Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation

Chey, William D.; Drossman, Douglas A.; Johanson, John F.; Scott, Charles; Panas, Raymond M.; Ueno, Ryuji

doi:10.1111/j.1365-2036.2011.04983.x

Cited by 96 publications

(55 citation statements)

References 19 publications

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“…In the most common -chronic constipation, laxatives remain the mainstay of pharmacological intervention, although new drugs have recently been introduced. These include prucalopride, a selective 5-HT4 receptor agonist, which facilitates enteric cholinergic and nitrergic activities to promote intestinal motility (Cellek et al, 2006), and lubiprostone and linaclotide, which, respectively, activate chloride type-2 channels and guanylate cyclase type-C receptors to promote defecation primarily by increasing fluid secretion into the lumen (Lembo et al, 2011;Chey et al, 2012). Such breakthroughs have renewed interest in how best to treat other conditions associated with hypomotility and also with acute or chronic small and/or large intestinal dilation.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

Broad

Kung

Boundouki

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSECholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. EXPERIMENTAL APPROACHNeuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. KEY RESULTSPrucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3-7, each concentration). CONCLUSIONS AND IMPLICATIONSPotential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction. AbbreviationsAUC, area under the curve; Cmax, peak concentration of drug measured in blood after a single dose; EFS, electrical field stimulation; Emax, maximum response to agonist; GI, gastrointestinal; L-NAME, Nω-nitro-L-arginine methyl ester; NK, neurokinin; TTX, tetrodotoxin BJP IntroductionRestoration of normal intestinal motility is a key objective in treatment of a range of acute and chronic digestive motility disorders. In the most common -chronic constipation, laxatives remain the mainstay of pharmacological intervention, although new drugs have recently been introduced. These include prucalopride, a selective 5-HT4 receptor agonist, which facilitates enteric cholinergic and nitrergic activities to promote intestinal motility (Cellek et al., 2006), and lubiprostone and linaclotide, which, respectively, activate chloride type-2 channels and guanylate cyclase type-C receptors to promote defecation primarily by increasing fluid secretion into the lumen (Lembo et al., 2011;Chey et al., 2012). Such breakthroughs have renewed interest in how best to treat other conditions associated with hypomotility and also with acute or chronic small...

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Section: Introductionmentioning

confidence: 99%

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

Broad

Kung

Boundouki

et al. 2013

British J Pharmacology

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“…It is also efficacious in IBS (NNT of 12.5) [56]. Diarrhoea is a side effect, and in practice nausea can be an issue in up to one in five patients, although the mechanism of nausea is unknown [124]. Normally one of these options may be considered if firstline dietary and laxative therapy has failed in patients with IBS and constipation.…”

Section: Targeting Symptoms In Ibsmentioning

confidence: 99%

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

2015

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Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brain-gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2 % of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases.For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-togut and gut-to-brain pathways appear to be activated.

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“…The combined results of 2 large phase III trials (n = 1,171) demonstrated a modest efficacy for overall response (17.9 vs. 10.1%, p = 0.001) [38]. The most common adverse event was nausea (10-25%), which was usually self-limited but caused some discontinuations [39]. …”

Section: Treatments Targeting Constipation In Ibsmentioning

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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Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation

Abstract: SUMMARY BackgroundIrritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities.

Cited by 96 publications

References 19 publications

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

Modern Management of Irritable Bowel Syndrome: More Than Motility

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