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Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Parker CH, Yuan Y, Liu LW - Clin Med Insights Gastroenterol (2013)

Bottom Line: Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders.Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients.Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

No MeSH data available.


Related in: MedlinePlus

Mechanism of Action of Linaclotide. Linaclotide binds to the guanylate cyclase C (GC-C) receptor on the luminal side of intestinal epithelial cells, causing activation of the intracellular cyclic 3′,5′-monophosphate (cGMP) pathway.8 Subsequently, the cGMP-dependent protein kinase II (PKG II) is activated which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR).9,10 This leads to chloride (Cl−) and bicarbonate  secretion from the cell, promoting excretion of sodium (Na+) from the basolateral cell membrane through tight junctions into the lumen and diffusion of water (H2O) out of cells.10,42 Furthermore, the activation of GC-C and production of cGMP appear to modulate the sensitivity of nociceptors to mechanical stimuli. The exact molecular mechanism of this anti-nociceptive effect of linaclotide has yet to be elucidated. Initial in vitro studies suggest it is an effect of extracellular cGMP on nociceptors found on colonic afferent pain fibers.10,14,15Abbrevations: ATP, adenosine triphosphate; K+, potassium.
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f1-cgast-6-2013-021: Mechanism of Action of Linaclotide. Linaclotide binds to the guanylate cyclase C (GC-C) receptor on the luminal side of intestinal epithelial cells, causing activation of the intracellular cyclic 3′,5′-monophosphate (cGMP) pathway.8 Subsequently, the cGMP-dependent protein kinase II (PKG II) is activated which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR).9,10 This leads to chloride (Cl−) and bicarbonate secretion from the cell, promoting excretion of sodium (Na+) from the basolateral cell membrane through tight junctions into the lumen and diffusion of water (H2O) out of cells.10,42 Furthermore, the activation of GC-C and production of cGMP appear to modulate the sensitivity of nociceptors to mechanical stimuli. The exact molecular mechanism of this anti-nociceptive effect of linaclotide has yet to be elucidated. Initial in vitro studies suggest it is an effect of extracellular cGMP on nociceptors found on colonic afferent pain fibers.10,14,15Abbrevations: ATP, adenosine triphosphate; K+, potassium.

Mentions: Linaclotide is a GC-C receptor agonist that shares its mechanism of action with the endogenous molecules guanylin and uroguanylin, and with bacterial heat stable enterotoxins. Guanylin and uroguanylin, produced by enterocytes in the duodenum and colon, are responsible for the regulation of water and electrolyte secretion in the gastrointestinal tract by binding GC-C on the luminal surface of epithelial cells. This activates the cyclic 3′,5′-monophosphate (cGMP) signaling pathway,8 which in turn activates the cGMP-dependent protein kinase II (PKG II).9,10 PKG II activates the cystic fibrosis transmembrane conductance regulator (CFTR) that increases chloride and bicarbonate secretion from the epithelial cell10 (Fig. 1). This subsequently promotes sodium excretion and water diffusion from the cell into the intestinal lumen, thus decreasing colonic transit time.10 Heat stable enterotoxins produced by Escherichia coli act on the same pathway to cause diarrhea in an infected host.11 In an in vitro study, linaclotide was found to inhibit the ability of bacterial heat stable enterotoxin to bind to GC-C, confirming that GC-C is the molecular target of linaclotide.12


Linaclotide: a new option for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

Parker CH, Yuan Y, Liu LW - Clin Med Insights Gastroenterol (2013)

Mechanism of Action of Linaclotide. Linaclotide binds to the guanylate cyclase C (GC-C) receptor on the luminal side of intestinal epithelial cells, causing activation of the intracellular cyclic 3′,5′-monophosphate (cGMP) pathway.8 Subsequently, the cGMP-dependent protein kinase II (PKG II) is activated which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR).9,10 This leads to chloride (Cl−) and bicarbonate  secretion from the cell, promoting excretion of sodium (Na+) from the basolateral cell membrane through tight junctions into the lumen and diffusion of water (H2O) out of cells.10,42 Furthermore, the activation of GC-C and production of cGMP appear to modulate the sensitivity of nociceptors to mechanical stimuli. The exact molecular mechanism of this anti-nociceptive effect of linaclotide has yet to be elucidated. Initial in vitro studies suggest it is an effect of extracellular cGMP on nociceptors found on colonic afferent pain fibers.10,14,15Abbrevations: ATP, adenosine triphosphate; K+, potassium.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020405&req=5

f1-cgast-6-2013-021: Mechanism of Action of Linaclotide. Linaclotide binds to the guanylate cyclase C (GC-C) receptor on the luminal side of intestinal epithelial cells, causing activation of the intracellular cyclic 3′,5′-monophosphate (cGMP) pathway.8 Subsequently, the cGMP-dependent protein kinase II (PKG II) is activated which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR).9,10 This leads to chloride (Cl−) and bicarbonate secretion from the cell, promoting excretion of sodium (Na+) from the basolateral cell membrane through tight junctions into the lumen and diffusion of water (H2O) out of cells.10,42 Furthermore, the activation of GC-C and production of cGMP appear to modulate the sensitivity of nociceptors to mechanical stimuli. The exact molecular mechanism of this anti-nociceptive effect of linaclotide has yet to be elucidated. Initial in vitro studies suggest it is an effect of extracellular cGMP on nociceptors found on colonic afferent pain fibers.10,14,15Abbrevations: ATP, adenosine triphosphate; K+, potassium.
Mentions: Linaclotide is a GC-C receptor agonist that shares its mechanism of action with the endogenous molecules guanylin and uroguanylin, and with bacterial heat stable enterotoxins. Guanylin and uroguanylin, produced by enterocytes in the duodenum and colon, are responsible for the regulation of water and electrolyte secretion in the gastrointestinal tract by binding GC-C on the luminal surface of epithelial cells. This activates the cyclic 3′,5′-monophosphate (cGMP) signaling pathway,8 which in turn activates the cGMP-dependent protein kinase II (PKG II).9,10 PKG II activates the cystic fibrosis transmembrane conductance regulator (CFTR) that increases chloride and bicarbonate secretion from the epithelial cell10 (Fig. 1). This subsequently promotes sodium excretion and water diffusion from the cell into the intestinal lumen, thus decreasing colonic transit time.10 Heat stable enterotoxins produced by Escherichia coli act on the same pathway to cause diarrhea in an infected host.11 In an in vitro study, linaclotide was found to inhibit the ability of bacterial heat stable enterotoxin to bind to GC-C, confirming that GC-C is the molecular target of linaclotide.12

Bottom Line: Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders.Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients.Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

No MeSH data available.


Related in: MedlinePlus