Effect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome

Andresen, Viola; Camilleri, Michael; Busciglio, Irene; Grudell, April; Burton, Duane D.; McKinzie, Sanna; Foxx‐Orenstein, Amy E.; Kurtz, Caroline B.; Sharma, Vineeta; Johnston, Jeffrey M.; Currie, Mark G.; Zinsmeister, Alan R.

doi:10.1053/j.gastro.2007.06.067

Cited by 218 publications

(143 citation statements)

References 25 publications

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“…Induction of this proteolytic system may increase the quantity of active uroguanylin at the hypothalamus and thus increase satiation. The potential for developing therapies targeted to this pathway is underscored by the recent advance of GUCY2C ligands into late-stage therapeutic trials for irritable bowel syndrome and chronic constipation (46).…”

Section: Discussionmentioning

confidence: 99%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

138

275

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Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino

Lin²,

Snook³

et al. 2011

J. Clin. Invest.

138

275

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“…Activation of intestinal GC-C induces secretion of fluid, sodium and bicarbonate in the intestinal lumen (118). Linaclotide is a synthetic GC-C agonist.…”

Section: New Agentsmentioning

confidence: 99%

Irritable bowel syndrome; update on pathophysiology and management

Quigley¹,

Craig²

2012

Turk J Gastroenterol

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The functional gastrointestinal disorders (FGID) are symptom-based disorders that cannot be currently explained by definable structural or biochemical causes (1). These disorders are common: the presence of at least one functional GI disorder was identified in 70% of participants in a large US householder survey (2). An associated co-morbid psychiatric condition such as anxiety, mood or panic disorder is seen in up to 60% of those attending gastroenterology outpatient clinics with a functional compliant (3). Functional GI disorders are associated with significant impairment of quality of

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“…It is evidenced that linaclotide specifically mimics the guanylate cyclase-C receptor for stimulating fluid secretion and transit in the intestine and is effective for chronic gastrointestinal disorders [3][4][5]. In addition to intestinal secretagogue, linaclotide has been demonstrated to be an efficient antihyperalgesic during stress-induced hypersensitivity (chemical-induced acute colitis and other stress conditions) in rat models [6].…”

Section: Introductionmentioning

confidence: 99%

Stress testing of linaclotide: Development of a validated stability-indicating RP-HPLC method

Pyla¹,

Sahu²,

Srinivas³

2017

Acta Chromatographica

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Summary.Linaclotide, a first-in-class guanylate cyclase-C agonist, was recently approved by US Food and Drug Administration (FDA) as a promising pharmacotherapy for the management of constipation-predominant irritable bowel syndrome (IBS). In this communication, we present a novel stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantitative determination of linaclotide along with its degradation products. During the International Conference on Harmonization (ICH) prescribed stress study, linaclotide was found susceptible to degrade under hydrolytic (acid and base) and oxidative (peroxide) conditions. The separation of the degradants from the analyte was achieved on a Zorbax Eclipse XDB C 8 Column (250 mm × 4.6 mm, 5 μm) using 0.01 N potassium dihydrogen orthophosphate buffer and acetonitrile (80:20 v/v) as mobile phase at a flow rate of 1.00 mL min −1 at column temperature of 40 °C. The detection of the column effluents was realized on a photodiode array detector set at 220 nm. Under the above optimal condition, the method was validated with respect to specificity, linearity, range, precision, robustness, and sensitivity in compliance to the regulatory requirements.

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Effect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome

Cited by 218 publications

References 25 publications

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Irritable bowel syndrome; update on pathophysiology and management

Stress testing of linaclotide: Development of a validated stability-indicating RP-HPLC method

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