INHIBITORY EFFECTS OF RUPATADINE ON MAST-CELL HISTAMINE-RELEASE AND SKIN WHEAL DEVELOPMENT INDUCED BY ASCARIS-SUUM IN HYPERSENSITIVE DOGS

The present studies were performed to compare the cutaneous antiallerg ic effects of rupatadine, a new potent dual antagonist of histamine an d platelet-activating factor (PAF), with those of loratadine (an H-1-a ntihistamine) and SR-27417A (a PAF antagonist). Two experimental model s were used: an in vivo skin challenge by Ascaris suum extract adminis tered intradermically in conscious hypersensitive dogs and an in vitro assay of Asc S 1 antigen-induced histamine release from isolated cani ne skin mast cells. In antigen-induced skin inflammation, both rupatad ine and loratadine administered orally inhibited wheal formation in a dose-dependent manner at the studied doses. At the 0.1 mg/kg dose, max imum inhibition values for rupatadine and loratadine were similar, but the effect of rupatadine lasted 24 h, whereas loratadine's effect dis appeared after 8 h. At the 1 mg/kg dose, the two compounds behaved sim ilarly, with maximum effects of about 65% (4 h after treatment) and ac tivity lasting more than 24 h in both cases. At the 10 mg/kg dose, rup atadine and loratadine exhibited maximum effects of 84 and 64% in whea l inhibition 2 and 4 h after drug administration, respectively. SR-274 17A did not inhibit ascaris-induced wheal at the doses studied (1 and 10 mg/kg p.o.). In isolated canine skin mast cells, rupatadine and lor atadine inhibited antigen-induced histamine release in a concentration -dependent manner. Rupatadine was more potent than loratadine at each concentration studied (100 nM-30 mu M). Maximum inhibitory effects wer e 83 and 67% for rupatadine and loratadine, respectively, after a 30 m u M concentration. Rupatadine, with an IC50 value of 5.3 mu M, was abo ut fourfold more potent than loratadine, with an IC50 value of 19 mu M . SR-27417A exhibited no effect in our experimental model. Moreover, n either loratadine or rupatadine showed cytotoxic or prodegranulating e ffects at any concentration, whereas SR-27417A was cytotoxic at the hi ghest concentration (30 mu M). Thus, rupatadine is effective in contro lling inflammatory reactions in dog skin and the effect may be partly due to its modulation of mast cell degranulation, but not to its PAF-a ntagonist properties. Drug Dev. Res. 44:49-55, 1998. (C) 1998 Wiley-Li ss, Inc.