EFFECTS OF EM574 AND CISAPRIDE ON GASTRIC CONTRACTILE AND EMPTYING ACTIVITY IN NORMAL AND DRUG-INDUCED GASTROPARESIS IN DOGS

EM574, an erythromycin derivative and potent motilin receptor agonist, is now undergoing clinical trials as a gastroprokinetic drug. The aim of this study was to compare the effect of EM574 with that of cisapri de on gastric motility and emptying in normal and gastroparesis dogs. Six dogs were each implanted with two duodenal cannulas for infusion o f phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Both solid and liquid gas tric emptying were determined by a novel freeze-drying method develope d in our laboratory. A freeze-dried standard meal (100 g, 400 kcal) wa s given with 100 mi normal saline containing 15 g of polyethylene glyc ol as a liquid marker. Gastric muscle contractility was measured by me ans of a force transducer implanted on the gastric antrum. EM574 (3-30 mu g/kg) and cisapride (0.3-3.0 mg/kg) were administered intraduodena lly at the start of feeding. Clonidine (3-30 mu g/kg) was injected sub cutaneously 15 min before feeding to induce gastroparesis. EM574 and c isapride both enhanced gastric muscle contractility in a dose-dependen t manner. EM574 (30 mu g/kg and 10 mu g/kg) significantly accelerated gastric emptying of solids and liquids, respectively, Cisapride (1 mg/ kg) significantly accelerated solid gastric emptying, but 3.0 mg/kg si gnificantly delayed liquid gastric emptying. Clonidine (10 and 30 mu g /kg) significantly delayed solid and liquid gastric emptying and reduc ed gastric muscle contractility. EM574, at a dose of 30 mu g/kg, compl etely restored solid and liquid gastric emptying and muscle contractil ity to the normal range in dogs with clonidine-induced gastroparesis. Cisapride(1 mg/kg) restored liquid gastric emptying in dogs with gastr oparesis to the normal range and partially restored solid emptying. EM 574 accelerated gastric muscle contractility and emptying of solids an d liquids in normal dogs. The stimulating activity of EM574 on gastric muscle contractility and emptying was comparable to that of cisapride , but EM574 was as effective as cisapride in normalizing gastric muscl e contractility and emptying in dogs with clonidine-induced gastropare sis.