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Mohammad Abdollahi - One of the best experts on this subject based on the ideXlab platform.
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The safety of novel drugs used to treat irritable bowel syndrome
Expert opinion on drug safety, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process. Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval. Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and Renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the trea...
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systematic review meta analysis efficacy and tolerability of Renzapride in irritable bowel syndrome a meta analysis of randomized controlled clinical trials including 2528 patients
Archives of Medical Science, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:Introduction By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of Renzapride in the management of IBS.
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Systematic review/Meta-analysis Efficacy and tolerability of Renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients
Archives of medical science : AMS, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of Renzapride in the management of IBS. A search was done from 1992 to February 2013 for placebo-controlled trials that investigated the efficacy of Renzapride in IBS. Relative risk (RR) for clinical efficacy in IBS patients treated for 5 weeks or less comparing Renzapride to placebo was 1.07 (95% CI = 0.89-1.29, p = 0.38). This value for IBS patients treated for more than 5 weeks was 1.04 (95% CI = 0.78-1.239, p = 0.77). The RR for clinical efficacy in IBS patients treated with Renzapride (4 mg) for 5 weeks or less and more than 5 weeks in comparison to placebo was 1.2 (95% CI = 0.97-1.48, p = 0.1) and 1.16 (95% CI = 0.98-1.37, p = 0.08), respectively, which were statistically non-significant but clinically important. The analysis of tolerability demonstrated that amongst different reported adverse effects, Renzapride caused diarrhea more than placebo (RR = 1.61 with a 95% CI = 1.16-2.24, p = 0.004). The RR for withdrawals from Renzapride compared to placebo was 1.58 (95% CI = 1.26-2.07, p = 0.0007). Renzapride is not superior to placebo in relieving IBS symptoms and causes significant incidences of diarrhea and drop-outs due to adverse effects in treated patients vs. placebo. Thus, this medicine might be a cost burden to patients without providing good effectiveness.
R. I. Hickling - One of the best experts on this subject based on the ideXlab platform.
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Identification of Patients with Non-D, Non-C Irritable Bowel Syndrome and Treatment with Renzapride: An Exploratory, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Digestive Diseases and Sciences, 2008Co-Authors: R. C. Spiller, N. L. Meyers, R. I. HicklingAbstract:This was an exploratory study of Renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or Renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on Renzapride versus placebo of 18.2% (95% CI −5% to 42%; P = 0.066) during weeks 1–4 and 6% (95% CI −21% to 33%; P = 0.339) during weeks 5–8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether Renzapride is beneficial in this patient population.
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Clinical trial: Renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting.
Alimentary pharmacology & therapeutics, 2008Co-Authors: A. M. George, N. L. Meyers, R. I. HicklingAbstract:Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. To identify an appropriate dosage of Renzapride (a 5-HT(4) receptor full agonist/5-HT(3) receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or Renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5-12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life. Although there were no statistically significant differences between Renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the Renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.
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clinical trial Renzapride therapy for constipation predominant irritable bowel syndrome multicentre randomized placebo controlled double blind study in primary healthcare setting
Alimentary Pharmacology & Therapeutics, 2008Co-Authors: A. M. George, N. L. Meyers, R. I. HicklingAbstract:Summary Background Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. Aim To identify an appropriate dosage of Renzapride (a 5-HT4 receptor full agonist/5-HT3 receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. Methods In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or Renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5–12. Secondary efficacy measures included patients’ assessment of their bowel habits, stool consistency and quality of life. Results Although there were no statistically significant differences between Renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the Renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. Conclusions This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.
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The cardiovascular safety profile of Renzapride, a novel treatment for irritable bowel syndrome.
The Journal of international medical research, 2007Co-Authors: N. L. Meyers, R. I. HicklingAbstract:The cardiac safety of Renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QTci). No clinically or statistically significant prolongation of QTci after 4 or 20 mg Renzapride compared with placebo was observed. The relative effects of Renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 microM Renzapride, shortened by 20 microM Renzapride, and prolonged by 1 microM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than Renzapride. These studies indicate that therapeutic doses of Renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.
Shilan Mozaffari - One of the best experts on this subject based on the ideXlab platform.
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The safety of novel drugs used to treat irritable bowel syndrome
Expert opinion on drug safety, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:Introduction: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process. Areas covered: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval. Expert opinion: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and Renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the trea...
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systematic review meta analysis efficacy and tolerability of Renzapride in irritable bowel syndrome a meta analysis of randomized controlled clinical trials including 2528 patients
Archives of Medical Science, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:Introduction By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of Renzapride in the management of IBS.
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Systematic review/Meta-analysis Efficacy and tolerability of Renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients
Archives of medical science : AMS, 2014Co-Authors: Shilan Mozaffari, Shekoufeh Nikfar, Mohammad AbdollahiAbstract:By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of Renzapride in the management of IBS. A search was done from 1992 to February 2013 for placebo-controlled trials that investigated the efficacy of Renzapride in IBS. Relative risk (RR) for clinical efficacy in IBS patients treated for 5 weeks or less comparing Renzapride to placebo was 1.07 (95% CI = 0.89-1.29, p = 0.38). This value for IBS patients treated for more than 5 weeks was 1.04 (95% CI = 0.78-1.239, p = 0.77). The RR for clinical efficacy in IBS patients treated with Renzapride (4 mg) for 5 weeks or less and more than 5 weeks in comparison to placebo was 1.2 (95% CI = 0.97-1.48, p = 0.1) and 1.16 (95% CI = 0.98-1.37, p = 0.08), respectively, which were statistically non-significant but clinically important. The analysis of tolerability demonstrated that amongst different reported adverse effects, Renzapride caused diarrhea more than placebo (RR = 1.61 with a 95% CI = 1.16-2.24, p = 0.004). The RR for withdrawals from Renzapride compared to placebo was 1.58 (95% CI = 1.26-2.07, p = 0.0007). Renzapride is not superior to placebo in relieving IBS symptoms and causes significant incidences of diarrhea and drop-outs due to adverse effects in treated patients vs. placebo. Thus, this medicine might be a cost burden to patients without providing good effectiveness.
Jan Tack - One of the best experts on this subject based on the ideXlab platform.
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Systematic review: cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders
Alimentary pharmacology & therapeutics, 2012Co-Authors: Jan Tack, Michael Camilleri, James J. Galligan, Lin Chang, William D. Chey, Brian E. Lacy, Stefan Müller-lissner, Eamonn Martin Quigley, J. A. J. Schuurkes, J. H. De MaeyerAbstract:The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Articles reporting data on cisapride, clebopride, prucalopride, mosapride, Renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (Renzapride, clebopride, mosapride). 5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility. © 2012 Blackwell Publishing Ltd.
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Renzapride: a new drug for the treatment of constipation in the irritable bowel syndrome
Expert Opinion on Investigational Drugs, 2008Co-Authors: Emidio Scarpellini, Jan TackAbstract:Renzapride is a novel drug currently under clinical evaluation for the treatment of irritable bowel syndrome (IBS). Renzapride is a mixed 5-hydroxytryptamine type 4 (5-HT4) agonist and 5-HT3 receptor antagonist that has a stimulatory effect on gastrointestinal motility and transit, as established by in vivo and in vitro studies. Its therapeutic efficacy, tolerability and safety have been evaluated in diabetic gastroparesis in a single study, as well as in IBS in a few other studies. Phase II studies indicated potential beneficial effects on symptoms and bowel habits in patients with constipation-predominant IBS and mixed-type IBS. The outcome of Phase III studies is currently under evaluation.
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Sumatriptan is an agonist at 5-HT receptors on myenteric neurones in the guinea-pig gastric antrum.
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2007Co-Authors: Jan Tack, P. Vanden Berghe, Bernard Coulie, Jozef JanssensAbstract:Sumatriptan, a 5-hydroxytryptamine(1D) (5-HT(1D))-receptor agonist used in the treatment in migraine, inhibits gastric motility via the enteric nervous system. As no studies have reported enteric neuronal 5-HT(1D) receptors, we used conventional intracellular recordings to characterize the actions of sumatriptan on 145 guinea-pig antral myenteric neurones. In 24 of 29 neurones with a 5-HT(1P) receptor-mediated depolarizing response to 5-HT, application of sumatriptan caused a dose-dependent depolarization, accompanied by increased membrane resistance and enhanced excitability. Depolarizing responses to sumatriptan occurred both in cholinergic and in nitrergic neurones. Sumatriptan did not mimic the 5-HT(3) receptor-mediated fast-depolarizing responses or 5-HT(1A) receptor-mediated inhibitory responses to 5-HT. Sumatriptan had no effect on neurones not responding to 5-HT. The depolarizing response to sumatriptan was inhibited by Renzapride, but not by 5-HT(1-7) receptor antagonists. We conclude that sumatriptan behaves as an agonist at the 5-HT(1P) receptor on myenteric neurones in the guinea-pig gastric antrum. The actions of sumatriptan on gastric motility seem to be attributable to a direct action on enteric neurones.
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Pilot study of the efficacy of Renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome
Alimentary pharmacology & therapeutics, 2006Co-Authors: Jan Tack, N. L. Meyers, S J Middleton, M C Horne, Hubert Piessevaux, J S Bloor, R M J PalmerAbstract:To investigate the efficacy and safety of Renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, Renzapride 2 mg o.d. and Renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; Renzapride 2 mg o.d., 2.6 +/- 1.4 days; Renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for Renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on Renzapride and placebo. Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of Renzapride in patients with constipation-predominant irritable bowel syndrome.
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pilot study of the efficacy of Renzapride on gastrointestinal motility and symptoms in patients with constipation predominant irritable bowel syndrome
Alimentary Pharmacology & Therapeutics, 2006Co-Authors: Jan Tack, N. L. Meyers, S J Middleton, M C Horne, Hubert Piessevaux, J S Bloor, R M J PalmerAbstract:Aim To investigate the efficacy and safety of Renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. Methods In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, Renzapride 2 mg o.d. and Renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. Results Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; Renzapride 2 mg o.d., 2.6 +/- 1.4 days; Renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for Renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on Renzapride and placebo. Conclusions Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of Renzapride in patients with constipation-predominant irritable bowel syndrome.
N. L. Meyers - One of the best experts on this subject based on the ideXlab platform.
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Identification of Patients with Non-D, Non-C Irritable Bowel Syndrome and Treatment with Renzapride: An Exploratory, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Digestive Diseases and Sciences, 2008Co-Authors: R. C. Spiller, N. L. Meyers, R. I. HicklingAbstract:This was an exploratory study of Renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or Renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on Renzapride versus placebo of 18.2% (95% CI −5% to 42%; P = 0.066) during weeks 1–4 and 6% (95% CI −21% to 33%; P = 0.339) during weeks 5–8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether Renzapride is beneficial in this patient population.
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Clinical trial: Renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting.
Alimentary pharmacology & therapeutics, 2008Co-Authors: A. M. George, N. L. Meyers, R. I. HicklingAbstract:Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. To identify an appropriate dosage of Renzapride (a 5-HT(4) receptor full agonist/5-HT(3) receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or Renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5-12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life. Although there were no statistically significant differences between Renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the Renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.
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clinical trial Renzapride therapy for constipation predominant irritable bowel syndrome multicentre randomized placebo controlled double blind study in primary healthcare setting
Alimentary Pharmacology & Therapeutics, 2008Co-Authors: A. M. George, N. L. Meyers, R. I. HicklingAbstract:Summary Background Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. Aim To identify an appropriate dosage of Renzapride (a 5-HT4 receptor full agonist/5-HT3 receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. Methods In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or Renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5–12. Secondary efficacy measures included patients’ assessment of their bowel habits, stool consistency and quality of life. Results Although there were no statistically significant differences between Renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the Renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. Conclusions This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.
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The cardiovascular safety profile of Renzapride, a novel treatment for irritable bowel syndrome.
The Journal of international medical research, 2007Co-Authors: N. L. Meyers, R. I. HicklingAbstract:The cardiac safety of Renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QTci). No clinically or statistically significant prolongation of QTci after 4 or 20 mg Renzapride compared with placebo was observed. The relative effects of Renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 microM Renzapride, shortened by 20 microM Renzapride, and prolonged by 1 microM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than Renzapride. These studies indicate that therapeutic doses of Renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.
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Pilot study of the efficacy of Renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome
Alimentary pharmacology & therapeutics, 2006Co-Authors: Jan Tack, N. L. Meyers, S J Middleton, M C Horne, Hubert Piessevaux, J S Bloor, R M J PalmerAbstract:To investigate the efficacy and safety of Renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, Renzapride 2 mg o.d. and Renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; Renzapride 2 mg o.d., 2.6 +/- 1.4 days; Renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for Renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on Renzapride and placebo. Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of Renzapride in patients with constipation-predominant irritable bowel syndrome.
