Linaclotide - a secretagogue and antihyperalgesic agent - what next?

Abstract

Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose-effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors.

• Authors: A E Bharucha, D R Linden
• Journal: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society (Neurogastroenterol Motil) Vol. 22 Issue 3 Pg. 227-31 (Mar 2010) ISSN: 1365-2982 [Electronic] England
• PMID: 20377786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Peptides
• linaclotide

Topics

• Animals
• Clinical Trials as Topic
• Colon (drug effects)
• Constipation (complications, drug therapy)
• Humans
• Irritable Bowel Syndrome (complications, drug therapy)
• Peptides (therapeutic use)
• Rats