Luminary Learning Gastrointestinal Disorder- Issue 1

Pharmacological and Clinical Treatment of Irritable Bowel Syndrome •  23 Linaclotide Linaclotide is a 14 amino acid peptide agonist of GC-C which has been approved by FDA for the treatment of IBS-C in 2012 and to date is considered as a first-in-class drug by majority of gastro- enterologists. It is characterized by low bioavailability (approx. 0.1 %), what enables local action in the intestines. Linaclotide activates GC-C and causes an increase in the level of intracellular cGMP with concomitant upregulation of HCO 3 -and chloride ions what results in an increased secretion and acceleration of intestinal transit [8]. Clinical data demonstrated that linaclotide improves severity of abdominal pain as well as bowel movements in IBS-C patients (for more details please see Jarmuz et al. [8]). Phase I trial showed that linaclotide provides relief and is well tolerated in 42 patients [61]. Rao et al. [62] reported the effects of 12-week treatment with linaclotide in IBS-C patients (n = 800). One-third of patients receiving linaclotide reached the FDA-recommended primary endpoint (improvement of ≥30 % from baseline in the average of the daily worst abdominal pain score on a standardized scale and an increase of at least 1 CSBM from baseline in the same week for at least 6 of first 12 weeks of treatment). During the withdraw- al period patients receiving linaclotide experienced sustained decrease of abdominal pain while placebo-treated patients had a gradual increase of the pain score. In another clinical study linaclo- tide administered orally improved global IBS-C symptoms during 26-week therapy [63]. In line with the previous studies linaclotide induced significant relief in approx. one-third of the patients. Abdominal discomfort, fullness, cramping and bloating were also significantly improved. The most common adverse effect, which leads to discontinuation of the medication with linaclotide is diarrhea, occurring in approximately 5 % of patients [64]. Lubiprostone Lubiprostone (approved by FDA in 2008 to treat IBS-C) is a bicyclic fatty acid derived from pros- taglandin E1 that activates ClC-2 chloride channels located on the apical area of GI epithelial cells. It is poorly absorbed from the gut what facilitates its local activity in the GI tract [65]. Although it is widely accepted that lubiprostone acts via apical CIC-2 channels, recently some novel insights into its mechanism of action have been demonstrated. It was shown that lubiprostone, not only activates apical CIC-2 channels but also induces the internalization of basolateral ClC-2 into the cytoplasm with concomitant trafficking of CFTR and chloride/hydrogen carbonate exchanger PAT-1 to the apical membrane [66]. At the molecular level events triggered by lubiprostone leads to the increased luminal secretion of chloride and decreased absorption of this ion by basolateral CIC-2 channels. These events soften the stool, increase motility, and promote SCBMs. In clinical trials lubiprostone was shown to improve SCBMs frequency after 1 week of therapy. Of note, some of the patients (approx. 55 %) experienced a relief in the first day of the treat- ment. Improved stool consistency, straining, and constipation severity, as well as patient-reported assessments of treatment effectiveness, were also reported [67–69]. The most common adverse events of lubiprostone are nausea, diarrhea, headache and abdominal distention.