Tag Archives: guanylin

FDA Approves Plecanatide (Trulance) for Adults with Idiopathic Constipation

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Here’s the link: FDA approves Trulance for Chronic Idiopathic Constipation (Jan 19.2017).  Plecanatide is a guanylate cyclase-C agonist.

An excerpt:

Trulance, taken orally once daily, works locally in the upper GI tract to stimulate secretion of intestinal fluid and support regular bowel function.

The safety and efficacy of Trulance were established in two 12-week, placebo-controlled trials including 1,775 adult participants. Participants were randomly assigned to receive a placebo or Trulance, once daily. Participants in the trials were required to have been diagnosed with constipation at least six months prior to the study onset and to have less than three defecations per week in the previous three months, as well as other symptoms associated with constipation. Participants receiving Trulance were more likely to experience improvement in the frequency of complete spontaneous bowel movements than those receiving placebo, and also had improvements in stool frequency and consistency and straining.

Trulance should not be used in children less than six years of age due to the risk of serious dehydration… The safety and effectiveness of Trulance have not been established in patients less than 18 years of age.

The most common and serious side effects of Trulance was diarrhea.

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Diarrhea, GC-C and guanylin

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During my fellowship, I participated in research studying the effects of guanylin and its interaction with the receptor, guanylate cyclase C (GC-C).  So whenever clinical articles demonstrate clinical significance, I am interested.  This month there is evidence that some cases of familial diarrhea are due to mutations which activate the GC-C receptor (NEJM 2012; 366: 1586-95).

The authors describe a novel dominant disease in 32 members of a Norwegian family due  to a mutation in the sequence of GUCYC which encodes GC-C.  Exposure of this mutant receptor to its ligands results in increased cyclic guanosine monophosphate (cGMP).  This in turn likely causes hyperactivation of the cystic fibrosis transmembrance regulator (CFTR)  resulting in diarrhea.  Individuals with this mutation tended to have mild chronic diarrhea with an early onset as well as a susceptibility to inflammatory bowel disease and small bowel obstruction.

While this mutation is rare, there is a larger role for GC-C.  Heat-stable enterotoxins form E. coli bind to this receptor starting a cascade which results in diarrhea.  Since there had to be a role for GC-C other than facilitating development of diarrhea after exposure to pathogens (Why would our body create a receptor for a pathogen?), researchers discovered an endogenous ligand for GC-C, guanylin.   Guanylin acts as an agonist of  GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.  In addition, guanylin and GC-C serve as a model for intestinal gene regulation.  Also, GC-C has been investigated as a predictive marker for colorectal cancer and for a role in renal electrolyte transport in humans; in animals, GC-C and its ligands have been shown to have effects on behavior and satiety.  

Additional references:

  • -Steinbrecher KA, Cohen MB. Transmembrane guanylate cylase in intestinal pathophysiology. Curr Opin Gastroenterol 2011; 27: 139-45.
  • -Gastroenterology 2010; 138: 886.  Linaclotide -a guanylin analog –use for constipation.
  • -Hochman JA, Sciaky D, Whittaker T, Hawkins JA, Witte DP, Cohen MB. “HNF-1 Regulates the Transcriptional Activation of Guanylin” Am. J.  Physiol. 273 (Gastrointest. Liver Physiol. 36): G833-G841, 1997.
  • It’s often elemental  Previous post discusses protracted diarrhea of infancy