Pharmacology of the New Treatments for Lower Gastrointestinal Motility Disorders and Irritable Bowel Syndrome

Camilleri, Michael

doi:10.1038/clpt.2011.261

Cited by 40 publications

(45 citation statements)

References 190 publications

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“…These effects of BAs have therapeutic implications. The ingestion of bile has been used to alleviate constipation for millennia 13 , and drugs that target the ileal BA transporter can ameliorate constipation by increasing the colonic delivery of BAs 14 The mechanisms by which luminal BAs affect intestinal functions are unknown.…”

Section: Introductionmentioning

confidence: 99%

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

et al. 2013

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Background & Aims: Abnormal delivery of bile acids (BAs) to the colon, due to disease or therapy, causes constipation or diarrhea by unknown mechanisms. The G protein-coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion. Methods: We analyzed gastrointestinal and colon transit, and defecation frequency and water content, in wild-type, knockout and transgenic mice (trg5-wt, tgr5-ko and tgr5-tg, respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release. Results: Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5-hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with TGR5 localization to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5. Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice, compared to tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%). Conclusions: The receptor TGR5 mediates the effects of BAs on colonic motility; TGR5 deficiency causes constipation in mice. These findings might mediate the long-known laxative properties of BAs; TGR5 might be a therapeutic target for digestive diseases.

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Section: Introductionmentioning

confidence: 99%

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

et al. 2013

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“…Serotonin [5-hydroxytryptamine (5-HT)] is involved in controlling GI secretion, motility, and visceral perception (41,63). It is, therefore, not surprising that, in patients with IBS, studies have documented alterations in 5-HT levels (6) and 5-HT signaling (4); serotonin and serotonin receptormodulating drugs are vigorously pursued in IBS, despite poor consensus on the optimal end points for trials and the regulatory agency requirement of rigorous safety standards for serotonergic agents because of potential vascular effects (14,15,24). As a result of the widespread interest in serotonin, genetic alterations in serotonergic mechanisms are the most extensively studied genetic associations with IBS.…”

Section: Neurotransmitter Mechanismsmentioning

confidence: 99%

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Camilleri

Katzka

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

103

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The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, ␣ 2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNF␣, GN␤3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT3 genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klotho␤ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published. adrenergic; serotonergic; solute carrier 6A4; 5-hydroxytryptamine transporter-linked polymorphic region; inflammation; susceptibility; klotho␤; bile acid malabsorption EPIDEMIOLOGICAL STUDIES of familial aggregation (57, 99) and twins (7,70,72,82,83) suggest a genetic contribution to irritable bowel syndrome (IBS). While the data are conflicting, they are generally consistent with the hypothesis that IBS may be a complex genetic disorder. Understanding of genetic variation and its influence on gut motility, secretion, sensation, and inflammation, as it is applied to IBS, has the potential to help elucidate mechanisms of control of a poorly understood syndrome. Similarly, the impact of genetic variation on the targets of therapy in IBS may enhance the efficacy of pharmacological therapies. These targets include receptors and regulators of gut function and variations in drug metabolism.This review addresses the available literature on the role of genetics in IBS. There are no published genome-wide association studies in functional gastrointestinal (GI) or motility disorders specifically focusing on genetic epidemiology and pharmacogenetics. Genetic Epidemiology of IBS: Candidate Gene ApproachAs the general approach followed in genotype association studies (Fig. 1), investigators have sought the relationship between genotype and clinical phenotype, while appreciating that intermediaries, such as th...

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“…Velusetrag and naronapride are also in development in phase IIB studies. Both have been efficacious in pharmacodynamic studies (71), and velusetrag is efficacious in patients with chronic constipation (73).…”

Section: Ref 71)mentioning

confidence: 99%

Pharmacological agents currently in clinical trials for disorders in neurogastroenterology

Camilleri¹

2013

J. Clin. Invest.

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Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients' symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain. IntroductionGastrointestinal motility and functional disorders result in either abnormal propulsion of content or excessive sensation of normal or abnormal functions in different regions of the gut. These conditions constitute about 40% of referrals to gastroenterologists, and they result in significant disease burden. Advances in clinical management of these disorders are based on understanding the basic mechanisms involved in sensorimotor and secretory functions, coupled with clinical investigation and trial methodology.The most frequent gastrointestinal motility and functional disorders are esophagitis, gastroparesis, chronic diarrhea, chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), and visceral pain. This review summarizes the pathophysiology, lists commonly used current medications, and focuses on pharmacological agents in development for each disorder. At present, several approved medications relieve constipation and diarrhea; the major unmet needs are in gastroparesis, OIC, and visceral pain.

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Pharmacology of the New Treatments for Lower Gastrointestinal Motility Disorders and Irritable Bowel Syndrome

Cited by 40 publications

References 190 publications

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Pharmacological agents currently in clinical trials for disorders in neurogastroenterology

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