td-5108 and mosapride

Two-photon microscopy (2PM) can enable high-resolution deep imaging of thick tissue by exciting a fluorescent dye and protein at anastomotic sites in the mouse small intestine in vivo. We performed gut surgery and transplanted neural stem cells (NSC) from the embryonic central nervous system after marking them with the fluorescent cell linker, PKH26. We found that neurons differentiated from transplanted NSC (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSC (YFP [+]) could be localized within the granulation tissue of anastomoses. A 5-HT4-receptor agonist, mosapride citrate (MOS), significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P<0.005). The distribution patterns of PKH (+) neurons were similar to those of YFP (+) neurons. On the other hand, the 5-HT4-receptor antagonist, SB-207266 abolished these effects of MOS. These results indicate that neurogenesis from transplanted NSC is facilitated by activation of 5-HT4-receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than exclusive cell transplantation in treating Hirschsprung's disease and related disorders including post rectal cancer surgery. The underlying mechanisms for its action were explored using immunohistochemistry of the longitudinal mouse ileum and rat rectal preparations including an anastomosis. MOS significantly increased the number of new neurons, but not when co-administered with either of a protein tyrosine kinase receptor, c-RET two inhibitors. The c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS. In the future, we would perform functional studies of new neurons over the thick granulation tissue at anastomoses, using in vivo imaging with 2PM and double transgenic mice expressing a calcium indicator such as GCaMP6 and channelrhodopsin.

Topics: Anastomosis, Surgical; Animals; Benzamides; Cell Differentiation; Enteric Nervous System; Granulation Tissue; Guinea Pigs; Hirschsprung Disease; Humans; Intestine, Small; Mice; Morpholines; Neural Stem Cells; Neurogenesis; Neurons; Proto-Oncogene Proteins c-ret; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Signal Transduction

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT(4) receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT(4) receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT(4) receptors which may be post-synaptically located in the myenteric plexus of the anorectum.

Topics: Anal Canal; Animals; Benzamides; Defecation; Denervation; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Lumbosacral Plexus; Morpholines; Rectum; Reflex; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Stimulation, Chemical

Impaired gastric accommodation is one of the major features of functional dyspepsia. Mosapride citrate is a 5-hydroxytryptamine receptor 4 (5-HT4) agonist, which is shown to improve upper abdominal symptoms. However, effect of mosapride on gastric accommodation was not clear. We tested the hypothesis that mosapride enhances the gastric accommodation in normal individuals.. Fourteen male healthy volunteers completed this study. Single administration of mosapride or placebo was performed randomly with more than 1-week interval. Subjects swallowed a triple-lumen polyvinyl tube with a polyethylene bag. The bag was positioned in the proximal stomach and the minimal distending pressure (MDP) was determined. The ramp distension starting from the MDP was then performed and subjects were instructed to score their perception using ordinate scales. Next the intra-bag pressure was set at MDP + 2 mmHg and a liquid meal was administered 30 min later, and the intra-bag volume was recorded for 60 min. We compared the MDP, perception scores, and the intra-bag volume changes by administering placebo and mosapride.. Minimal distending pressure was not significantly different in subjects receiving mosapride or placebo. Treatment with mosapride had no effect on intra-bag pressures or volumes inducing first sensation or discomfort. Gastric accommodation, expressed as the difference between pre- and postmeal intra-bag volumes, and the percent change of the intra-bag volumes by the meal was significantly enhanced by mosapride compared with placebo.. This is the first study clearly demonstrating that single administration of 5-HT4 agonist can enhance gastric accommodation in humans. (Umin.ac.jp, number UMIN000014063).

Topics: Adult; Benzamides; Cross-Over Studies; Double-Blind Method; Gastrointestinal Motility; Humans; Male; Morpholines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stomach; Young Adult

Mosapride citrate, a selective agonist of the 5-hydroxytryptaine (5-HT)₄ receptor, is typically used to treat heartburn, nausea, and vomiting associated with chronic gastritis or to prepare for a barium enema X-ray examination. Mosapride citrate reportedly improves insulin sensitivity in patients with type 2 diabetes. As mosapride citrate activates the motility of the gastrointestinal tract, we hypothesized that mosapride citrate affects incretin secretion. We examined the effect of the administration of mosapride citrate on the plasma glucose, serum insulin, plasma glucagon, and plasma incretin levels before breakfast and at 60, 120, and 180 min after breakfast in men with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) to exclude gastropathy. Mosapride citrate was administered according to two different intake schedules (C: control (no drug), M: mosapride citrate 20 mg) in each of the subject groups. The area under the curve (AUC) of the plasma glucose levels was smaller in the M group than in the C group. The time profiles for the serum insulin levels at 60 and 120 min after treatment with mosapride citrate tended to be higher, although the difference was not statistically significant. The AUCs of the plasma active and total glucagon-like peptide-1 (GLP-1) levels were significantly larger in the M group than in the C group. No significant difference in the AUC of the plasma glucose-dependent insulinotropic polypeptide (GIP) level was observed between the two groups. Our results suggest that mosapride citrate may have an antidiabetic effect by increasing GLP-1 secretion.

Topics: Adult; Benzamides; Blood Glucose; Gastric Inhibitory Polypeptide; Gastrointestinal Agents; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Morpholines; Postprandial Period; Serotonin 5-HT4 Receptor Agonists; Up-Regulation

The 5-HT(4) receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS).. Thirty-seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n=19) or placebo (n=18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10-min period.. The pain threshold in the patients was significantly lower than that in controls (P<0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P<0.01; group × period interaction by two-way anova) and increased the mean number of contractions (P<0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea-predominant subjects), mosapride (n=13) increased rectosigmoid tone (P<0.01) and contractions (P<0.05) more than placebo (n=14).. Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.

Topics: Adult; Animals; Benzamides; Colon, Sigmoid; Female; Gastrointestinal Motility; Humans; Irritable Bowel Syndrome; Male; Manometry; Morpholines; Pain Perception; Receptors, Serotonin, 5-HT4; Rectum; Serotonin 5-HT4 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Young Adult

Mosapride citrate is a novel selective 5-HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K(+) channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrate's effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinson's disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre- and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Student's t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects.

Topics: Aged; Benzamides; Colon; Constipation; Female; Functional Laterality; Gastrointestinal Transit; Humans; Male; Middle Aged; Morpholines; Parkinson Disease; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Video Recording

To evaluate the efficiency of the 5-HT4 agonist and 5-HT3 antagonist mosapride, as compared with cisapride, on oesophageal acid reflux variables and oesophageal motor function in patients with chronic gastro-oesophageal reflux disease (GORD).. Forty-one patients with proven GORD were included in a double-blind, randomised, double-dummy, three-way crossover study. All patients received mosapride 60 mg twice daily, mosapride 30 mg three times daily, and cisapride 20 mg twice daily for seven days in a randomised order, separated by a washout period of at least five days. Twenty-three patients underwent four combined ambulatory 24-h motility and pH recordings within two weeks before the start of treatment and on day seven of each treatment period. The remaining 18 patients underwent three ambulatory 24-h pH recordings only, i.e. on treatment day seven of each treatment period.. Mosapride had no significant effect on the total number of contractions in the oesophagus, or on the effectiveness, or possible effectiveness, of the propagations. Significant but numerically small effects on peristaltic durations and amplitudes were noted during both mosapride and cisapride treatment as compared with baseline values. The effect on acid reflux for both mosapride and cisapride was most pronounced for the duration of the longest reflux episode. The fraction of time with pH less than 4 was reduced by mosapride 30 mg three times daily in the supine position and by cisapride both totally and in the supine position. The number of reflux episodes was reduced significantly only by cisapride. Oesophageal clearance was reduced significantly by cisapride only in the supine position.. Mosapride had small but statistically significant effects, comparable to those of cisapride, on acid reflux variables and oesophageal motor function in patients with GORD.

Topics: Adult; Aged; Benzamides; Cisapride; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Esophagus; Female; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Hydrogen-Ion Concentration; Male; Manometry; Middle Aged; Morpholines; Peristalsis; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

To synthesize the new bioactive metabolites of mosapride (R)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]-propyl-5-chlorine-4-amino-2-ethoxyben-zamide (R-isomer) and (S)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]-propyl-5-chlorine-4-amino-2-ethoxybenzamide (S-isomer) and evaluate their in vitro and in vivo pharmacological and pharmacokinetic profiles.. S-isomer as a gastroprokinetic agent showed significant pharmacological activities in vivo. Furthermore, compared with the EC. S-isomer might have great potential as a safe and effective prokinetic agent capable of lessening gastrointestinal symptoms and increasing quality of life.

Topics: Animals; Benzamides; Gastrointestinal Absorption; Gastrointestinal Agents; Male; Mice; Molecular Structure; Morpholines; Peristalsis; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism

An orally administered serotonin-4 (5-HT4) receptor agonist, mosapride citrate (MOS), promotes enteric neurogenesis in anastomoses after gut surgery. We performed gut surgery and transplanted 2 × 10(5) neural stem cells (NSCs) from the embryonic central nervous system after marking them with the cell linker, PKH26. We found that neurons differentiated from transplanted NSCs (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSCs (YFP [+]) in the deep granulation tissue of the anastomotic ileum. MOS significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P < 0.005) (n = 4). The distribution patterns of PKH (+) neurons and YFP (+) neurons were similar along the depth of the anastomosis. A 5-HT4 receptor antagonist, SB-207266, abolished these effects of MOS (n = 4). Our results indicate that neurogenesis from transplanted NSCs is potentiated by activation of 5-HT4 receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than cell transplantation alone in treating Hirschsprung's disease and related disorders.

Topics: Anastomosis, Surgical; Animals; Antibodies; Benzamides; Fluorescent Dyes; Ileum; Immunohistochemistry; Mice; Mice, Transgenic; Morpholines; Neural Stem Cells; Neurogenesis; Organic Chemicals; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Ubiquitin Thiolesterase

Acute administration of 5-hydroxytryptamine4 (5-HT4) receptor agonist, mosapride or esophageal infusion of the transient receptor potential vanilloid receptor-1 (TRPV1) agonist capsaicin promotes secondary peristalsis. We aimed to investigate whether acute esophageal instillation of capsaicin-containing red pepper sauce or administration of mosapride has different effects on the physiological characteristics of secondary peristalsis.. Secondary peristalsis was induced with mid-esophageal air injections in 14 healthy subjects. We compared the effects on secondary peristalsis subsequent to capsaicin-containing red pepper sauce (pure capsaicin, 0.84 mg) or 40 mg oral mosapride.. The threshold volume for generating secondary peristalsis during slow air distensions was significantly decreased with capsaicin infusion compared to mosapride (11.6 ± 1.0 vs. 14.1 ± 0.8 mL, P = 0.02). The threshold volume required to produce secondary peristalsis during rapid air distension was also significantly decreased with capsaicin infusion (4.6 ± 0.5 vs. 5.2 ± 0.6 mL, P = 0.02). Secondary peristalsis was noted more frequently in response to rapid air distension after capsaicin infusion than mosapride (80% [60-100%] vs. 65% [5-100%], P = 0.04). Infusion of capsaicin or mosapride administration didn't change any parameters of primary or secondary peristalsis.. Esophageal infusion with capsaicin-containing red pepper sauce suspension does create greater mechanosensitivity as measured by secondary peristalsis than 5-HT4 receptor agonist mosapride. Capsaicin-sensitive afferents appear to be more involved in the sensory modulation of distension-induced secondary peristalsis.

Topics: Adult; Benzamides; Capsaicin; Capsicum; Esophagus; Female; Heartburn; Humans; Male; Manometry; Morpholines; Peristalsis; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; TRPV Cation Channels

MP 3950 is an active metabolite of mosapride which exhibits high 5-HT4 receptor agonistic effect. The present paper describes an enantioselective chiral HPLC method for separation and quantification of MP 3950 enantiomers in rat plasma. The plasma samples were prepared by liquid-liquid extraction with ethyl acetate and the baseline chromatographic separation was achieved on a Chiralcel OJ-H column with a mobile phase consisting n-hexane/ethanol/methanol/diethylamine (85:5:10:0.4, v/v/v/v) at the flow rate of 1.0mL/min. The ultraviolet detection was performed at 276nm. The calibration curve was linear in the range from 0.100 to 5.00μg/mL with the lower limit of quantification of 0.100μg/mL for each enantiomer. The intra- and inter-day precisions were not more than 14.7%. The accuracy was from -6.4% to 14.0%. The validated method was successfully applied to chiral inversion and stereoselective pharmacokinetic study in rats after oral administration of MP 3950 racemate. The results indicated that no stereochemical inversion was occurred in rats. And the plasma concentrations and area under plasma concentration-time curve of (S)-MP 3950 were all significantly higher than those of (R)-MP 3950 in both male and female rats, which indicated that the disposition of MP 3950 in rats might be stereoselective.

Topics: Animals; Area Under Curve; Benzamides; Chromatography, High Pressure Liquid; Female; Limit of Detection; Male; Morpholines; Rats; Reproducibility of Results; Sensitivity and Specificity; Serotonin 5-HT4 Receptor Agonists; Stereoisomerism

We previously reported that a serotonin 4 (5-HT4) receptor agonist, mosapride citrate (MOS), increased the number of c-RET-positive cells and levels of c-RET mRNA in gel sponge implanted in the necks of rats. The 5-HT4 receptor is a G protein coupled receptor (GPCR) coupled to G protein Gs-cAMP cascades. We investigated the possibility that 5-HT4 receptor activation induced c-RET activation and/or PKA activation by elevating cAMP levels. Rodents were orally administered MOS by adding it to drinking water for 2 weeks after enteric nerve circuit insult via gut transection and anastomosis, together with the RET inhibitors withaferin A (WA) and RPI-1 or the PKA inhibitor H89. We then examined PGP9.5-positive cells in the newly formed granulation tissue at the anastomotic site. MOS significantly increased the number of new neurons, but not when co-administered with WA or RPI-1. Co-administration of H89 failed to alter MOS-induced increases in neurogenesis. In conclusion, the c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS, though the contribution of PKA activation seems unlikely.

Topics: Anastomosis, Surgical; Animals; Benzamides; Enteric Nervous System; Female; Ileum; Indoles; Male; Mice; Mice, Inbred BALB C; Models, Neurological; Morpholines; Neurogenesis; Proto-Oncogene Proteins c-ret; Rats; Rats, Wistar; Receptor Protein-Tyrosine Kinases; Serotonin 5-HT4 Receptor Agonists; Signal Transduction; Ubiquitin Thiolesterase; Withanolides

Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

Topics: Animals; Benzamides; Blood Glucose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Morpholines; Piperidines; Serotonin 5-HT4 Receptor Agonists; Uracil

Mosapride citrate hydrate (mosapride) has been known to act as a 5-HT4 agonist and to enhance gastric emptying. However, its mode of action, such as time course and dosage effect, on gastric emptying has not been clarified. This study aimed to clarify these points by the breath test using [1-(13)C]acetic acid in conscious rats. Mosapride significantly and dose-dependently enhanced the gastric emptying increased Cmax and AUC120 min at doses between 0.1 and 3 mg/kg. Pre-treatment with GR113808 (5-HT4 antagonist) significantly attenuated the enhancement of gastric emptying by mosapride. On the contrary, at a dose of 30 mg/kg, mosapride significantly inhibited the gastric emptying. The major metabolite (M1: 5-HT3 receptor antagonist) significantly inhibited gastric emptying at doses of 19.2 and 64.1 mg/kg (equimolar to 30 and 100 mg/kg of mosapride, respectively), suggesting that the inhibitory effect by mosapride may be caused at least in part by the 5-HT3 receptor antagonistic effect of M1. These findings show that mosapride has dual role on the gastric emptying and may support the usefulness of mosapride for the therapy of postprandial distress syndrome such as early satiation and postprandial fullness.

Topics: Acetic Acid; Animals; Benzamides; Breath Tests; Carbon Radioisotopes; Depression, Chemical; Dose-Response Relationship, Drug; Gastric Emptying; Indoles; Male; Morpholines; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Stimulation, Chemical; Sulfonamides

Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. The aim of this study was to investigate the effects of different 5-hydroxytryptamine 4 (5-HT₄) receptor agonists, which stimulate excitatory pathways, on a POI model.. The experimental model of POI in guinea pigs was created by laparotomy, gentle manipulation of the cecum for 60 seconds, and closure by suture, all under anesthesia. Different degrees of restoration of GI transit were measured by the migration of charcoal. Colonic transit was indirectly assessed via measurement of fecal pellet output every hour for 5 hours after administration of various doses of mosapride, tegaserod, prucalopride, and 5-HT.. Charcoal transit assay showed that various 5-HT₄ receptor agonists can accelerate delayed upper GI transit in a dose-dependent manner. However, fecal pellet output assay suggested that only prucalopride had a significant effect in accelerating colonic motility in POI.. Although mosapride, tegaserod, and prucalopride produce beneficial effects to hasten upper GI transit in the POI model, prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig. This drug may serve as a useful candidate for examination in a clinical trial for POI.

Topics: Administration, Oral; Animals; Benzamides; Benzofurans; Charcoal; Colon; Dose-Response Relationship, Drug; Gastrointestinal Motility; Guinea Pigs; Ileus; Indoles; Laparotomy; Male; Morpholines; Postoperative Complications; Serotonin; Serotonin 5-HT4 Receptor Agonists

Although selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, they frequently cause gastrointestinal adverse effects, such as nausea and emesis. In the present study, we investigated the anti-emetic effect of mosapride, a 5-HT(4) receptor agonist, on SSRIs-induced emesis in Suncus murinus and dogs. We also examined the effect of mosapride on SSRIs-induced delay in gastric emptying and increase in gastric vagal afferent activity in rats. Oral administration of paroxetine, but not its subcutaneous administration, dose-dependently caused emesis in both animals. Mosapride inhibited paroxetine-induced emesis in Suncus murinus and dogs with ID(50) values of 7.9 and 1.1 mg/kg, respectively. The anti-emetic effect of mosapride was partially inhibited by SB207266, a selective 5-HT(4) antagonist. Intragastric administration of paroxetine increased gastric vagal afferent discharge in anesthetized rats. Mosapride failed to suppress this increase. On the other hands, mosapride improved the delay in gastric emptying caused by paroxetine in rats. We have shown in this study that oral administration of SSRIs causes emesis and activates gastric vagal afferent activity in experimental animals and that mosapride inhibits SSRIs-induced emesis, probably via improvement of SSRIs-induced delay in gastric emptying. These findings highlight the promising potential of mosapride as an anti-emetic agent.

Topics: Administration, Oral; Afferent Pathways; Animals; Benzamides; Dogs; Dose-Response Relationship, Drug; Gastric Emptying; Male; Morpholines; Paroxetine; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT4 Receptor Agonists; Shrews; Stomach; Vagus Nerve; Vomiting

It was recently reported that activation of enteric neural 5-HT(4) receptors (SR4) promotes reconstruction of enteric neural circuit injury in distal gut of guinea pigs and that this reconstruction involves neural stem cells. We aimed to explore a novel approach using a selective serotonin reuptake inhibitor (SSRI), which increases endogenous 5-HT, to repair enteric nerve fiber injury in the rat distal gut. Enteric nerve fiber injury was performed by rectal transection and subsequent end-to-end one-layer anastomosis. The SSRI fluvoxamine maleate (100 μmol/l) was applied locally at the anastomotic site to compare with the 5-HT(4) agonist mosapride citrate (100 μmol/l) (applied for patent) applied locally and orally. Unlike mosapride, fluvoxamine failed to promote the regeneration of the nerve fiber tract across the anastomosis. Furthermore, fluvoxamine did not generate anti-distal-less homeobox 2 (DLX2)- and anti-SR4-positive cells (neural stem cells) and/or anti-neurofilament (NF)-positive cells (neural cells) in newly formed granulation tissue at the anastomosis, whereas these cell types were observed in mosapride-treated preparations. In contrast to its effects in guinea pigs, mosapride generated 5-bromo-2'-deoxyuridine (BrdU)-positive neural cells in ganglia sites 3 mm oral and anal from the anastomosis 2 wk after nerve fiber injury. All actions of mosapride were observed after local and or oral applications. These findings indicate that local SSRI treatment does not induce in vivo nerve fiber tract growth across the anastomosis in the rat distal gut. Mosapride induces nerve fiber tract growth across the anastomosis, mediated through enteric neural stem cells possibly from neural crest-derived stem cells or mesenchymal stem cells in the bone marrow.

Topics: Administration, Topical; Anastomosis, Surgical; Animals; Benzamides; Defecation; Fluvoxamine; Guinea Pigs; Male; Morpholines; Nerve Fibers; Neurogenesis; Rats; Rectum; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT4 Receptor Agonists

Mosapride citrate is known to affect gastric motility. However, whether mosapride citrate has any effect on visceral pain in the colon or rectum is not certain. The aim of this study was to assess the effects of mosapride citrate on visceral pain in a rat visceral hypersensitivity model.. The perception of visceral pain was evaluated by the visceromotor response to colorectal distension observed on electromyographs of the abdominal musculature in urethane-anesthetized rats. Visceral hypersensitivity was induced by the intrarectal instillation of 4% acetic acid or 1.5% zymosan. Mosapride citrate was administered intraperitoneally 3 h later. VMRs to CRD were recorded prior to the instillation of acetic acid or zymosan and before and after mosapride citrate treatment.. The intracolonic instillation of acetic acid resulted in a significant increase in VMRs of the abdominal muscles to CRD, compared with the pretreatment state (174 ± 24%, P < 0.05). The intracolonic instillation of zymosan resulted in a significant increase in VMRs of the abdominal muscles to CRD, compared with the pretreatment state (144 ± 9%, P < 0.05). Intraperitoneal injection of mosapride citrate resulted in a significant reduction in the VMRs to CRD in an acetic acid-induced visceral hypersensitivity rat model (61 ± 9%, P < 0.05). The intraperitoneal injection of mosapride citrate also resulted in a significant reduction in the VMRs to CRD in a zymosan-induced visceral hypersensitivity rat model (67 ± 9%, P < 0.05).. Mosapride citrate diminished visceral pain in rats.

Topics: Animals; Benzamides; Disease Models, Animal; Electromyography; Gastrointestinal Motility; Hypersensitivity; Injections, Intraperitoneal; Male; Morpholines; Pain Measurement; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Visceral Pain

We investigated the activity of NO-synthases, lipoperoxidation processes, antioxidant defense enzymes in the muscular layers of stomach and large intestine. The L-arginine concentration in blood plasma was also monitored under conditions of 2-weeks activation of 5-HT4 receptors by mosaprid in streptozocin-induced diabetes mellitus. We showed that the onset of diabetes mellitus is accompanied by a 2.4-2.8-fold increase in the activity of inducible NO-synthase and a 23-40% increase in the SOD activity. The nitric oxide content and TBA products in the muscular layers of stomach and large intestine were increased, whereas the motor-evacuational function of the stomach and large intestine decreased. Activation of 5-HT4 receptors by mosaprid under conditions of diabetes mellitus decreased the activity of inducible NO-synthase, the lipoperoxidation processes, nitrite anion content and TBA products in muscular layers of stomach and large intestine by 23%. At the same time, we observed an increase in the motor-evacuational function of stomach and large intestine without affecting the blood sugar level.

Topics: Animals; Benzamides; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Gastric Mucosa; Humans; Intestine, Large; Lipid Peroxidation; Male; Morpholines; Muscle, Smooth; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Rats; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Stomach; Streptozocin; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.

Topics: Analgesics, Opioid; Animals; Benzamides; Brain Stem; Chronic Disease; Indoles; Ligation; Male; Mice; Mice, Inbred ICR; Morphine; Morpholines; Pain; Peripheral Nervous System Diseases; Receptors, Serotonin, 5-HT4; Respiration; Respiratory Insufficiency; Sciatic Nerve; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Sulfonamides

The main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT₄R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI.. To determine the effects of the 5-HT₄R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI.. Intestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured.. After IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 β (IL-1β), IL-6, tumour necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the α7-nicotinic acetylcholine receptor (α7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, α7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine.. Stimulating the 5-HT₄R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates α7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT₄R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Aminopyridines; Animals; Benzamides; Cholinergic Fibers; Disease Models, Animal; Drug Evaluation, Preclinical; Gastrointestinal Transit; Ileum; Ileus; Imidazoles; Inflammation Mediators; Macrophages; Male; Morpholines; Muscle Contraction; Muscle, Smooth; Myenteric Plexus; Neutrophil Infiltration; Postoperative Complications; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Tissue Culture Techniques

Using an embryoid body (EB) culture system, we developed a functional organ-like cluster, a "gut", from mouse embryonic stem (ES) cells (ES gut). Each ES gut exhibited various types of spontaneous movements. In these spontaneously contracting ES guts, dense distributions of interstitial cells of Cajal (ICC) (c-kit, a transmembrane receptor that has tyrosine kinase activity, positive cells; gut pacemaker cells) and smooth muscle cells were discernibly identified, but enteric neural networks were not identified. In the present study, we succeeded in forming dense enteric neural networks by a 5-HT(4)-receptor (SR4) agonist, mosapride citrate (1-10 μM) added only during EB formation. Addition of an SR4-antagonist, GR113808 (10 μM) abolished the SR4-agonist-induced formation of enteric neural networks. The SR4-agonist (1 μM) up-regulated the expression of mRNA of SR4 and the SR4-antagonist abolished this upregulation. 5-HT per se exerted similar effects to those of SR4-agonist, though less potent. These results suggest SR4-agonist differentiated enteric neural networks, mediated via activation of SR4 in the ES gut.

Topics: Animals; Benzamides; Cell Culture Techniques; Cells, Cultured; Embryonic Stem Cells; Gastrointestinal Tract; Mice; Morpholines; Nerve Net; Neurogenesis; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold.

Topics: Abdominal Pain; Analgesics, Non-Narcotic; Animals; Benzamides; Benzyl Compounds; Dose-Response Relationship, Drug; Dyspepsia; Gastric Dilatation; Gastrointestinal Agents; Gastrointestinal Motility; Granisetron; Male; Morpholines; Random Allocation; Rats; Rats, Wistar; Reflex, Abdominal; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Stomach

The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT(4) agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).. Acute gastric ulcers were induced in rats by the oral administration of indomethacin.. Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT(4) agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT(4)-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of alpha7 nicotinic acetylcholine (ACh) receptors (alpha7nAChRs), ablated the antiulcerogenic action of mosapride.. These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT(4) receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the alpha7nAChR may be involved in the antiulcerogenic action of mosapride.

Topics: Acetylcholine; Administration, Oral; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Dose-Response Relationship, Drug; Gastric Mucosa; Indomethacin; Morpholines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Stomach Ulcer

It was recently reported that some 5-HT(4)-receptor agonists increased neuronal numbers and length of neurites in enteric neurons developing in vitro from immunoselected neural crest-derived precursors. We aimed to explore a novel approach in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex.. The neural circuit insult was performed in guinea pigs by rectal transection and subsequent end-to-end one layer anastomosis. A 5-HT(4)-receptor agonist, mosapride citrate (10-100 micromol L(-1)) (applied for a patent) was applied locally at the anastomotic site.. Mosapride promoted the regeneration of the neural circuit in the impaired myenteric plexus and the recovery of the defecation reflex in the distal gut. Furthermore, mosapride generated neurofilament (NF)-, 5-HT(4)-receptor- and 5-bromo-2'-deoxyuridine (BrdU)-positive cells and surprisingly formed neural network in the newly formed granulation tissue at the anastomotic site 2 weeks after enteric nerve circuit insult. Possible neural stem cell markers, anti-distal less homeobox 2 (DLX2)- and p75-positive and NF-positive cells increased during the same time period. All actions by mosapride were inhibited by the specific 5-HT(4)-receptor antagonist, GR113808 (10 micromol L(-1)).. These results indicate that activation of enteric neural 5-HT(4)-receptors promotes reconstruction of an enteric neural circuit leading to the recovery of the defecation reflex in the distal gut, and that this reconstruction involves possibly neural stem cells. These findings indicate that treatment with 5-HT(4) agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic gut disorders.

Topics: Animals; Benzamides; Defecation; Enteric Nervous System; Epithelial Cells; Gastrointestinal Agents; Guinea Pigs; Immunohistochemistry; Indoles; Male; Mesenchymal Stem Cells; Morpholines; Nerve Fibers; Nerve Regeneration; Neural Crest; Neural Pathways; Neuronal Plasticity; Reflex; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists; Stem Cells; Sulfonamides

Polyethylene glycol electrolyte lavage solution (PEG-ELS) is widely used for colon cleansing prior to colonoscopy and colonic surgery. It has recently been shown that coadministration of PEG-ELS and mosapride citrate hydrate (mosapride), a selective 5-HT(4)-receptor agonist, is clinically useful for barium enema examination as it allows adequate barium coating. However, there is no report showing that mosapride has beneficial effects on colon cleansing and its underlying mechanism in experimental animals. In the present study, we investigated the effects of mosapride on colonic transit and on the colon cleansing action of PEG-ELS in guinea pigs. Mosapride (10 - 20 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs. Although PEG-ELS alone showed adequate colon cleansing action, excess fluid remained in the colon. Coadministration of mosapride (20 mg/kg) and PEG-ELS, regardless of mosapride timing, reduced colonic content weight (dry residue and water amount) as compared to PEG-ELS alone. These findings suggest that mosapride enhances the colon cleansing action of PEG-ELS via an increase in colonic transit in guinea pigs, that is, it reduces not only fecal residue but also excessive fluid in the colonic lumen. It is therefore believed that coadministration of mosapride and PEG-ELS can allow better visualization in barium enema examination.

Topics: Animals; Benzamides; Colon; Colonoscopy; Dose-Response Relationship, Drug; Electrolytes; Gastrointestinal Transit; Guinea Pigs; Male; Morpholines; Polyethylene Glycols; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Therapeutic Irrigation

The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT(4) receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT(4) receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptor (pEC(50) = 8.3) and 5-HT(4) receptor-mediated relaxation of the rat esophagus (pEC(50) = 7.9) and contraction of the guinea pig colon (pEC(50) = 7.9). In all in vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pK (i) = 7.7) and selectivity (> or =25-fold) for h5-HT(4(c)) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT(2B) and h5-HT(3A)) and, at 3 microM, had no effect on human ether-à-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT(4) receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.

Topics: Animals; Azabicyclo Compounds; Benzamides; Cell Line; Cisapride; Colon; Cyclic AMP; Esophagus; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Humans; Indoles; Kidney; Morpholines; Protein Binding; Rats; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Moderate rectal distension elicits recto-rectal reflex contractions and simultaneous recto-internal anal sphincter reflex relaxations that together comprise the defecation reflex. Both reflexes are controlled by 1) pelvic nerves, 2) lumbar colonic nerves, and 3) enteric nervous system. The aim of the present study was to explore a novel approach to repairing the defecation reflex dysfunction by using the plasticity of enteric nervous pathways. Experiments were performed in anesthetized guinea pigs with ethyl carbamate. The rectum 30 mm oral from the anal verge was transected without damage to extrinsic nerves, and subsequent end-to-end one-layer anastomosis was performed. Recovery of the defecation reflex and associated reflex pathways were evaluated. Eight weeks after sectioning of intrinsic reflex nerve pathways in the rectum, the defecation reflex recovered to the control level, accompanied with regeneration of reflex pathways. The 5-HT(4)-receptor agonist mosapride (0.5 and 1.0 mg/kg) significantly (P < 0.01) enhanced the recovered defecation reflex 8 wk after surgery. Two weeks after local treatment with brain-derived neurotrophic factor (BDNF: 10(-6) g/ml) at the rectal anastomotic site, the recto-internal anal sphincter reflex relaxations recovered and some bundles of fine nerve fibers were shown to interconnect the oral and anal ends of the myenteric plexus. These results suggested a possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system with local application of BDNF.

Topics: Anal Canal; Anastomosis, Surgical; Animals; Benzamides; Brain-Derived Neurotrophic Factor; Cell Proliferation; Defecation; Dose-Response Relationship, Drug; Enteric Nervous System; Gastrointestinal Agents; Guinea Pigs; Homeodomain Proteins; Immunohistochemistry; Male; Morpholines; Nerve Regeneration; Nerve Tissue Proteins; Neurofilament Proteins; Neuronal Plasticity; Pressure; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-kit; Receptor, trkB; Receptors, Growth Factor; Receptors, Nerve Growth Factor; Recovery of Function; Rectum; Reflex; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Time Factors; Transcription Factors

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.

Topics: Administration, Oral; Animals; Azabicyclo Compounds; Benzamides; Cisapride; Colon; Dogs; Dose-Response Relationship, Drug; Esophagus; Female; Gastrointestinal Transit; Guinea Pigs; Indoles; Male; Morpholines; Muscle Contraction; Muscle, Smooth; Rats; Rats, Sprague-Dawley; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

The blocking effect of three 5-HT(4) agonists, cisapride, mosapride, and the newly discovered CJ-033466 on the human ether-a-go-go-related gene (hERG) channel was studied using a whole cell patch-clamp technique in HEK293 cells. Cisapride was found to be the most potent of the hERG blockers. CJ-033466 had the widest safety margin between its hERG blocking activity and 5-HT(4) agonism among the tested compounds. This suggests a lower clinical risk of cardiac arrhythmia in CJ-033466 compared with the other 2 agonists. Therefore, CJ-033466 has the potential to be a drug with higher therapeutic efficacy and less cardiac risk than both cisapride and mosapride.

Topics: Aminopyridines; Arrhythmias, Cardiac; Benzamides; Cell Line; Cisapride; Electrophysiology; Ether-A-Go-Go Potassium Channels; Humans; Imidazoles; Inhibitory Concentration 50; Morpholines; Patch-Clamp Techniques; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Irritable bowel syndrome is a functional gastrointestinal disorder characterized by abnormal sensation and motility in the lower gastrointestinal tract. In constipation-type irritable bowel syndrome, decreased bowel motility causes stagnation of feces and gas, resulting in enhanced pain sensation of the bowel. Mosapride citrate is a selective serotonin 5- HT4 receptor agonist and enhances propulsive activity throughout the gastrointestinal tract. Mosapride citrate was orally administered to 11 patients with constipation-type irritable bowel syndrome to investigate its effect on this disease. The result showed that mosapride citrate alleviated abdominal pain and abdominal distension, loosened stools, shortened bowel transit time, and decreased flatus in the bowel. The results suggest that mosapride citrate is useful for the treatment of irritable bowel syndrome.

Topics: Benzamides; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Morpholines; Serotonin 5-HT4 Receptor Agonists

Distension-evoked reflex of rectorectal (R-R) contractions and rectointernal anal sphincter (R-IAS) relaxations can be generated in guinea pigs through an extrinsic sacral excitatory neural pathway (pelvic nerves) as well as intrinsic cholinergic excitatory and nitrergic inhibitory pathways. The aim of the present study was to create intrinsic R-R and R-IAS reflex models by pithing (destruction of the lumbar and sacral cords; PITH) and to evaluate whether the prokinetic benzamide mosapride, a 5-HT(4) receptor agonist, enhances these reflexes. The mechanical activities of the R-R and R-IAS were recorded in the anesthetized guinea pig on days 2-9 after PITH. Although the basal rectal pressure at distension after PITH was significantly lower than control, the reflex indexes of R-R contractions and synchronous R-IAS relaxations were unchanged between days 4 and 9 after PITH. The frequency of spontaneous rectal and IAS motility were also unchanged. Immunohistochemical studies revealed that the distribution of myenteric and intramuscular interstitial cells of Cajal (ICC) were not altered after PITH. Mosapride (0.1-1.0 mg/kg iv) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indexes (maximum: 2.76) from control (1.0) 6-9 days after PITH. The 5-HT(4) receptor antagonist, GR-113808 (1.0 mg/kg iv) decreased the R-R and R-IAS reflex indexes by approximately 50% and antagonized the effect of mosapride (1.0 mg/kg iv). The present results indicate that mosapride moderately enhanced intrinsic R-R and R-IAS reflexes functionally compensated after deprivation of extrinsic nerves, mediated through endogenously active intrinsic 5-HT(4) receptors.

Topics: Acute Disease; Anal Canal; Animals; Benzamides; Chronic Disease; Denervation; Disease Models, Animal; Gastrointestinal Agents; Gastrointestinal Motility; Guinea Pigs; Indoles; Male; Morpholines; Rectum; Reflex; Serotonin 5-HT4 Receptor Agonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Spinal Cord Injuries; Sulfonamides

To examine the effects of various doses of mosapride, a 5-hydroxytryptamine 4 receptor agonist, on motility of the small intestine and cecum in horses by use of electrical activity and to determine the dose that provides the optimal response.. 6 healthy adult Thoroughbreds.. Electrical activity of the small intestine and cecum was recorded before and after mosapride administration by use of an electrogastrograph. Mosapride (0.5, 1, 1.5, and 2 mg/kg) was dissolved in 200 mL of water and administered orally to horses through a nasogastric tube. Three hours after drug administration, mean amplitude of electrical activity calculated for a period of 30 minutes was expressed as the percentage of the mean amplitude of electrical activity for a period of 30 minutes before drug administration.. Mosapride administered orally increased the percentage of the mean amplitude of electrical activity in the small intestine and cecum in a dose-dependent manner. Mean +/- SD values differed significantly for 1, 1.5, and 2 mg/kg (127.0 +/- 12.5%, 137.7 +/- 22.2%, and 151.1 +/- 24.0%, respectively) in the small intestine and for 1.5 and 2 mg/kg (130.1 +/- 34.5% and 151.6 +/- 45.2%, respectively) in the cecum.. Analysis of results of this study clearly documents that mosapride promotes motility in the small intestine and cecum of horses and that the optimal orally administered dosage is 1.5 to 2 mg/kg. Therefore, mosapride may be useful for treatment of horses with gastrointestinal tract dysfunction.

Topics: Animals; Benzamides; Cecum; Dose-Response Relationship, Drug; Electrophysiology; Gastrointestinal Motility; Horses; Intestine, Small; Morpholines; Serotonin 5-HT4 Receptor Agonists