Term High Dose Research Articles

Time-dependence in benzodiazepine pharmacokinetics. Mechanisms and clinical significance.

Several studies investigating changes with time in pharmacokinetic parameters of several benzodiazepines are reviewed. At least 3 possibilities (enzyme induction, enzyme inhibition by metabolic products, and unchanged kinetics following long term therapy or high doses) have been postulated in the disposition processes of diazepam. It seems likely that the contradictory results which have been reported can be explained by differences in 1 or several experimental factors influencing the outcome of a study (patient compliance, multiple drug therapy or statistical design). With the 3-hydroxybenzodiazepine lorazepam and the nitro-benzodiazepine nitrazepam, no changes in metabolic activity were observed. Studies with clonazepam in monkeys have confirmed previous observations that reduced metabolic activity during periods of physical inactivity gives rise to circadian fluctuations in steady-state concentrations of the drug. Furthermore, systemic and intrinsic clearances of midazolam were found to be higher following an intravenous dose in the late afternoon than after a morning dose. The protein binding of diazepam is also subject to diurnal variations, and concomitant changes in apparent volume of distribution and clearance have been observed. From the existing data it seems likely that the rate of absorption of several benzodiazepines (including diazepam, clobazam and clorazepate) varies periodically with a 24-hour cycle, pointing to diurnal effects on drug absorption processes.

Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function.

Studies of adrenal function were performed on 54 asthmatic patients who were taking long term high doses of inhaled beclomethasone dipropionate ranging from 500 to 2000 micrograms/day for between six and 60 months. Of the 43 patients taking up to 1500 micrograms/day, 39 (91%) had normal basal plasma cortisol concentrations and normal short tetracosactrin responses and 24 hour urinary free cortisol excretion was within the normal range in eight of nine patients tested. Some evidence of adrenal suppression was found in patients taking 2000 micrograms/day, with basal plasma cortisol below the normal range in four out of 11 patients and 24 hour urinary free cortisol excretion below the normal range in five out of six patients tested. Only one of the 11 patients taking 2000 micrograms/day had a short tetracosactrin response below the normal range: the mean rise in plasma cortisol was, however, significantly lower in this group than in those taking 1000 micrograms/day (328 (SE 30) and 506 (34) nmol/l respectively) (p less than 0.01). Patients taking more than 1500 micrograms/day of inhaled beclomethasone may require systemic corticosteroids during prolonged stress.

Effect of 6-mercaptopurine on homograft reaction in rats.

Conclusion and SummaryThere was an apparent, brief prolongation of the mean skin homograft survival in 241 rats which were given 6-MP. However, neither long term administration nor high doses of this drug consistently prolonged survival time. A few of the treated animals in the higher dosage groups had unusually long graft survivals which accounted for the over-all increase of mean graft survival. Most of the animals in all groups sloughed off their grafts at or near the expected time.