Preclinical efficacy and antiallergic profile of desloratadine, a potent histamine H1-receptor antagonist

Desloratadine is a novel antiallergic therapy for allergic rhinitis, chronic idiopathic urticaria and other allergic conditions. The studies reported here demonstrate the Potent antihistaminic and antiallergic effects as well as the exceptional safety profile of desloratadine. In vivo studies of antihistamine activity showed that orally administered desloratadine (median effective dose [ED50] = 0.15 mg/kg) was 2.5 to 4-fold more potent than loratadine in inhibiting histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Applied topically into the nose of guinea pigs, desloratadine (ED50 = 0.9 mug) was tenfold more potent than loratadine in blocking histamine-induced increases in nasal microvascular permeability. The antiallergic profile of desloratadine has been expanded by two recent studies. In vivo, orally administered desloratadine inhibited the increase in airway resistance and decrease in compliance in allergic cynomolgus monkeys challenged by inhaling the Ascaris suum antigen. Also, in allergic guinea pigs that cough in response to inhaled ovalbumin, desloratadine exhibited antitussive activity with an ED50 = 0.3 mg/kg. The safety of desloratadine has been demonstrated by numerous preclinical studies that have focused mainly on examining potential central nervous system or cardiovascular effects of desloratadine. In mice, desloratadine produced no behavioral, neurologic, or autonomic effects at doses up to 300 mg/kg. Furthermore, desloratadine did not protect mice from electroconvulsive shock, acetic-acid-induced writhing, or physostigmine-induced death. It is likely that desloratadine does not have access to histamine H, receptors in the brain that are linked to sedation because the in vivo administration of desloratadine to guinea pigs did not interfere with the subsequent binding of H-3-mepyramine to brain H-1 receptors in vitro. In cardiovascular studies, desloratadine at concentrations up to 10 muM did not inhibit the human ether-ago-go (HERG) K+ channel. Furthermore, studies in numerous animal species, including monkeys, indicated that desloratadine, even at large doses, did not alter heart rate, blood pressure, or the electrocardiogram, including QT(c), or QRS intervals. In radioligand receptor-binding assays utilizing cloned human H-1-receptor expressed in Chinese hamster ovary (CHO) cells, desloratadine binding affinity was at least 25 times and Up to 200 times more potent than terfenadine, fexofenadine, cetirizine, loratadine, ebastine, and mizolastine. Similar results were obtained from Ca-2 flux assays in CHO cells. Preclinical studies support clinical data that desloratadine is a potent antihistamine with multiple antiallergic effects and an excellent safety profile.