motilin and renzapride

Renzapride is a novel drug currently under clinical evaluation for the treatment of irritable bowel syndrome (IBS). Renzapride is a mixed 5-hydroxytryptamine type 4 (5-HT4) agonist and 5-HT3 receptor antagonist that has a stimulatory effect on gastrointestinal motility and transit, as established by in vivo and in vitro studies. Its therapeutic efficacy, tolerability and safety have been evaluated in diabetic gastroparesis in a single study, as well as in IBS in a few other studies. Phase II studies indicated potential beneficial effects on symptoms and bowel habits in patients with constipation-predominant IBS and mixed-type IBS. The outcome of Phase III studies is currently under evaluation.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Constipation; Gastrins; Humans; Irritable Bowel Syndrome; Motilin

Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5-Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a mu-opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate-induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cholecystokinin; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Indoles; Motilin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The effects of cisapride and renzapride (BRL 24924), on plasma concentration of motilin and gastroduodenal motility were studied in seven dogs with implanted force transducers in the antrum and duodenum. In the interdigestive state, the i.v. administration of cisapride (5 mg) or renzapride (5 mg) administered in phase I resulted in a prompt and marked increase in plasma motilin concentration and in gastroduodenal motility. Mean plasma motilin levels during the first 30 min after cisapride and after renzapride injection were 85.0 +/- 6.5 (+/- S.E.) and 96.1 +/- 6.3 pM., respectively. These values were significantly greater (P < .001) than those for the corresponding time period of the control cycle, 52.2 +/- 5.6 and 57.4 +/- 5.3 pM (mean phase III level, 120 +/- 8.1 pM), respectively. The increases in the motilin level after cisapride or renzapride coincided with significant increases in contractile activities of the antrum to 43.2 +/- 5.3% and 44.9 +/- 4.6% and of the duodenum to 28.4 +/- 3.1% and 34.2 +/- 2.2% of phase III activity (100%) from that in the corresponding control period, 0.7 +/- 0.4% and 0.2 +/- 0.1%, respectively. The changes in both plasma motilin and motility in response to the two drugs were abolished completely by the i.v. administration of atropine. The drugs also enhanced the meal-induced contractile activities of the antrum as well as the duodenum but failed to influence the postprandial plasma motilin concentration. We conclude that cisapride and renzapride have similar effects on plasma motilin and gastroduodenal motility: 1) the two drugs increase plasma motilin levels and stimulate gastroduodenal motility in the interdigestive state, and 2) in the digestive state, both drugs enhance motility without influencing the plasma motilin levels.

Topics: Animals; Anti-Ulcer Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Dogs; Gastrointestinal Motility; Motilin; Piperidines

We studied the effect of 5-hydroxytryptamine 3 (5-HT3) receptor antagonists on gastrointestinal (GI) motor activity in conscious dogs with force transducers implanted chronically. During the digestive state, GR38032F, BRL 43694 and ICS 205-930 did not affect GI motor activity at all at doses up to 1 mg/kg, whereas BRL 24924 at 1.0 mg/kg i.v. significantly stimulated GI motor activity from the stomach to the colon. When GR38032F, BRL 43694 or ICS 205-930 was given i.v. at doses of 0.1 to 1.0 mg/kg during the phase I period, no direct effect was observed on GI motor activity, but the treatment inhibited the occurrence of the subsequent phase III activity in the stomach completely and inhibited it partially in the duodenum without affecting the plasma motilin concentration. GR38032F, BRL 43694 and ICS 205-930 did not influence the caudal migration of phase III activity in the small intestine. In contrast, BRL 24924 at doses of 0.1 to 1.0 mg/kg i.v. significantly stimulated GI motor activity during the phase I period. On the other hand, when GR38032F, BRL 43694 or ICS 205-930 was given during natural or motilin-induced phase III activity, the total contractions in the stomach and partial contractions in the duodenum were inhibited but the caudal propagation of phase III activity in the small intestine was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Digestion; Dogs; Dose-Response Relationship, Drug; Female; Gastrointestinal Motility; Granisetron; Imidazoles; Indazoles; Indoles; Infusions, Intravenous; Injections, Intravenous; Male; Motilin; Motor Activity; Muscle Contraction; Muscle, Smooth; Ondansetron; Serotonin Antagonists; Time Factors; Tropisetron

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Gastrointestinal Motility; Granisetron; Imidazoles; In Vitro Techniques; Indazoles; Indoles; Motilin; Ondansetron; Rabbits; Serotonin Antagonists; Tropisetron