Pharmacokinetic and pharmacodynamic effects of the novel benzodiazepine antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one in humans

2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-related and relatively low considering the doses administered. A high plasma concentration ratio of metabolite vs. parent compound (3:1) points to an extensive gastrointestinal first-pass metabolism. CGS 8216 influences the human electroencephalogram similar to anxiolytic and vigilance enhancing drugs in doses which do not change performance of psychometric tests. CGS 8216 antagonizes the diazepam-induced impairment of alertness.     

Monoamine oxidase inhibition by phenelzine and brofaromine in healthy volunteers

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.     

Influence of oestradiol on alpha2-adrenoceptor binding sites on intact platelets of young male volunteers

Summary The specific binding (B_max) of (³H-methyl)yohimbine to alpha₂-adrenoceptor binding sites on intact platelets was increased by 43% in 6 out of 7 young male volunteers 4 days after a single i.m. injection of 10 mg sustained release oestradiol, and it had returned to the starting value 4 weeks after drug administration. Mean plasma oestradiol was 331 pg/ml on Day 4 and it was within the pre-treatment control range of 19 pg/ml 4 weeks after the injection.A close correlation between the post-injection plasma oestradiol concentration and the increase in alpha₂-adrenoceptor binding sites on intact platelets was not found.     

Effect of brofaromine and pargyline on human plasma melatonin concentrations

1. Plasma melatonin was used to determine the influence of two monoamine oxidase inhibitor drugs in 11 normal subjects. 2. Acute oral administration of the selective reversible MAO-A inhibitor brofaromine but not of the - in low doses - selective MAO-B inhibitor pargyline increased daytime melatonin with large variations in onset, degree and duration. 3. Further investigation of this selective action on melatonin might help to better understand the action of the therapeutically effective antidepressive therapy with selective MAO-A inhibitors.     

Ausschüttung lipolytisch wirksamer Hypophysenhormone durch Stimulierung von „Muscarin-Receptoren“ im Gehirn

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Prostata und Psyche

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Discovery of altered pharmacokinetics of CGP 15 210 G in poor hydroxylators of debrisoquine during early drug development.

The pharmacokinetics of CGP 15 210 G, a new 5-HT uptake inhibitor in poor and extensive metabolisers of debrisoquine, give indirect evidence of an association between its metabolism and polymorphic hydroxylation of the debrisoquine type.