Eluxadoline Benefits Patients With Irritable Bowel Syndrome With Diarrhea in a Phase 2 Study

Dove, Leonard S.; Lembo, Anthony; Randall, Charles; Fogel, Ronald; Andrae, David; Davenport, James M.; McIntyre, Gail; Almenoff, June; Covington, Paul S.

doi:10.1053/j.gastro.2013.04.006

Cited by 126 publications

(152 citation statements)

References 13 publications

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“…Recent studies with new peripherally restricted therapies targeting opioidergic mechanisms are showing promise for IBS treatment, particularly IBS-D, although it is currently unknown whether alterations in enteric or extrinsic neural opioid pathways underlie symptoms in IBS patients (Dove et al, 2013;Mangel and Hicks, 2012).…”

Section: Discussionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients, Brain, Behavior, and Immunity (2014), doi: http://dx.doi.org/10. 1016/j.bbi.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. supernatants from HS and IBS patients were applied to colo-rectal sensory afferent endings in mice with post-inflammatory chronic visceral hypersensitivity (CVH). β-endorphin was identified predominantly in monocyte / macrophages relative to T or B cells in human PBMC and colonic lamina propria. Monocyte derived β-endorphin levels and colonic macrophage numbers were lower in IBS patients than healthy subjects. PBMC supernatants from healthy subjects had greater inhibitory effects on colo-rectal afferent mechanosensitivity than those from IBS patients. The inhibitory effects of PBMC supernatants were more prominent in CVH mice compared to healthy mice due to an increase in µ-opioid receptor expression in dorsal root ganglia neurons in CVH mice. Monocyte / macrophages are the predominant immune cell type responsible for β-endorphin secretion in humans. IBS patients have lower monocyte derived β-endorphin levels than healthy subjects, causing less inhibition of colonic afferent endings. Consequently, altered immune function contributes toward visceral hypersensitivity in IBS.

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Section: Discussionmentioning

confidence: 99%

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Hughes

Moretta

Lim

et al. 2014

Brain, Behavior, and Immunity

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“…Dose-dependent efficacy was found for improvement of stool pattern, abdominal pain and quality of life, with the best results obtained with the 100 mg dose [63]. Two phase III studies in 2,426 IBS-D patients evaluated 75 and 100 mg twice daily vs. placebo in a total of IBS-D patients [64].…”

Section: Emerging Drugsmentioning

confidence: 99%

Modern Management of Irritable Bowel Syndrome: More Than Motility

Tack

Vanuytsel²,

Corsetti³

2016

Dig Dis

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In the treatment of irritable bowel syndrome (IBS), loperamide seems efficacious for diarrhea and ispaghula for constipation, while musculotropic spasmolytics may relieve abdominal pain. Antidepressants were found to be efficacious for abdominal pain, but their tolerance may be problematic and the therapeutic effect varied largely between trials. While meta-analyses suggest efficacy of probiotics as a group, the quality of the trials is often suboptimal and there is large variability. Lubiprostone, a chloride channel activator, and linaclotide, a guanylyl cyclase-C agonist, showed favorable effects on multiple symptoms in IBS with constipation. For IBS with diarrhea (IBS-D), the 5-HT₃ receptor antagonist ramosetron showed efficacy in men and women, but is currently only approved in Japan. A multicenter study with the anti-emetic 5-HT₃ receptor antagonist ondansetron showed efficacy on stool pattern in IBS-D. The poorly absorbable antibiotic rifaximin and eluxadoline, a mu opioid receptor agonist and delta antagonist, both showed efficacy in phase III trials in IBS-D and were approved by the FDA. Eluxadoline was associated with increased occurrence of sphincter of Oddi spasm and biliary pancreatitis. The non-pharmacological treatment of IBS, with dietary interventions (mainly gluten elimination and low FODMAP (fructose, oligo-, di-, monosaccharides and polyols)) has received a lot of attention lately. While responder rates vary across studies, perhaps based on regional variations in dietary intake of FODMAPs, the dietary approach seems to have acquired recognition as a valid therapeutic alternative. Long-term studies and comparative studies with pharmacotherapy, as well as elucidation of the underlying mechanisms of action, are needed.

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“…In the spinal cord, the μ -opioid receptor can also form heteromers with the metabotropic glutamate receptor 5. A new drug candidate, MMG22, which stimulates the μ -opioid receptor but inhibits the metabotropic glutamate receptor 5, was found to have powerful analgesic properties with little, if any, liability for tolerance ( 24 ).…”

Section: Physiology and Pharmacology Of Opioid Peptides And Receptorsmentioning

confidence: 99%

Pharmacology of Opioids and their Effects on Gastrointestinal Function

Holzer¹

2014

Am J Gastroenterol Suppl

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Opioids are perhaps the most effi cacious analgesic agents available to the clinician in everyday clinical practice. While providing highly effective pain relief, the therapeutic activity of opioids is compromised by gastrointestinal adverse events related to their interaction with the opioid signaling system of the gut, a complex network of peptides and receptors with opioid-like properties that helps to coordinate gastrointestinal motility and secretion. The effects of opioids on the gut are modulated by genetic polymorphisms in opioid receptors, downstream signaling pathways, and enzymes involved in the metabolism of these opioid analgesics. Here, we focus on the physiology of endogenous opioids and their receptors with particular reference to their effects on gastrointestinal function, the pharmacology of opioid drugs, and molecular and genetic factors that drive the activity of these powerful agents.

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Eluxadoline Benefits Patients With Irritable Bowel Syndrome With Diarrhea in a Phase 2 Study

Cited by 126 publications

References 13 publications

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Immune derived opioidergic inhibition of viscerosensory afferents is decreased in Irritable Bowel Syndrome patients

Modern Management of Irritable Bowel Syndrome: More Than Motility

Pharmacology of Opioids and their Effects on Gastrointestinal Function

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