ABSTRACT
Duration of Action of Betaadrenergic Blockers Determined with Holter-ECG in Healthy Volunteers In phase I, the duration of action of betaadrenergic blockers is usually determined from the reduction of exercise induced tachycardia. In this randomized placebocontrolled doubleblind trial, however, ambulatory 24-h heart rate monitoring was used in 12 healthy volunteers to evaluate the duration of action of the new cardioselective and vasodilating betaadrenergic blocker ridazolol (CAS413). After the control periods as well as after prospectively defined hours the following mean values of heart rate were obtained: Ridazolol: Control 65.2, 12 h 69.6, 16 h 64.9, 24 h 74.0 beasts/min, placebo: Control 64.8, 12 h 78.5, 16 h 69.7, 24 h 73.5 beats/min. Differences after 12 h were statistically significant and would have been significant after 16 h with more volunteers. Additional explorative analysis with adjustment of significance levels for multiple analysis resulted in significant effects from 2 to 14 h. It was not useful, however, to calculate the time of maximal and half-maximal effects because of the large individual variation. Holter-monitoring of spontaneous heart rate in volunteers provides a rapid orientation on the duration of action of betaadrenergic blockers. The method allows to fix prospectively reasonable times of evaluation in efficacy trials in patients with coronary artery disease.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Electrocardiography, Ambulatory , Adult , Double-Blind Method , Heart/drug effects , Heart Rate/drug effects , Humans , Male , Middle Aged , Pyridazines/pharmacology , Time Factors , Vasodilation/drug effectsABSTRACT
The pharmacokinetics of molsidomine were investigated in the plasma and urine of healthy male volunteers and patients with coronary heart disease after intravenous and/or oral administration of different galenic dosage forms of molsidomine. Following the rapid attainment of mean peak concentration (15 +/- 7 mg/ml) 0.5 to 1.0 hour after single oral dosing of 2 mg of molsidomine, the plasma levels of the unchanged drug decline monoexponentially with a mean half-life of 1.6 +/- 0.8 hours. Molsidomine is absorbed almost completely. Its absolute bioavailability (44 +/- 15%) and a 14C-labeled triale give evidence of quick biotransformation of molsidomine to active metabolites. Less than 2% of the unchanged drug appear in the urine, but renal excretion is the main route of elimination of the metabolites in humans (90% to 95%). The kinetics parameters after administration of multiple dosages of 4 mg of molsidomine over 29 days do not account for accumulation of or enzyme induction by molsidomine. The finding of obvious good correlations between plasma levels of the predrug molsidomine and corresponding pharmacodynamic data can be made plausible by the time course of concentration values of the active metabolite SIN-1 in plasma.
Subject(s)
Oxadiazoles/metabolism , Sydnones/metabolism , Vasodilator Agents/metabolism , Animals , Biological Availability , Coronary Disease/blood , Coronary Disease/metabolism , Dogs , Half-Life , Humans , Kinetics , Molsidomine , Sydnones/administration & dosage , Sydnones/blood , Vasodilator Agents/administration & dosage , Vasodilator Agents/bloodABSTRACT
Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3-5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.
Subject(s)
Coronary Disease/metabolism , Oxadiazoles/metabolism , Sydnones/metabolism , Aged , Angina Pectoris/drug therapy , Angina Pectoris/metabolism , Biological Availability , Clinical Trials as Topic , Coronary Disease/drug therapy , Double-Blind Method , Humans , Kinetics , Middle Aged , Molsidomine , Sydnones/administration & dosage , Sydnones/therapeutic use , Time FactorsABSTRACT
A high-performance liquid chromatographic method is described for the analysis of pirlindole [2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino(3,2,1-jk)carbazole hydrochloride], a new antidepressive drug. The drug was extracted from plasma into dichloromethane, and the analysis was carried out on a reversed-phase column, the effluent being monitored by fluorescence detection. The method is selective and sensitive (limit of detection 1-2 ng/ml plasma). Urine analysis was done by direct injection of the diluted sample. The method was applied to the analysis of plasma and urine samples of eight healthy male volunteers who received a 75-mg oral dose of a tablet formulation of pirlindole. The method was also applied to a study in three beagle dogs which received pirlindole (1 mg/kg) by infusion (0.1 mg/kg/min) and orally (10 mg/kg) to estimate the absolute bioavailability of the drug.
Subject(s)
Carbazoles/blood , Animals , Biological Availability , Carbazoles/metabolism , Carbazoles/urine , Chromatography, High Pressure Liquid/methods , Dogs , Half-Life , Humans , KineticsABSTRACT
3-(2-Diethylaminoethyl)4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensaïn) shows dose dependent platelet aggregation inhibitory activity in vitro according to the methods of Born (following ADP, epinephrine and collagen) and of Breddin (platelet agglutination test--PAT--, adhesively). The effect was found to be more pronounced than that of acetylsalicylic acid. Furthermore, in vivo carbocromen inhibited the increased spontaneous platelet aggregation in man.
