basis for the transient deficiency in drug metabolism seen in newborn infants.

Adult↗