motilin and tegaserod

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

Gastrointestinal motility disorders represent a diagnostic and therapeutic challenge. Disorders of gastrointestinal motility may result in accelerated transit, delayed transit, impaired relaxation, or inappropriate relaxation. The delayed transit disorders are the most important motility disorders of companion animals and may involve the esophagus (hypomotility and megaesophagus), stomach (delayed gastric emptying), small intestine (postoperative ileus and intestinal pseudo-obstruction), or colon (constipation and megacolon).

Topics: Animals; Benzofurans; Cisapride; Dog Diseases; Dogs; Gastrointestinal Agents; Gastrointestinal Motility; Indoles; Intestinal Diseases; Motilin

Motilin or 5-HT4 receptor agonists stimulate gastrointestinal motility. Differences in activity are suggested but direct comparisons are few. A method was devised to directly compare the gastric prokinetic activities of motilin, the motilin receptor agonist, erythromycin, and the 5-HT4 receptor agonist, tegaserod.. Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergically-mediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses.. Rabbit motilin (r.motilin) 0.003-0.3 microM, [Nle13]motilin 0.003-0.3 microM, erythromycin 0.3-10 microM and tegaserod 0.1-10 microM caused concentration - dependent potentiation of EFS-evoked contractions. The potency ranking was r.motilin = [Nle13]motilin > tegaserod > erythromycin. The Emax ranking was r.motilin = [Nle13]motilin = erythromycin > tegaserod. Responses to r.motilin and [Nle13]motilin faded rapidly (t1/2 9 and 11 min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t1/2 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1 microM [Nle13]motilin were not different from those caused by the first application).. Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. This novel approach highlighted important differences between classes (greater Emax of motilin, compared with tegaserod) and for the first time, within each class (short t1/2 for motilin, compared with erythromycin).

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Electric Stimulation; Erythromycin; Gastrointestinal Agents; Gastrointestinal Motility; Half-Life; In Vitro Techniques; Indoles; Ligands; Male; Manometry; Motilin; Muscarinic Agonists; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Stimulation, Chemical