ORAL SINGLE DOSES OF ERYTHROMYCIN AND ROXITHROMYCIN MAY INCREASE THE EFFECTS OF MIDAZOLAM ON HUMAN-PERFORMANCE

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant intera ctions 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 form were gi ven with and without 750 mg erythromycin or 300 mg roxithromycin to pa rallel groups of healthy subjects in four placebo-controlled double-bl ind studies. Objective tests and subjective assessments were made befo re the intake of hypnotics and 30 and 90 min after it. In Study I, tri azolam impaired letter cancellation, the combination triazolam+erythro mycin impaired digit symbol substitution and letter cancellation, and triazolam + roxithromycin impaired digit symbol substitution, all at 9 0 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite in ert but the combination midazolam 5 mg+erythromycin impaired digit sym bol 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 wit h midazolam 10 mg+erythromycin which differed from placebo and midazol am (10 mg and 15 mg) in several objective and subjective test variable s. In Study IV, the combination midazolam 10 mg+roxithromycin impaired several objective and subjective variables but it was not stronger th an midazolam 15 mg. These results were supported by the direct measure ments of plasma midazolam in three subjects: erythromycin increased pl asma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg. Our results suggest that seda tion produced by hypnotic doses of midazolam is enhanced by erythromyc in and perhaps by roxithromycin after single oral doses. The combined effects of triazolam together with erythromycin and roxithromycin were unclear, partly due to the relatively lower dose of triazolam.