The irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more common in women than men. Female serotonin transporter (SERT) gene knockout (KO) rats exhibit hypersensitivity to colorectal balloon distention (CRD) that mimics colonic hypersensitivity occurring in female IBS patients. Alosetron, (5-HT3 receptor antagonist), is used to treat diarrhea-predominant IBS in female patients. Other 5-HT3 receptor antagonists are ineffective in treating IBS symptoms. The visceromotor response (VMR) to CRD in SERT KO and wild type (WT) rats was measured following subcutaneous (s.c.), intracerobroventricular (i.c.v.) or intrathecal (i.t.) treatment with 5-HT3 receptor antagonists and an agonist. Alosetron (s.c.) and granisetron (antagonists) caused a paradoxical increase in the VMR to CRD in SERT KO female rats. Alosetron (s.c.) increased the VMR to CRD in WT male rats. Alosetron (i.t.) increased the VMR to CRD in SERT KO female rats only and the 5-HT3 receptor agonist, SR 52772, increased the VMR to CRD in SERT KO male rats. Depletion of spinal 5-HT using 5,7-dihydroxytryptamine prevented the increase in VMR to CRD in SERT KO female and male rats treated i.t. with alosetron and SR 52772, respectively. Alosetron (i.c.v.) did not affect the VMR to CRD in WT or KO female rats but it increased the VMR in male SERT KO but not WT male rats. These data suggest that 5-HT3 receptor signaling at the dorsal spinal cord mediates visceral hypersensitivity in female SERT KO rats. Such differences could facilitate development of sex-specific drug treatments for visceral pain.

Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain that occurs with defecation or alterations in bowel habits. Further classification is based on the predominant bowel habit: constipation-predominant IBS, diarrhea-predominant IBS (IBS-D), or mixed IBS. The pathogenesis of IBS is unclear and is considered multifactorial in nature. GI dysbiosis, thought to play a role in IBS pathophysiology, has been observed in patients with IBS. Alterations in the gut microbiota are observed in patients with small intestinal bacterial overgrowth, and overgrowth may occur in a subset of patients with IBS. The management of IBS includes therapies targeting the putative factors involved in the pathogenesis of the condition. However, many of these interventions (eg, eluxadoline and alosetron) require long-term, daily administration and have important safety considerations. Agents thought to modulate the gut microbiota (eg, antibiotics and probiotics) have shown potential benefits in clinical studies. However, conventional antibiotics (eg, neomycin) are associated with several adverse events and/or the risk of bacterial antibiotic resistance, and probiotics lack uniformity in composition and consistency of response in patients. Rifaximin, a nonsystemic antibiotic administered as a 2-week course of therapy, has been shown to be safe and efficacious for the treatment of IBS-D. Rifaximin exhibits a favorable benefit-to-harm ratio when compared with daily therapies for IBS-D (eg, alosetron and tricyclic antidepressants), and rifaximin was not associated with the emergence of bacterial antibiotic resistance. Thus, short-course therapy with rifaximin is an appropriate treatment option for IBS-D.

No information is available on the use of alosetron during breastfeeding. Because of relatively high protein binding and only moderate bioavailability, exposure of the breastfed infant is likely to be low. If alosetron is required by the mother, it is not a reason to discontinue breastfeeding. However, until more data are available alosetron should only be used with careful infant monitoring during breastfeeding.

Objective: To establish a canine model of slow transit constipation (STC), and to test the changes in defecation, gastrointestinal transit time and pathology sections. Methods: Baseline information was measured in 8 beagle dogs, and these dogs were randomly divided into the control group and the model group. The dogs in model group were given a diet of canned meat, as well as a combination of compound diphenoxylate and alosetron hydrochloride for 5 weeks. Dogs in control group were given normal diet with no special intervention. Stool frequency and consistency were observed and recorded daily, and the gastrointestinal transit time (GITT) were measured every week. All animals underwent the midline laparotomy and the colonic tissues were taken from the rectosigmoid colon, then investigated by light microscopy, electron microscopy, and immunohistochemistry to evaluate changes of protein gene product 9.5(PGP9.5), synaptophysin and c-kit between two groups. Results: 8 beagle dogs underwent all experiment items successfully.Both of the stool frequency and scores of stool consistency decreased in model group(F=6.568, P=0.043; F=25.954, P=0.002). GITT delayed in model group(F=42.573, P=0.001). After 5 weeks of intervention, in the model group, the myenteric neurons and interstitial cells of Cajal showed damage such as swelling of mitochondria under electron microscopy, and both of the PGP9.5 and synaptophysin integrated option density of rectosigmoid colon were decreased (t=3.471, P=0.013; t=2.506, P=0.046)under immunohistochemistry. The c-kit integrated option density showed no statistically significant differences between two groups(t=1.709, P=0.138). Conclusions: The canine model of STC which was consistent with clinical symptoms and pathological changes was successfully established, and it can be used to observe and evaluate the therapeutic effect of electrical stimulation, surgery and so on.

The objectives are to review the role of pharmacogenomics in drug metabolism of medications typically used in patients with irritable bowel syndrome (IBS) focusing predominantly on cytochrome P450 metabolism. Other aims are to provide examples of genetic variation of receptors or intermediary pathways that are targets for IBS drugs and to critically appraise the situations where precision medicine is impacting health in IBS. Pharmacogenomics impacts both pharmacokinetics and pharmacodynamics. Although large clinical trials have not incorporated testing for genetic variations that could impact the efficacy of medications in IBS, there are therapeutic advantages to inclusion of pharmacogenomics testing for individual patients, as has been demonstrated particularly in the treatment with central neuromodulators in psychiatry practice. Clinical practice in IBS is moving in the same direction with the aid of commercially available tests focused on drug metabolism. Specific mechanisms leading to pathophysiology of IBS are still poorly characterized, relative to diseases such as cancer and inflammatory bowel disease, and, therefore, pharmacogenomics related to drug pharmacodynamics is still in its infancy and requires extensive future research. With increased attention to pharmacogenomics affecting drug metabolism, it is anticipated that pharmacogenomics will impact care of IBS.

Irritable bowel syndrome (IBS), a complex disorder of the gastrointestinal tract, is characterized by abdominal pain associated with defecation or changes in stool form or frequency. IBS is associated with substantial burden, including direct medical costs and indirect costs. Direct costs associated with IBS in the United States have been estimated to exceed $1 billion. However, indirect costs, such as negative effect on quality of life (QOL) and work productivity, are difficult to quantify. There are 3 main subtypes: IBS with prominent diarrhea (IBS-D), IBS with constipation, and IBS with mixed symptoms of both constipation and diarrhea. A number of pharmacologic agents have been used to treat IBS-D despite lack of approval by the FDA for this indication. The pharmacologic agents that are indicated by the FDA for the treatment of IBS-D include alosetron, eluxadoline, and rifaximin. The negative impact of IBS-D symptoms on QOL reported by patients indicate there is an unmet need for therapies that effectively treat and manage the symptoms of this condition. Addressing gaps in treatment is an important priority.