Chronopharmacological study of antihistamines in man with special references to terfenadine

Summary

A double blind, placebo-controlled, randomized, single dose, cross-over chronopharmacological study of two antihistamines (Terfenadine 20 and 60 mg and Clemastine 1 and 3 mg) was undertaken in 10 healthy volunteers (8 males and 2 females), 21–28 years of age. Drug or placebo was administered at 07.00 h or 19.00 h at one week intervals to subjects with diurnal activity from 07.00–23.00 h and nocturnal rest. The responses measured before and at fixed intervals after each dose of drug or placebo were surface area measurement of skin reaction (wheal and erythema) to intradermal histamine, self-rating for sleepiness using a visual analogue technique, random number addition and eye-hand skill tests. Circadian variation in the response to I. D. histamine 2 µg and vigilance and psychomotor skills were validated. Chronopharmacological changes in the inhibitory effects of the antihistamines Terfenadine and Clemastine on the skin reaction to intradermal histamine were documented. The time from drug administration to maximal effect and the duration of effect was longer with both drugs when administered at 07.00 than at 19.00 h, and the degree of maximal inhibition was greater when the drugs were administered at 19.00 h. Dose-related inhibition of the histamine skin reaction was obtained with both drugs; Terfenadine 60 mg had approximately equivalent inhibitory activity to that of Clemastine 3 mg. Only Clemastine 3 mg had a significant central depressant effect, as shown by self-rating of sleepiness and random number addition. Terfenadine 60 mg administered at 19.00 h tended to produce a lower sleepiness score than did the placebo. A chronotherapeutic optimization approach to a Terfenadine dosage schedule is proposed.