COMPARATIVE CENTRAL-NERVOUS-SYSTEM EFFECTS AND PHARMACOKINETICS OF NEU-METOCLOPRAMIDE AND METOCLOPRAMIDE IN HEALTHY-VOLUNTEERS

Metoclopramide, a drug used for the relief of nausea and emesis, is cu rrently under development as a radio- and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous s ystem side effects. Neu-metoclopramide (Neu-Sensamide), a novel, conce ntrated, phosphate-buffered, pH-adjusted (pH = 6.5-7.0) formulation of metoclopramide, has been shown to have an improved side-effect profil e in animal studies. The present double-blind, four-way crossover stud y compared the central nervous system effects and pharmacokinetics of neu-metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) wi th intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one becau se of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclop ramide administration, whereas 16, 15, and 6 such events were attribut ed to intravenous neu-metoclopramide, intramuscular neu-metoclopramide , and placebo, respectively. Extra-pyramidal effects occurred on 10 oc casions: 7 after intravenous metoclopramide, 2 after intravenous neu-m etoclopramide, and 1 after intramuscular neu-metoclopramide. No signif icant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore , that the molecular conformational changes inherent to neu-metoclopra mide result in a reduced side-effect profile compared with conventiona l metoclopramide formulations.