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Constipation-predominant Irritable Bowel Syndrome (constipation-predominant + irritable_bowel_syndrome)
Selected AbstractsStudy on functional constipation and constipation-predominant irritable bowel syndrome by using the colonic transit test and anorectal manometryJOURNAL OF DIGESTIVE DISEASES, Issue 4 2002Li Xing ZHAN OBJECTIVE: To investigate the visceral perception, anorectal pressure and colonic transit time (CTT) in patients with functional constipation and constipation-predominant irritable bowel syndrome (C-IBS), and to study the manometric abnormalities of these two conditions. METHODS: The CTT in patients with functional constipation and C-IBS was studied by using radiopaque markers. Rectal visceral perception thresholds, rectal compliance and anorectal pressure were examined by electric barostat. RESULTS: The CTT in both groups of constipated patients was abnormal. A lot of radiopaque markers remained in the right colon in C-IBS patients, whereas in patients with functional constipation, the radiopaque markers remained in each segment of the colon. The anorectal resting pressure, squeezing pressure and relaxation pressure were normal in both groups. Rectal compliance and defecation thresholds were much higher compared with controls, and the rectal visceral perception of functional constipation was also abnormal. CONCLUSIONS: The motility abnormalities of functional constipation and C-IBS occurred in different colonic segments. Results suggest that CTT measurement and anorectal manometry could be helpful in the differential diagnosis of these two conditions. [source] Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral painNEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2010H. Eutamene Abstract Background, Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). Methods,Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. Key Results,In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. Conclusions & Inferences,These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C. [source] Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2004Michael Hall Abstract Dexloxiglumide (DEX) is a cholecystokinin type-1 receptor antagonist under development for the treatment of constipation-predominant irritable bowel syndrome. Studies of the potential interaction of DEX with human cytochromes P450 (CYPs) were conducted in vitro. DEX (300µM), both with and without a 15-min pre-incubation, was incubated with pooled human liver microsomes and substrates selective for each of eight CYPs. This resulted in >30% inhibition of tolbutamide 4-methyl-hydroxylase (CYP2C9/10) and lauric acid 11-hydroxylase (CYP2E1) activities. Mean Ki (SD) for CYP2C9/10 and CYP2E1 were 69.0 (24.3) and 426 (60)µM, respectively. Incubations of [14C]DEX with pooled human liver microsomes produced one major phase I metabolic fraction, with Vmax=131 pmol/min/mg protein and Km=23.7µM. Further incubations with (i) liver microsomes from 16 individual donors (correlation analysis), (ii) SupersomesÔ and (iii) selective chemical inhibitors, implicated CYP3A4/5, CYP2B6 and CYP2C9 in the formation of this component. Thus, DEX interacts with CYP2C9 both as inhibitor (Ki=69.0µM) and as substrate in vitro. However, based on the maximum concentration (27µM) after repeated oral doses of 200mg t.i.d. and the unbound fraction (0.03) of DEX in human plasma, no clinically relevant metabolic interactions with other CYP substrates are predicted. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||