Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract

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

doi:10.1016/j.lfs.2010.03.015

Cited by 157 publications

(148 citation statements)

References 27 publications

(28 reference statements)

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“…Finally, the role of GC-C in chloride secretion can be exploited in the treatment of constipation as suggested by a recent study on linaclotide, a GC-C agonist (35). Our finding of a polar response to GC-C provides a novel view of the role of GC-C.…”

Section: Discussionmentioning

confidence: 57%

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

et al. 2011

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Guanylin receptor guanylate cyclase (GC-C) peaks in neonatal intestine and is involved in either enterocyte proliferation or chloride secretion. The latter is more potent when GC-C activator guanylin, or its analog Escherichia coli heat-stable enterotoxin (ST), is added to the mucosal rather than serosal side of intestinal monolayers. By using Ussing chambers, we investigated transepithelial ion transport and enterocyte proliferation and their mechanisms in response to the addition of guanylin or ST to the mucosal or serosal side of Caco-2 monolayers and in ileal specimens from neonates. GC-C activation showed a polar pattern of the effects. GC-C mucosal activation resulted in a potent cGMP-chloride secretion activation and in a marginal enterocyte proliferation. Conversely, serosal GC-C activation induced a potent enterocyte proliferation, through MAP kinase ERK 1/2. Finally, the inhibition of ERK1/2 enhanced the Isc increase in response to serosal but not to mucosal ST stimulation, indicating that ERK1/2 also acts as a brake of chloride secretion. These data suggest that the guanylin/GC-C system plays a key role in early postnatal intestinal adaptation exploiting the polar structure of enterocyte. (Pediatr Res 69: 17-22, 2011) T he human intestinal epithelium is organized in crypt-villus units with stem cells in the crypt that proliferate and mature while migrating along the villus (1). The mature enterocyte is a polarized cell whose structure is functional to create a barrier between the intestinal environment and the bloodstream and to transport ions, solutes, and macromolecules between the apical and basal compartments (2). A number of autocrine and paracrine messengers act on either side of the enterocyte to modulate these functions (3). Human guanylin is one such modulator, and similar to its bacterial analog, Escherichia coli heat-stable enterotoxin (ST), it binds to intestinal guanylyl cyclase C (GC-C) and induces an increase in cGMP (4) that triggers active chloride secretion. GC-C receptors are located along the entire intestine of mammals including humans (5-7). However, GC-C is in a polar fashion distributed in the enterocyte, with a lower receptor density in the basolateral than in brush border membranes (8). We previously reported that the rate of chloride secretion is lower when guanylin is added to the basolateral side than to the apical side of intestinal epithelium mounted in Ussing chambers (9).In addition, guanylin receptor density is age dependent (7), and the number of GC-C receptors is highest in the small intestine and colon of newborn infants and decreases with age (10). Because GC-C peaks sharply at birth, we suggested that the abundance of GC-C receptors in neonates induces copious intestinal water secretion on guanylin stimulation that allows meconium expulsion in the very first days of life (9). Guanylin is the endogenous ligand of GC-C. It is produced in intestinal cells, is detected in both the intestinal lumen and the blood (11), and induces chloride secretion. E. coli ...

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Section: Discussionmentioning

confidence: 57%

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

et al. 2011

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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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“…6.3.7. Linaclotide An agonist of guanylatecyclase, linaclotide is a unique agent which was recently approved by both American and European regulatory agencies for the treatment of IBS-C. Stimulation of guanylatecyclase receptors leads to increased secretion of both guanylin and uroguanylininto the intestinal lumen where they act as a second messenger for both fluid and electrolyte release into the large bowel 27 . Linaclotide is minimally absorbed and has a strong affinity for the guanylatecyclase receptor.…”

Section: 5 Fibermentioning

confidence: 99%

Approach to a Child with Irritable Bowel Syndrome: A Review

Rukunuzzaman

Karim

Mazumder

et al. 2017

J. Natl Inst. Neurosci Bangladesh

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Irritable bowel syndrome (IBS) is one of the most common and best studied disorders among the group of functional gastrointestinal disorders. It is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Visceral hypersensitivity and increased GIT motility are the main patho-physiological mechanism for developing IBS. IBS present with diarrhoea or constipation or both.

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Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract

Cited by 157 publications

References 27 publications

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

Polar Effects on Ion Transport and Cell Proliferation Induced by GC-C Ligands in Intestinal Epithelial Cells

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

Approach to a Child with Irritable Bowel Syndrome: A Review

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