Leukotrienes and histamine are thought to play important roles in the development of dermatitis. This study evaluated the in vivo efficacy of 5-{4-[(aminocarbonyl)(hydroxy)amino]but-1-ynyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)benzamide (ucb 35440), a dual function histamine H1 receptor antagonist/5-lipoxygenase enzyme inhibitor, in mouse skin. A single application of phorbol 12-myristate 13-acetate (PMA) was used to induce an acute inflammatory response over a 6-h period. PMA was applied on days 0, 2, 4, 7 and 9 to generate a chronic inflammatory response measured on day 10. ucb 35440 was applied topically at 1 h pre-PMA challenge and 3 h post-PMA challenge in the acute model. In the chronic PMA model, ucb 35440 was applied topically twice a day (AM and PM) on days 7, 8 and 9. Dose-response studies revealed that ucb 35440 inhibited PMA-induced ear weight gain with a 57% inhibition measured using a 3% w/v topical solution in the acute model. The compound appeared less potent in the chronic model with 43% inhibition measured using a 3% w/v topical solution of ucb 35440. Qualitative histologic assessment in PMA challenged ears showed that ucb 35440 produced a moderate reduction of polymorphonuclear cell infiltration in the acute model whereas, a more substantial reduction in polymorphonuclear infiltration was noted in the chronic model. In addition, the oral efficacy of ucb 35440 was evaluated in vivo against histamine-induced extravasation in guinea pig skin. Single oral doses of ucb 35440 (10 mg/kg in 0.5% methylcellulose suspension) at 1, 2, 6 or 24 h pre-histamine challenge produced minimal inhibition of histamine-induced extravasation in the dermis. However, when ucb 35440 (10 mg/kg in a 0.5% methylcellulose suspension) was orally administered 24 and 2 h prior to dermal histamine challenge, significant inhibition of extravasation was observed. Similar inhibition of histamine-induced extravasation was observed when animals were orally dosed twice a day (AM and PM 10 mg/kg in a 0.5% methylcellulose suspension) for 5.5 days prior to dermal histamine challenge. Collectively, these results suggest that ucb 35440 may represent an important therapeutic class for the treatment of dermatologic inflammatory conditions.
