Effects of Lerisetron, a New 5-HT3 Receptor Antagonist, on Ipecacuanha- induced Emesis in Healthy Volunteers

Abstract

The purpose of these studies was to evaluate the effect of lerisetron (1-phenyl-methyl-2-piperazinyl-1H-benzimidazole hydrochloride, CAS 143257-98-1, F-0930-RS2), a new 5-HT3 receptor antagonist, on ipecacuanha-induced nausea and vomiting. The ipecacuanha model of emesis has been used to test the anti-emetic activity of several different 5-HT3 antagonists and the anti-emetic doses that were effective in the ipecacuanha model have been found to correlate well with the clinically effective doses. Study 1 investigated oral doses of lerisetron from 4 mg to 40 mg. Study 2 evaluated the duration of effect of a single dose of 20 mg oral lerisetron. Study 3 evaluated intravenous doses of 18 mg and 12 mg lerisetron. In Study 1, the 40 mg dose of oral lerisetron inhibited emesis in all test subjects. The percentage of subjects who experienced an emetic episode increased as the dose of lerisetron decreased. At the lowest dose level tested five of six subjects had an emetic episode compared with four out of five in the placebo group. In Study 2, 20 mg oral lerisetron was effective up to 12 h after administration. When ipecacuanha was administered at 18 h post-dose three of seven subjects had an emetic episode and at 24 h post-dose the incidence of emesis was similar to the placebo treatment groups in the previous study. Study 3 demonstrated the effectiveness of intravenous doses of lerisetron. The 18 mg intravenous dose reduced the number of patients experiencing emetic episodes by 75% compared with placebo, doses below 12 mg i.v. were not evaluated because of the reduced efficacy of the compound at this dose level. In conclusion, lerisetron has been shown to be effective in the treatment of ipecacuanha-induced nausea and vomiting at intravenous doses of 18 mg and at oral doses of 20 mg for up to 12 hours.

Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure–Activity Relationship Studies, and Biological Assessment

“…Nor-astemizole is an active metabolite of astemizole with supposedly lower cardiac risks . Lerisetron, a related benzimidazole derivative, is an effective antagonist of the 5-HT 3 receptor and was used in clinical trials as a highly potent antiemetic drug . Very few reports are available in the literature regarding efforts toward improving the off-target activity (hERG) of Astemizole and Lerisetron derivatives…”