Linaclotide

Linaclotide (marketed under the trade name Linzess in the US and Mexico, and as Constella elsewhere) is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others are gastrointestinal. Linaclotide (marketed under the trade name Linzess in the US and Mexico, and as Constella elsewhere) is a drug used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause.It has a black box warning about the risk of serious dehydration in children in the US; the most common adverse effects in others are gastrointestinal. It is an oligo-peptide agonist of guanylate cyclase 2C and remains in the GI tract after it is taken orally. It was approved in the US and Europe in 2012. It is priced at around $400 for thirty pills in the US and is marketed by Allergan in most of the world and by Astellas in Asia; Ironwood Pharmaceuticals was the originator. Linaclotide is used to treat irritable bowel syndrome with constipation and chronic constipation with no known cause. It has not been tested in pregnant women and it is unknown if it is excreted in breast milk. The US label has a black box warning to not use linaclotide in children less than 6 years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration. More than 10% of people taking linaclotide have diarrhea. Between 1% and 10% of people have decreased appetite, dehydration, low potassium, dizziness when standing up too quickly, nausea, vomiting, urgent need to defecate, fecal incontinence, and bleeding in their colon, rectum, and anus. Systemic absorption of the globular tetradecapeptide is minimal. Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C). The medication binds to the surface of the intestinal epithelial cells. Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C increases cyclic guanosine monophosphate (cGMP). Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel activation. This results in increased intestinal fluid and accelerated transit. By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain; and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.