ABSTRACT
We assessed and compared the effects of oral mitemcinal (an orally active, erythromycin-derived motilin-receptor agonist; Code name: GM-611), erythromycin, EM-574 and cisapride on gastric emptying in conscious Rhesus monkeys using the acetaminophen method. Mitemcinal and erythromycin induced significant, dose-dependent increases in indices of gastric emptying, but mitemcinal required a much lower dose for the same effect. Cisapride induced a bell-shaped dose response, and EM-574, a potent erythromycin derivative and originally developed as an enteric coated formulation, had little effect when it was given orally uncoated. Since our previous study showed that response to motilin is similar in Rhesus monkeys and humans, these results suggest that oral mitemcinal may be effective for the treatment of symptoms in human disorders related to delayed gastric emptying (e.g., functional dyspepsia and gastroparesis). Combined with the results of other studies, these results suggest that mitemcinal may be able to replace the withdrawn drug, cisapride, as the drug of choice for treating delayed gastric emptying.
Subject(s)
Cisapride/pharmacology , Erythromycin/analogs & derivatives , Erythromycin/pharmacology , Gastric Emptying/drug effects , Gastrointestinal Agents/pharmacology , Acetaminophen/metabolism , Administration, Oral , Analgesics, Non-Narcotic/metabolism , Animals , Cisapride/administration & dosage , Consciousness , Erythromycin/administration & dosage , Gastrointestinal Agents/administration & dosage , Macaca mulatta , MaleABSTRACT
Neither the presence of motilin receptors nor their action has been investigated in monkeys. The object of this study was to determine the effects of motilin and mitemcinal (GM-611), an erythromycin derivative, on the gastrointestinal tract in rhesus monkeys in vivo and in vitro. In in vivo investigations in conscious monkeys, both motilin and mitemcinal induced migrating motor complex-like contractions in the interdigestive state and also accelerated gastric emptying. In in vitro investigations, the presence of motilin receptors in the gastrointestinal tract was demonstrated by receptor binding assays. Motilin and mitemcinal contracted isolated duodenum strips in a concentration-dependent manner. In conclusion, rhesus monkeys may be useful for studying the physiological and pharmacological roles of the motilin agonistic mechanism because they show reactivity to motilin both in vivo and in vitro.
