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Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule from were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam+erythromycin impaired digit symbol substitution and letter cancellation, and triazolam+roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg+erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg+erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

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1 Effects of two new inhibitors of catechol O-methylation (CGP 28014 and entacapone; 30 mg kg-', i.p.) were compared by means of brain microdialysis in rats treated with L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa (50/50 mg kg-', i.p., respectively) or saline. 2 In saline-treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, respectively, whereas homovanillic acid (HVA) levels were decreased by 71%. 3 In the presence of L-dopa/carbidopa, a peripherally active inhibitor of catechol O-methyltransferase (COMT) entacapone had a short-lasting increasing effect on L-dopa efflux. Compared to the effects of L-dopa/carbidopa alone 3-O-methyldopa (3-OMD) levels were effectively reduced (max 79%) by entacapone, but not by CGP 28014. 4 Entacapone, in contrast to CGP 28014, increased striatal dopamine efflux (max 492% of that after L-dopa/carbidopa alone). Also DOPAC levels were increased by entacapone (255% at 180 min), but not significantly by CGP 28014 (159% at 180 min). 5 Both compounds initially decreased HVA efflux. The effect of CGP 18014 was longer-lasting. By the end of the measurement, entacapone even increased HVA levels (max 259%). 6 Our results demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O-methylation.