The Experts below are selected from a list of 141 Experts worldwide ranked by ideXlab platform
Nicholas J Talley - One of the best experts on this subject based on the ideXlab platform.
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effects of a Motilin Receptor Agonist abt 229 on upper gastrointestinal symptoms in type 1 diabetes mellitus a randomised double blind placebo controlled trial
2001Co-Authors: Nicholas J Talley, Marleen Verlinden, D Riff, D J Geenen, R B Hogan, R W Mccallum, R J MackAbstract:INTRODUCTION—Erythromycin, a Motilin Agonist, is a potent prokinetic. ABT-229 is a specific Motilin Agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. METHODS—Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C13 octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit. RESULTS—The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline −169, −101, −155, −143, and −138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms. CONCLUSIONS—The Motilin Agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying. Keywords: prokinetic; Motilin; dyspepsia; gastric motility; type 1 diabetes; controlled trial; postprandial
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:SUMMARY Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying.
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying. Methods: Patients were randomized with postprandial symptoms and documented functional dyspepsia by endoscopy (n=589 in intention-to-treat analysis). Patients were assigned to either the delayed or normal gastric emptying strata, based on a validated 13C octanoic acid breath test. Patients were then further randomized within each strata, to receive one of four doses of ABT-229 (1.25, 2.5, 5 or 10 mg b.d. before breakfast and dinner) or placebo for 4 weeks, following a 2-week baseline. The primary outcome was the assessment of change in symptom severity over the 2 weeks from baseline to final visit, based on a self-report questionnaire measuring severity on visual analogue scales. Results: Baseline characteristics across the treatment arms were very similar. No significant differences in the upper abdominal discomfort severity score (maximum 800 mm) were observed for any active treatment arm vs. placebo (mean change from baseline −139, −141, −145, −160 and −134 mm for placebo, 1.25, 2.5, 5, and 10 mg, respectively, at 4 weeks by intention-to-treat). More patients on placebo reported a good or excellent global response than patients on 1.25 or 5 mg of active therapy (both P < 0.05). The results were very similar in those with and without delayed gastric emptying. Helicobacter pylori status did not predict response. Excluding patients with any baseline heartburn (total remaining n=240), ABT-229 10 mg was inferior to placebo in relief of upper abdominal discomfort. Conclusions: ABT-229 was of no value for relief of symptoms in functional dyspepsia, compared with placebo.
Gareth J Sanger - One of the best experts on this subject based on the ideXlab platform.
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rq 00201894 a Motilin Receptor Agonist causing long lasting facilitation of human gastric cholinergically mediated contractions
2016Co-Authors: John Broad, Nobuyuki Takahashi, Masaomi Tajimi, Masaki Sudo, Adam Goralczyk, Umesh Parampalli, Kesava R Mannur, Toshinori Yamamoto, Gareth J SangerAbstract:The aim was to characterise RQ-00201894, a novel non-macrolide Motilin Agonist, using human recombinant Receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed Motilin Receptor function. Selectivity of action was determined using a panel of different Receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, Motilin and erythromycin acted as full Motilin Receptor Agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin Receptor (EC50 19 nM) and greater selectivity over all other Receptors/mechanisms tested. In human stomach RQ-00201894 0.1-30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1-10 μM this activity was usually prolonged. At higher concentrations (3-30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the Motilin Receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying.
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the antibiotic azithromycin is a Motilin Receptor Agonist in human stomach comparison with erythromycin
2013Co-Authors: John Broad, Gareth J SangerAbstract:Background and Purpose The antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate Motilin Receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed Motilin Receptors in human stomach, comparing azithromycin with erythromycin. Experimental Approach [125I]-Motilin binding and calcium flux experiments were conducted using human recombinant Motilin Receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves. Key Results Azithromycin (1–100 μM) and erythromycin (3–30 μM) concentration-dependently displaced [125I]-Motilin binding to the Motilin Receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 μM respectively). Azithromycin, erythromycin and Motilin concentration-dependently caused short-lived increases in intracellular [Ca2+] in cells expressing the Motilin Receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 μM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30–300 μM each) facilitated these contractions (apparent Emax values of 2007 ± 396 and 1924 ± 1375%, n = 3–4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short-lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug. Conclusions and Implications Azithromcyin activates human recombinant Motilin Receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.
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gsk962040 a small molecule Motilin Receptor Agonist which increases gastrointestinal motility in conscious dogs
2011Co-Authors: Shawn C Leming, John Broad, S J Cozens, Mary F Otterson, Wendy J Winchester, Kevin Lee, George E Dukes, Gareth J SangerAbstract:Background GSK962040, a small molecule Motilin Receptor Agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional Motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin Agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. Methods The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant Receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. Key Results GSK962040 activated the dog Motilin Receptor (pEC50 5.79; intrinsic activity 0.72, compared with [Nle13]-Motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg−1), driven by mean plasma concentrations >1.14 μmol L−1. After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg−1 GSK962040 but at 6 mg kg−1, MMCs returned 253 min after dosing, compared with 101 min after saline (n = 5 each). Conclusions & Inferences The results are consistent with lower potency for Agonists at the dog Motilin Receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.
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GSK962040: a small molecule, selective Motilin Receptor Agonist, effective as a stimulant of human and rabbit gastrointestinal motility
2009Co-Authors: Gareth J Sanger, Susan Marie Westaway, A A Barnes, David T. Macpherson, Alison I. Muir, Emma M. Jarvie, V N Bolton, Selim Cellek, Erik Näslund, Per M. HellströmAbstract:There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5-hydroxytryptamine type 4 Receptor Agonist and an antAgonist at brain D2 Receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule Motilin Receptor Agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human Receptors, rabbit and human isolated stomach preparations known to respond to Motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human Motilin Receptor, the pEC50 (the negative logarithm to base 10 of the EC50 value, the concentration of Agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as Agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other Receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L(-1)-10 micromol L(-1) caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 +/- 47% at 3 micromol L(-1). In human-isolated stomach, GSK962040 10 micromol L(-1), erythromycin 10 micromol L(-1) and [Nle13]-Motilin 100 nmol L(-1), each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg(-1) GSK962040 or 10 mg kg(-1) erythromycin significantly increased faecal output over a 2-h period. Together, these data show that GSK962040, a non-motilide structure, selectively activates the Motilin Receptor. Simplification of the structural requirements to activate this Receptor greatly facilitates the design of potentially new medicines for gastroparesis.
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differences between the abilities of tegaserod and Motilin Receptor Agonists to stimulate gastric motility in vitro
2007Co-Authors: Emma M. Jarvie, V North J Laidler, S Corcoran, Anna K Bassil, Gareth J SangerAbstract:Background and purpose: 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. Experimental approach: Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergicallymediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses. Key results: Rabbit Motilin (r.Motilin) 0.003–0.3mM, [Nle 13 ]Motilin 0.003–0.3mM, erythromycin 0.3–10mM and tegaserod 0.1–10mM caused concentration – dependent potentiation of EFS-evoked contractions. The potency ranking was r.Motilin ¼ [Nle 13 ]Motilin 4 tegaserod 4 erythromycin. The Emax ranking was r.Motilin ¼ [Nle 13 ]Motilin ¼ erythromycin 4 tegaserod. Responses to r.Motilin and [Nle 13 ]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 [Nle 13 ]Motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1mM [Nle 13 ]Motilin were not different from those caused by the first application).
Philip B Miner - One of the best experts on this subject based on the ideXlab platform.
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:SUMMARY Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying.
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying. Methods: Patients were randomized with postprandial symptoms and documented functional dyspepsia by endoscopy (n=589 in intention-to-treat analysis). Patients were assigned to either the delayed or normal gastric emptying strata, based on a validated 13C octanoic acid breath test. Patients were then further randomized within each strata, to receive one of four doses of ABT-229 (1.25, 2.5, 5 or 10 mg b.d. before breakfast and dinner) or placebo for 4 weeks, following a 2-week baseline. The primary outcome was the assessment of change in symptom severity over the 2 weeks from baseline to final visit, based on a self-report questionnaire measuring severity on visual analogue scales. Results: Baseline characteristics across the treatment arms were very similar. No significant differences in the upper abdominal discomfort severity score (maximum 800 mm) were observed for any active treatment arm vs. placebo (mean change from baseline −139, −141, −145, −160 and −134 mm for placebo, 1.25, 2.5, 5, and 10 mg, respectively, at 4 weeks by intention-to-treat). More patients on placebo reported a good or excellent global response than patients on 1.25 or 5 mg of active therapy (both P < 0.05). The results were very similar in those with and without delayed gastric emptying. Helicobacter pylori status did not predict response. Excluding patients with any baseline heartburn (total remaining n=240), ABT-229 10 mg was inferior to placebo in relief of upper abdominal discomfort. Conclusions: ABT-229 was of no value for relief of symptoms in functional dyspepsia, compared with placebo.
Marleen Verlinden - One of the best experts on this subject based on the ideXlab platform.
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efficacy of a Motilin Receptor Agonist abt 229 for the treatment of gastro oesophageal reflux disease
2002Co-Authors: Chienlin Chen, Marleen Verlinden, A Dettmer, H Brinkhoff, William C Orr, D Riff, S Schwartz, R D Soloway, R Krause, Frank L LanzaAbstract:Background: ABT-229 is a potent Motilin Agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. Aim: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. Methods: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. Results: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. Conclusion: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.
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effects of a Motilin Receptor Agonist abt 229 on upper gastrointestinal symptoms in type 1 diabetes mellitus a randomised double blind placebo controlled trial
2001Co-Authors: Nicholas J Talley, Marleen Verlinden, D Riff, D J Geenen, R B Hogan, R W Mccallum, R J MackAbstract:INTRODUCTION—Erythromycin, a Motilin Agonist, is a potent prokinetic. ABT-229 is a specific Motilin Agonist that dose dependently accelerates gastric emptying. Dyspepsia and gastroparesis are common problems in type 1 diabetes mellitus. We aimed to evaluate the efficacy of ABT-229 in symptomatic diabetic patients with and without delayed gastric emptying. METHODS—Patients with type 1 diabetes and postprandial symptoms were randomised (n=270). Based on a validated C13 octanoic acid breath test, patients were assigned to either the delayed or normal gastric emptying strata. Patients received one of four doses of ABT-229 (1.25, 2.5, 5, or 10 mg twice daily before breakfast and dinner) or placebo for four weeks following a two week baseline. A self report questionnaire measured symptoms on visual analogue scales; the primary outcome was assessment of change in the total upper abdominal symptom severity score (range 0-800 mm) from baseline to the final visit. RESULTS—The treatment arms were similar regarding baseline characteristics. There was symptom improvement on placebo and a similar level of improvement on active therapy for the upper abdominal discomfort severity score (mean change from baseline −169, −101, −155, −143, and −138 mm for placebo, and 1.25, 2.5, 5, and 10 mg ABT-229, respectively, at four weeks by intent to treat). The results were not significantly different in those with and without delayed gastric emptying. The severity of bloating, postprandial nausea, epigastric discomfort, heartburn, and acid regurgitation worsened dose dependently in a greater number of patients receiving ABT-229 than placebo. Overall, 63% of patients on placebo reported a good or excellent global response, and this was not different from the active treatment arms. CONCLUSIONS—The Motilin Agonist ABT-229 was not efficacious in the relief of postprandial symptoms in diabetes mellitus in the presence or absence of delayed gastric emptying. Keywords: prokinetic; Motilin; dyspepsia; gastric motility; type 1 diabetes; controlled trial; postprandial
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:SUMMARY Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying.
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failure of a Motilin Receptor Agonist abt 229 to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying a randomized double blind placebo controlled trial
2000Co-Authors: Nicholas J Talley, Marleen Verlinden, W Snape, J A Beker, P Ducrotte, A Dettmer, H Brinkhoff, E Eaker, Gordon V Ohning, Philip B MinerAbstract:Introduction: Motilin-Receptor Agonists are prokinetics; whether they relieve the symptoms of functional dyspepsia is unknown. We aimed to test the efficacy of the Motilin Agonist ABT-229 in functional dyspepsia patients with and without delayed gastric emptying. Methods: Patients were randomized with postprandial symptoms and documented functional dyspepsia by endoscopy (n=589 in intention-to-treat analysis). Patients were assigned to either the delayed or normal gastric emptying strata, based on a validated 13C octanoic acid breath test. Patients were then further randomized within each strata, to receive one of four doses of ABT-229 (1.25, 2.5, 5 or 10 mg b.d. before breakfast and dinner) or placebo for 4 weeks, following a 2-week baseline. The primary outcome was the assessment of change in symptom severity over the 2 weeks from baseline to final visit, based on a self-report questionnaire measuring severity on visual analogue scales. Results: Baseline characteristics across the treatment arms were very similar. No significant differences in the upper abdominal discomfort severity score (maximum 800 mm) were observed for any active treatment arm vs. placebo (mean change from baseline −139, −141, −145, −160 and −134 mm for placebo, 1.25, 2.5, 5, and 10 mg, respectively, at 4 weeks by intention-to-treat). More patients on placebo reported a good or excellent global response than patients on 1.25 or 5 mg of active therapy (both P < 0.05). The results were very similar in those with and without delayed gastric emptying. Helicobacter pylori status did not predict response. Excluding patients with any baseline heartburn (total remaining n=240), ABT-229 10 mg was inferior to placebo in relief of upper abdominal discomfort. Conclusions: ABT-229 was of no value for relief of symptoms in functional dyspepsia, compared with placebo.
Kenichi Ozaki - One of the best experts on this subject based on the ideXlab platform.
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stimulatory action of mitemcinal gm 611 an acid resistant non peptide Motilin Receptor Agonist on colonic motor activity and defecation spontaneous and mitemcinal induced giant migrating contractions during defecation in dogs
2009Co-Authors: Takeshi Hirabayashi, Yasuhide Morikawa, Hiroshi Matsufuji, Ken Hoshino, K Hagane, Kenichi OzakiAbstract:The aim of this study was to characterize giant migrating contractions (GMCs) during spontaneous defecation in dogs and to investigate the effect of mitemcinal (an orally active and highly acid-resistant Motilin Receptor Agonist) on colonic motility to assess the possibility of using it for the treatment of colonic motility disorders. To assess colonic motility, strain-gauge force transducers were implanted on the gastrointestinal tract of five dogs, and the behaviour of the dogs was monitored with a noctovision-video camera system. The effect of mitemcinal (0, 3, 10 or 30 mg per dog) and sennoside (300 mg per dog) on colonic motility was assessed 24 h after oral administration. During a 39-day period, the starting point of most of the 140 GMCs was between the transverse colon and the descending colon, but some variation was observed. In the daytime, the GMCs originated from somewhat more proximal positions than at night. Mitemcinal caused an increase in the GMC-index (integration of contractile amplitude and duration) and proximal translocation of the GMC starting point, but did not cause an increase in the number of defecations 12 h after administration. Sennoside, however, caused a significant increase in the number of defecations, an increase in the GMC-index, and prolongation of the duration of GMCs. The GMC starting point in the canine colon varied during spontaneous defecation. Mitemcinal was a potent prokinetic drug to mimic a spontaneous defecation compared with sennoside. Mitemcinal evacuates more intestinal luminal contents during the defecation than does sennoside.
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mitemcinal gm 611 an orally active Motilin Receptor Agonist improves delayed gastric emptying in a canine model of diabetic gastroparesis
2008Co-Authors: Mitsu Onoma, Kenichi Ozaki, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Makoto Monnai, Yoshiki Kawabe, Shuji Hayashi, Toshihiko Shiga, Saori MatsuoAbstract:SUMMARY 1 The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active Motilin Receptor Agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2 Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200–300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3 One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs comapred with normal dogs at both time points. 4 Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs comapred with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5 Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.
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effects of mitemcinal gm 611 an acid resistant nonpeptide Motilin Receptor Agonist on the gastrointestinal contractile activity in conscious dogs
2007Co-Authors: Kenichi Ozaki, Zen Itoh, Hirokazu Sudo, Kenji Yogo, Kenshi Kamei, Hiroshi Koga, Satoshi ōmura, Mitsu Onoma, Michitaka Akima, Hisanori TakanashiAbstract:The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine Motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a Motilin Receptor antAgonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via Motilin Receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.
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mitemcinal gm 611 an orally active Motilin Receptor Agonist accelerates colonic motility and bowel movement in conscious dogs
2007Co-Authors: Kenichi Ozaki, Zen Itoh, Hirokazu Sudo, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Hiroshi Koga, S Omura, Hisanori TakanashiAbstract:The prokinetic effects of mitemcinal, an orally active Motilin Receptor Agonist, on the lower gastrointestinal tracts were investigated in conscious dogs. Oral administration of mitemcinal (0.1–1 mg/kg) stimulated colonic motility, which was measured by chronically implanted force-transducers, as well as gastric motility in a dose-dependent manner. The gastrointestinal contractile activities induced by mitemcinal were inhibited by the continuous intravenous infusion of GM-109, a selective Motilin Receptor antAgonist. Oral administration of mitemcinal (0.3–3 mg/kg) also accelerated bowel movement after feeding without inducing diarrhea in dogs. The results demonstrate that mitemcinal stimulates colonic motility via Motilin Receptors and the effect of mitemcinal on colonic motility may reflect bowel movement after feeding. Thus, mitemcinal could be a promising agent for treatment of not only the upper but also the lower gastrointestinal motility disorders.
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in vitro pharmacological characterization of mitemcinal gm 611 the first acid resistant non peptide Motilin Receptor Agonist in smooth muscle of rabbit small intestine
2007Co-Authors: Hisanori Takanashi, Zen Itoh, Kenichi Ozaki, Kenji Yogo, Hiroshi Koga, Satoshi ōmuraAbstract:The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide Motilin Agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porc