Linaclotide - a secretagogue and antihyperalgesic agent - what next?
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.
Bharucha
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From the Enteric Neurosciences Program, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN, USA. bharucha.adil@mayo.edu
Linden
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D000818:Animals; D002986:Clinical Trials as Topic; D003106:Colon / Q000187:drug effects*; D003248:Constipation / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy*; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats
D010455:Peptides; C523483:linaclotide