Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation‐predominant irritable bowel syndrome

Tack, Jan; Middleton, S; Horne, M C; Piessevaux, Hubert; Bloor, Jonathon; Meyers, Nicholas; Palmer, Richard

doi:10.1111/j.1365-2036.2006.02940.x

Cited by 48 publications

(31 citation statements)

References 36 publications

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“…Acceleration of colon transit positively correlated with improvements in ease of passage and stool form, but not with stool frequency. In another study, Tack et al 106 found that renzapride at a dose of 2 mg twice daily produced a statistically significant reduction in overall colonic transit measured with radio-opaque markers compared with placebo. IBS symptoms showed some improvement with renzapride compared with placebo but did not reach statistical significance although sample sizes were small.…”

Section: The Current Approach To Drug Developmentmentioning

confidence: 97%

Functional GI disorders: from animal models to drug development

Mayer¹,

Bradesi²,

Chang³

et al. 2008

Gut

144

136

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Despite considerable efforts by academic researchers and by the pharmaceutical industry, the development of novel pharmacological treatments for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders has been slow and disappointing. The traditional approach to identifying and evaluating novel drugs for these symptom-based syndromes has relied on a fairly standard algorithm using animal models, experimental medicine models and clinical trials. In the current article, the empirical basis for this process is reviewed, focusing on the utility of the assessment of visceral hypersensitivity and GI transit, in both animals and humans, as well as the predictive validity of preclinical and clinical models of IBS for identifying successful treatments for IBS symptoms and IBS-related quality of life impairment. A review of published evidence suggests that abdominal pain, defecation-related symptoms (urgency, straining) and psychological factors all contribute to overall symptom severity and to health-related quality of life. Correlations between readouts obtained in preclinical and clinical models and respective symptoms are small, and the ability to predict drug effectiveness for specific as well as for global IBS symptoms is limited. One possible drug development algorithm is proposed which focuses on pharmacological imaging approaches in both preclinical and clinical models, with decreased emphasis on evaluating compounds in symptom-related animal models, and more rapid screening of promising candidate compounds in man.Despite the tremendous efforts by academia and industry alike during the past 15 years, the success rate for effective drug development for irritable bowel syndrome (IBS) and other functional gastrointestinal (GI) disorders (FGIDs) remains unimpressive. Only two new IBS treatments-that is, alosetron and tegaserod-have gained initial Food and Drug Administration (FDA) approval as a new IBS treatment so far. However, both of these medications are only available in the USA as part of a restricted access programme, due to side effects.1 Of the many failed compounds that never saw the light of the peer-reviewed literature, only a small number were officially announced as a failure, including the peripheral visceral k-opioid agonist fedotozine, the selective m 3 muscarinic receptor antagonist darifenacin and the selective NK 3 receptor antagonist talnetant. Despite this discouraging news, and despite the fact that several major companies have decided to leave the IBS field altogether, several new and promising compounds are in various stages of early clinical development. 3There have been advances in the field including development of agreed upon definitions of the major syndromes (as well as a myriad of other FGIDs), 4 animal models with some face and construct validity for the human syndrome 5 and identification of a continuously increasing number of molecular targets on epithelial and immune cells and visceral afferent neurons, 6 and in the central nervous system (CNS). ....

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Section: The Current Approach To Drug Developmentmentioning

confidence: 97%

Functional GI disorders: from animal models to drug development

Mayer¹,

Bradesi²,

Chang³

et al. 2008

Gut

144

136

View full text Add to dashboard Cite

show abstract

“…So, taking the binding and functional results together, they indicate that it is unlikely that renzapride would show any significant selectivity in vivo. This is a relevant consideration because the efficacy of renzapride has been established in treating patients with cIBS [16] and it is currently in phase III clinical trial for prokinetic effect in the upper gut [13] .…”

Section: Discussionmentioning

confidence: 99%

Investigations into the Binding Affinities of Different Human 5-HT<sub>4</sub> Receptor Splice Variants

Irving¹,

Tochon-Danguy²,

Chinkwo³

et al. 2010

Pharmacology

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This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT₄ receptor splice variants [h5-HT_4(a), h5-HT_4(b), h5-HT_4(c), h5-HT_4(d) and h5-HT_4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT₄ benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pK_i: 7.38–7.91) ≧ Y-36912 (pK_i: 7.03–7.85) = BIMU 1 (pK_i: 6.92–7.78) ≧ DAU 6236 (pK_i: 6.79–7.99) ≧ 5-HT (pK_i: 5.82–7.29) ≧ 5-MeOT (pK_i: 5.64–6.83) ≧ renzapride (pK_i: 4.85–5.56). We obtained affinity values for the 5-HT_4(b), (d) and (g) variants for RS67333 (pK_i: 7:48–8.29), prucalopride (pK_i: 6.86–7.37) and zacopride (pK_i: 5.88–7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.

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“…Es handelt sich dabei sowohl um einen 5-HT 4 -Rezeptor-Agonisten als auch um einen 5-HT 3 -Rezeptor-Antagonisten, der stimulierende Effekte auf die gastrointestinale Motilität und den Transit aufweist [19,20]. Dabei ist das Medikament für die beiden Indikationen funktionelle Obstipation wie auch Reizdarmsyndrom mit vorwiegender Obstipation untersucht worden.…”

Section: Renzapridunclassified

Neue Medikamente zur Behandlung der Obstipation

2010

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This review introduces new therapeutic options in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Therefore, prucalopride and lubiprostone are discussed including their mechanisms and side effects. In addition, other substances that are currently under evaluation such as renzapride and linaclotide are described, since recent results showed a significant effect in patients with constipation. Thus, after the withdrawal of tegaserod due to cardiac side effects, new potent drugs are now available for the treatment of constipation.

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Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation‐predominant irritable bowel syndrome

Cited by 48 publications

References 36 publications

Functional GI disorders: from animal models to drug development

Functional GI disorders: from animal models to drug development

Investigations into the Binding Affinities of Different Human 5-HT<sub>4</sub> Receptor Splice Variants

Neue Medikamente zur Behandlung der Obstipation

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