The pharmacological profile and initial clinical evaluation of tiacrilast (Ro 22-3747): a new antiallergic agent.

Tiacrilast (Ro 22-3747) is an allergic mediator release inhibitor which has demonstrated potent oral activity in two IgE-mediated animal models of immediate hypersensitivity: the rat passive cutaneous anaphylaxis test (ID50 of 0.65 mg/kg) and a model in which anaphylactic bronchospasm is induced in passively sensitized rats (ID50 of 0.022 mg/kg). In addition to oral efficacy, in the latter model Ro 22-3747 was 23-fold more potent than cromoglycate by the aerosol (nebulization) route of administration. In vitro studies have confirmed that the mechanism of action of Ro 22-3747 in the in vivo models is through allergic mediator release inhibition since Ro 22-3747 was a potent inhibitor of antigen-induced (IgE-mediated) histamine release from passively sensitized rat peritoneal cells in vitro (IC50 values of 0.25 and 1.5 microM for Ro 22-3747 and cromoglycate, respectively), and Ro 22-3747 did not display end organ antagonism to histamine, serotonin, or the leukotrienes. Clinical evaluations of Ro 22-3747 at a 350 mg oral dose have been conducted in patients with allergic asthma and allergic rhinitis. In a limited study in allergic asthmatics, Ro 22-3747 demonstrated significant inhibitory activity relative to placebo in reducing acute airway responses to inhaled pollen extracts in patients with ragweed sensitivity (measured by changes in log PD20 FEV1 and log PD35 SGaw). The activity seen, however, was less than that observed with cromoglycate (20 mg) administered by inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)