Linaclotide Management of Difficult Constipation
Linaclotide management of difficult constipation
Linaclotide is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors. Linaclotide is acid stable and protease resistant with low bioavailability; it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C stimulates the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), which then increases the flow of electrolytes(HCO3- and Cl–) and water into the lumen of the GI tract. This is associated with faster GI transit. Stimulation of the GC-C receptor on intestinal epithelial cells and release of cGMP into the serosa leads to a reduction in visceral hyperalgesia.
Johnston and colleagues were the first to investigate the safety, tolerability, and efficacy of linaclotide in patients with CC who met modified Rome II criteria. This multicenter, placebo-controlled pilot study published in 2009, showed that there was a trend towards a dose-dependent increase in the frequency of weekly spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs). Stool consistency, straining, and patient reported outcomes also improved in all dosing groups.