Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle

Allergic conjunctivitis is the most common ocular allergic disease. Althoug h very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H-1 and muscarinic M-1 and M -3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adve rse anticholinergic effects after topical administration. In the present st udy, we compare the anticholinergic activity of desloratadine with other kn own muscarinic antagonists and antihistamines on rabbit and guinea-pie iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA( 2) = 6.67 +/- 0.09) of carbachol-induced contractions in isolated rabbit ir is smooth muscle. Atropine (pA(2) = 9.44 +/- 0.02) and NPC-14695 (pA(2) = 9 .18 +/- 0.03) also behaved as competitive antagonists, whereas tiotropium b romide (pD(2)' = 9.06 +/- 0.02) exhibited a non-competitive behaviour in th is tissue. Carebastine (pA(2) = 5.64 +/- 0.04) and fexofenadine (pA(2) < 4. 0) were also studied. After topical administration on the guinea-pig eve co njunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long last ing mydriasis (>120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ ml). Atropine (ED50 = 30 mu g/ml) and tiotropium bromide (ED50 = 10 mu g/ml ) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vi tro, and its potency and duration of action in vivo, suggest that topical t reatment of allergic conjunctivitis and rhinitis with desloratadine could p roduce undesirable peripheral anticholinergic side effects such as mydriasi s and xerostomia. (C) 1999 Elsevier Science B.V. All rights reserved.