Pharmacokinetics of denbufylline in healthy elderly subjects.

A single 100 mg oral dose of denbufylline was administered in an open study to ten healthy, elderly subjects in order to characterise the pharmacokinetics of parent compound and its major pharmacologically active, circulating metabolites. Plasma concentrations were determined using a combination of GC and HPLC methods. Since denbufylline plasma concentrations were close to the assay limit of reliable determination, the disposition of the compound was assessed in terms of the pharmacokinetic parameters of three active metabolites. The general pharmacokinetic behaviour of debufylline was similar to that observed in young, healthy subjects, although plasma concentrations of the metabolites were higher and half-lives tended to be longer in the elderly group. None of the subjects presented any adverse events during the study.

[Metabolic interaction between cimetidine, ranitidine and amitriptyline/chlordiazepoxide]. / Metabolische Interaktion zwischen Cimetidin, Ranitidin und Amitriptylin/Chlordiazepoxid.

The effects of cimetidine and ranitidine on plasma levels of amitriptyline and chlordiazepoxide were examined in a biphasic study with 12 young male volunteers. During the first phase all subjects received a fixed combination of 2 X amitriptyline (25 mg) and chlordiazepoxide (10 mg) daily for one week. After the last dose blood samples were drawn up to 72 hours in order to detect plasma levels of the drugs and their main metabolites. Following a wash-out-period of 7 days two groups of 6 subjects, each were formed in a randomized order. In addition to the mentioned medication 3 X 200 mg plus 1 X 400 mg of cimetidine daily or 2 X 150 mg of ranitidine daily were administered for one week. After discontinuation of amitriptyline/chlordiazepoxide the medication with H2-blockers was kept and blood samples were collected again for plasma analysis. Plasma level detections were carried out employing HPLC. The change of the area under the plasma level-time curve (AUC), total clearance and terminal half-life served as parameters indicating interaction. Under treatment with cimetidine plasma levels of amitriptyline and chlordiazepoxide were significantly (5%) increased, whereas such effects could not be observed with ranitidine. Due to these interactions under the conditions of coadministration of H2-blockers and amitriptyline and/or chlordiazepoxide the use of ranitidine is recommended.

Hemodynamic effects of acebutolol and propranolol in hypertensive patients during exercise.

Acebutolol 400 mg vs. propranolol retard 160 mg were investigated in a multicentral, double-blind, cross-over study for their action on blood pressure and heart rate in outpatients during ergometer exercise. A 2-week single-blind placebo control phase, which served as a wash-out and to eliminate placebo responders, preceded the 6-week treatment phase with propranolol (or acebutolol) followed by a further 6-week phase with acebutolol (or propranolol). At the end of each treatment phase a bicycle ergometer test was carried out, the values for 18 patients (from 26 completed investigations) were carried forward to the evaluation of the ergometry. The treatment groups were shown to be comparable. Acebutolol and propranolol produced a similar fall in systolic and diastolic blood pressure and heart rate at rest. During ergometer exercise, acebutolol led to a significantly lower increase in both systolic and diastolic blood pressure and heart rate than propranolol. The possible role of the intrinsic sympathomimetic activity (ISA) and the relative cardioselectivity of the test agents and the clinical impact of the hemodynamic findings with respect to morbidity and mortality are briefly discussed. Questioning at the end of the study revealed that significantly more patients preferred the treatment with acebutolol.