Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit

Busby, Robert; Bryant, Alexander P.; Bartolini, Wilmin; Cordero, Etchell A.; Hannig, Gerhard; Kessler, Marco M.; Mahajan-Miklos, Shalina; Pierce, Christine; Solinga, Robert; Sun, Lijun; Tobin, Jenny; Kurtz, Caroline B.; Currie, Mark G.

doi:10.1016/j.ejphar.2010.09.019

Cited by 189 publications

(179 citation statements)

References 39 publications

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“…In animal models, linaclotide has also been shown to reduce visceral hypersensitivity; this effect may be related to cGMP modulating afferent nerve activity in the extracellular space. [10][11][12] In humans, linaclotide accelerated colonic transit in a pharmacodynamics study 13 and improved abdominal pain and constipation associated with IBS-C in two large phase 3, double-blind, placebo-controlled trials. 14,15 The phase 3 trials used primary responder endpoints according to both the current FDA and EMA guidelines (primary endpoints were specified for each territory) and also examined global endpoints, including AR, to assess overall IBS symptom improvement.…”

Section: Introductionmentioning

confidence: 99%

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS‐C

et al. 2015

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Background: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. Objective: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. Methods: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. Results: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively). Conclusions: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

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Section: Introductionmentioning

confidence: 99%

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS‐C

et al. 2015

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“…Previous studies using surgically ligated intestinal loops have demonstrated in vivo linaclotide-stimulated secretion of cGMP into the luminal compartment Busby et al, 2010). Similarly, linaclotide stimulated in vitro cyclic nucleotide efflux pump-dependent basolateral release of cGMP from polarized Caco-2 cells that were concentration-dependently inhibited by the cGMP transporter inhibitor, probenecid (Castro et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…The 14-amino-acid peptide linaclotide (CCEYCCNPACTGCY) Busby et al, 2010), synthesized by solid-phase synthesis, was obtained from Polypeptide Laboratories (Torrance, CA). MK571, isobutylmethylxanthine (IBMX), and sildenafil were obtained from R&D Systems (Minneapolis, MN).…”

Section: Methodsmentioning

confidence: 99%

“…This 14-amino-acid peptide is a member of the guanylin family of cGMP-regulating peptides that includes the natural hormones guanylin and uroguanylin Busby et al, 2010). In the studies described here, we have investigated the pharmacological effects of MRP4 inhibition on linaclotide-induced transepithelial ion currents and apical/ basolateral cGMP efflux in vitro in rat colon mucosa and we propose a novel mechanism that functionally couples compartmentalized linaclotide-induced electrolyte secretion and apical cGMP efflux to spatially restricted regulation by MRP4, following linaclotide activation of the GC-C/cGMP pathway.…”

Section: Introductionmentioning

confidence: 99%

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MRP4 Modulation of the Guanylate Cyclase-C/cGMP Pathway: Effects on Linaclotide-Induced Electrolyte Secretion and cGMP Efflux

Tchernychev

Kessler

et al. 2015

J Pharmacol Exp Ther

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MRP4 mediates the efflux of cGMP and cAMP and acts as an important regulator of these secondary messengers, thereby affecting signaling events mediated by cGMP and cAMP. Immunofluorescence staining showed high MRP4 expression localized predominantly in the apical membrane of rat colonic epithelium. In vitro studies were performed using a rat colonic mucosal layer mounted in an Ussing chamber. Linaclotide activation of the guanylate cyclase-C (GC-C)/cGMP pathway induced a concentration-dependent increase in transepithelial ion current [short-circuit current (I sc )] across rat colonic mucosa (EC 50 : 9.2 nM). Pretreatment of colonic mucosa with the specific MRP4 inhibitor MK571 potentiated linaclotide-induced electrolyte secretion and augmented linaclotide-stimulated intracellular cGMP accumulation. Notably, pretreatment with the phosphodiesterase 5 inhibitor sildenafil increased basal I sc , but had no amplifying effect on linaclotide-induced I sc . MRP4 inhibition selectively affected the activation phase, but not the deactivation phase, of linaclotide. In contrast, incubation with a GC-C/Fc chimera binding to linaclotide abrogated linaclotide-induced I sc , returning to baseline. Furthermore, linaclotide activation of GC-C induced cGMP secretion from the apical and basolateral membranes of colonic epithelium. MRP4 inhibition blocked cGMP efflux from the apical membrane, but not the basolateral membrane. These data reveal a novel, previously unrecognized mechanism that functionally couples GC-C-induced luminal electrolyte transport and cGMP secretion to spatially restricted, compartmentalized regulation by MRP4 at the apical membrane of intestinal epithelium. These findings have important implications for gastrointestinal disorders with symptoms associated with dysregulated fluid homeostasis, such as irritable bowel syndrome with constipation, chronic idiopathic constipation, and secretory diarrhea.

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“…Intracellularly, cGMP increases bicarbonate and chloride secretion unto the bowel lumen, and diffuses to the extracellular compartment to inhibit sensory nerve terminal activity. From a pharmacodynamic standpoint, its ultimate effect is increased intraluminal secretion leading to enhanced transit and a visceral analgesic action, with reduced sensory thresholds to mechanical distension (120,121).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Clinical Practice Guideline: Irritable bowel syndrome with constipation and functional constipation in the adult

Mearin¹,

Ciriza²,

Mínguez³

et al. 2016

Rev Esp Enferm Dig

104

151

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In this Clinical Practice Guideline we discuss the diagnostic and therapeutic approach of adult patients with constipation and abdominal complaints at the confluence of the irritable bowel syndrome spectrum and functional constipation. Both conditions are included among the functional bowel disorders, and have a significant personal, healthcare, and social impact, affecting the quality of life of the patients who suffer from them. The first one is the irritable bowel syndrome subtype, where constipation represents the predominant complaint, in association with recurrent abdominal pain, bloating, and abdominal distension. Constipation is characterized by difficulties with or low frequency of bowel movements, often accompanied by straining during defecation or a feeling of incomplete evacuation. Most cases have no underlying medical cause, and are therefore considered as a functional bowel disorder. There are many clinical and pathophysiological similarities between both disorders, and both respond similarly to commonly used drugs, their primary difference being the presence or absence of pain, albeit not in an "all or nothing" manner. Severity depends not only upon bowel symptom intensity but also upon other biopsychosocial factors (association of gastrointestinal and extraintestinal symptoms, grade of involvement, and perception and behavior variants). Functional bowel disorders are diagnosed using the Rome criteria. This Clinical Practice Guideline has been made consistent with the Rome IV criteria, which were published late in May 2016, and discuss alarm criteria, diagnostic tests, and referral criteria between Primary Care and gastroenterology settings. Furthermore, all the available treatment options (exercise, fluid ingestion, diet with soluble fiber-rich foods, fiber supplementation, other dietary components, osmotic or stimulating laxatives, probiotics, antibiotics, spasmolytics, peppermint essence, prucalopride, linaclotide, lubiprostone, biofeedback, antidepressants, psychological therapy, acupuncture, enemas, sacral root neurostimulation, surgery) are discussed, and practical recommendations are made regarding each of them.

show abstract

Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit

Cited by 189 publications

References 39 publications

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS‐C

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS‐C

MRP4 Modulation of the Guanylate Cyclase-C/cGMP Pathway: Effects on Linaclotide-Induced Electrolyte Secretion and cGMP Efflux

Clinical Practice Guideline: Irritable bowel syndrome with constipation and functional constipation in the adult

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