igmesine and Diarrhea

So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

Topics: Animals; Anxiety; Cinnamates; Clinical Trials as Topic; Cyclopropanes; Depression; Diarrhea; Disease Models, Animal; Humans; Ligands; MEDLINE; Opipramol; Receptors, sigma

Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound.. Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 microg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 microg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS.. Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED(50) values obtained using JO 2871 (1-20 microg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED(50) 50 microg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters.. JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release.

Topics: Animals; Antidiarrheals; Bacterial Toxins; Cinnamates; Cyclopropanes; Defecation; Diarrhea; Dose-Response Relationship, Drug; Ligands; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Pentazocine; Peptides, Cyclic; Pyrimidines; Receptors, sigma