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 antiallergic effects of rupatadine, a new potent dual antagonist of histamine and platelet-activating factor (PAF), with those of loratadine (an H1-antihistamine) and SR-27417A (a PAF antagonist). Two experimental models were used: an in vivo skin challenge by Ascaris suum extract administered intradermically in conscious hypersensitive dogs and an in vitro assay of Asc S 1 antigen-induced histamine release from isolated canine skin mast cells. In antigen-induced skin inflammation, both rupatadine and loratadine administered orally inhibited wheal formation in a dose-dependent manner at the studied doses. At the 0.1 mg/kg dose, maximum inhibition values for rupatadine and loratadine were similar, but the effect of rupatadine lasted 24 h, whereas loratadine's effect disappeared after 8 h. At the 1 mg/kg dose, the two compounds behaved similarly, with maximum effects of about 65% (4 h after treatment) and activity lasting more than 24 h in both cases. At the 10 mg/kg dose, rupatadine and loratadine exhibited maximum effects of 84 and 64% in wheal inhibition 2 and 4 h after drug administration, respectively. SR-27417A 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 loratadine inhibited antigen-induced histamine release in a concentration-dependent manner. Rupatadine was more potent than loratadine at each concentration studied (100 nM–30 μM). Maximum inhibitory effects were 83 and 67% for rupatadine and loratadine, respectively, after a 30 μM concentration. Rupatadine, with an IC50 value of 5.3 μM, was about fourfold more potent than loratadine, with an IC50 value of 19 μM. SR-27417A exhibited no effect in our experimental model. Moreover, neither loratadine or rupatadine showed cytotoxic or prodegranulating effects at any concentration, whereas SR-27417A was cytotoxic at the highest concentration (30 μM). Thus, rupatadine is effective in controlling inflammatory reactions in dog skin and the effect may be partly due to its modulation of mast cell degranulation, but not to its PAF-antagonist properties. Drug Dev. Res. 44:49–55, 1998. © 1998 Wiley-Liss, Inc.