The effect of a novel, dual function histamine H1 receptor antagonist/5-lipoxygenase enzyme inhibitor on in vivo dermal inflammation and extravasation.
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.
Giannaras
Alexander
A
Pharmacology Department, UCB Research Inc., 840 Memorial Drive, Cambridge, MA 02139, USA.
Selig
William
W
Ellis
James
J
Hullinger
Thomas
T
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000188:drug therapy* / Q000201:enzymology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011969:Receptors, Histamine H1 / Q000502:physiology*
D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D016859:Lipoxygenase Inhibitors; D011969:Receptors, Histamine H1; D001094:Arachidonate 5-Lipoxygenase