{"id":587,"date":"2016-12-29T01:30:25","date_gmt":"2016-12-29T06:30:25","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=587"},"modified":"2016-12-29T01:31:42","modified_gmt":"2016-12-29T06:31:42","slug":"linaclotide-novel-therapy-for-the-treatment-of-chronic-idiopathic-constipation","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/linaclotide-novel-therapy-for-the-treatment-of-chronic-idiopathic-constipation\/","title":{"rendered":"Linaclotide, Novel Therapy for the Treatment of Chronic Idiopathic Constipation"},"content":{"rendered":"

Chronic constipation (CC) and irritable bowel\u00a0syndrome with constipation (IBS-C) are common\u00a0gastrointestinal (GI) disorders. The overall\u00a0prevalence of CC in the general population\u00a0is approximately 20%. CC is defined by\u00a0infrequent bowel movements (less than three\u00a0bowel movements per week) with associated\u00a0straining or the sense of incomplete emptying\u00a0of the bowel. IBS-C is defined by constipation\u00a0with recurrent abdominal pain that is generally\u00a0relieved by defecation.<\/p>\n

Treatments for CC in the current US market\u00a0include nonprescription and prescription\u00a0medications. Nonprescription medications\u00a0include stool softeners, fiber supplements,\u00a0osmotic and stimulant laxatives, such as\u00a0polyethylene glycol and milk of magnesia and\u00a0bisacodyl, respectively. Lubiprostone is the only\u00a0prescription medication approved in the US\u00a0for CC and IBS-C. Tegaserod was a previously\u00a0approved medication for IBS-C that, although\u00a0effective, was withdrawn from the US market\u00a0due to reported adverse effects. Overall, these\u00a0treatments have variable benefit and efficacy, and\u00a0there is still great demand for more efficacious\u00a0and safer treatments for these chronic conditions.\u00a0Newer therapies for CC and IBS-C have been\u00a0developed with novel mechanism of actions.\u00a0Other agents that are either in clinical trials or\u00a0approved in Europe to treat CC or IBS-C include\u00a0the uroguanylin (UG) analog plecanatide;\u00a0prokinetics such as prucalopride<\/a>, velusetrag,\u00a0and naronapride;\u00a0and the ileal bile acid\u00a0transporter inhibitor, elobixibat, which increases\u00a0bile acid concentration in the colon leading to\u00a0accelerated colonic transit.<\/p>\n

LINACLOTIDE<\/a>
\nLinaclotide is a 14-amino acid peptide with\u00a0three disulfide bonds with a structure\u00a0analogous to the endogenous peptides GN\u00a0and UG. Linaclotide is stabilized by three\u00a0intramolecular disulfide bonds, similar to\u00a0the two disulfide bonds in GN and UG.\u00a0However, the UG sequence has two N-terminal\u00a0aspartate residues that are not in the amino acid\u00a0sequence of linaclotide.\u00a0Linaclotide is a guanylin (GN) and UG analog\u00a0that activates the guanylate cyclase-C (GC-C)\u00a0receptor. GN and UG are endogenous peptides\u00a0of the GN peptide family that are produced by\u00a0the enteroendocrine cells and activate the GC-C\u00a0receptor, increasing intestinal fluid secretion.\u00a0The GC-C receptor is expressed in enterocytes\u00a0from the small intestine to the distal colon and it\u00a0is the transmembrane receptor for the heat stable\u00a0enterotoxin (STa) responsible for acute secretory\u00a0diarrhea. Activation of the GC-C receptor\u00a0on the lumen of intestinal epithelial cells\u00a0stimulates the intrinsic GC-C activity that leads\u00a0to increases in intracellular cyclic guanosine\u00a0monophosphate (cGMP), which in turn leads to\u00a0phosphorylation of a cGMP-dependent protein\u00a0kinase II and phosphorylation of the cystic\u00a0fibrosis transmembrane conduction regulator\u00a0(CFTR). Activation of the CFTR channel results\u00a0in chloride and fluid secretion into the lumen\u00a0that leads to increased colonic transit.<\/p>\n

Mechanism of Action
\nLinaclotide binds to the GC-C receptor\u00a0and stimulates intestinal secretion by\u00a0increasing the production of cGMP. Increased\u00a0intracellular cGMP leads to phosphorylation\u00a0of a cGMP-dependent protein kinase II and\u00a0phosphorylation of the CFTR, which results\u00a0in chloride anion and fluid secretion into the\u00a0intestinal lumen.\u00a0The GC-C receptor is\u00a0the key receptor for the STa. These enterotoxins\u00a0are produced by organisms, such as Escherichia<\/i><\/em>\u00a0<\/i><\/em>coli<\/i><\/em>, and activate the GC-C receptor causing an\u00a0acute secretory diarrhea. The specific function of\u00a0this receptor has been confirmed in GC-C null\u00a0mice, which fail to elicit the STa stimulation\u00a0of fluid accumulation within the intestines,\u00a0evidence of the function of this receptor in\u00a0intestinal fluid secretion.\u00a0In vitro studies using human carcinoma\u00a0T84 cells have demonstrated that the binding\u00a0of linaclotide occurs in the luminal side of\u00a0the intestine. The selective binding of\u00a0linaclotide to the GC-C receptor was studied\u00a0with a competitive radioligand-binding assay\u00a0using a radiolabeled heat-stable enterotoxin\u00a0[125<\/sup>I]-STa in GC-C wild-type and null mice. In\u00a0wild-type mice, linaclotide inhibited binding\u00a0of [125<\/sup>I]-STa in a concentration-dependent\u00a0manner. However, in GC-C null mice a\u00a0low level of residual binding of [125<\/sup>I]-STa\u00a0to intestinal mucosa was demonstrated, an effect that was inhibited by linaclotide.\u00a0This is evidence that linaclotide binds to the\u00a0GC-C receptor and that this effect is abolished\u00a0in GC-C null mice.<\/p>\n

 <\/p>\n

Reference:<\/h4>\n

Maria I. Vazquez-Roque \u00b7 Ernest P. Bouras. Adv Ther (2013) 30(3):203\u201311.<\/p>\n","protected":false},"excerpt":{"rendered":"

Chronic constipation (CC) and irritable bowel\u00a0syndrome with constipation (IBS-C) are common\u00a0gastrointestinal (GI) disorders. The overall\u00a0prevalence of CC in the general population\u00a0is approximately 20%. CC is defined by\u00a0infrequent bowel movements (less […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[373,374,327],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/587"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=587"}],"version-history":[{"count":3,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/587\/revisions"}],"predecessor-version":[{"id":590,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/587\/revisions\/590"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=587"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=587"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=587"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}