Pharmacokinetic and pharmacodynamic evaluation of central effect of the novel antiallergic agent betotastine besilate.

Betotastine besilate (betotastine CAS 125602-71-3, TAU-284) is a novel antiallergic agent with histamine H1 receptor antagonistic activity. As the classical antihistamines are known to produce drowsiness, the present study was conducted to assess a possible influence of betotastine on the central nervous system (CNS). Measurement of the drug concentration in brain and plasma after i.v. administration revealed that betotastine, as well as cetirizine and epinastine, poorly penetrate into the CNS, while terfenadine do so slightly more and ketotifen remarkably more. In vitro receptor binding assays demonstrated that betotastine is a highly specific histamine H1 receptor ligand, having no significant binding affinity for histamine H3, adrenergic alpha 1, alpha 2, beta, dopamine D2L, serotonin 5-HT2, muscarinic, and benzodiazepine receptors. On global behavior of mice, oral administration of betotastine did not produce any marked changes at the doses of 100-1000 mg/kg, but suppressed huddling behavior at 1000 mg/kg and caused slight mydriasis at 300 mg/kg and more. Betotastine did not significantly affect spontaneous motor activity (SMA) and hexobarbital-induced anesthesia in mice up to 300 mg/kg p.o. In the sleep-wakefulness pattern of cats, it reduced the total duration of sleep at 10 mg/kg p.o., but did not show significant effect at 30 and 100 mg/ kg p.o. Cetirizine showed a similar profile as betotastine in these experiments, whereas ketotifen and epinastine induced sedative signs or toxic symptoms in lower doses, and terfenadine affected SMA and the anesthesia at a high dose. These results suggest the very low liability of betotastine to produce sedative side-effect in a therapeutic dose range.