Luminary Learning Gastrointestinal Disorder- Issue 1

18  • LUMINARY LEARNING: GASTROINTESTINAL DISORDERS (DPP IV)] [20]. Opioid receptors are widely distributed in the human body. All opioid recep- tor subtypes have been localized in the gastrointestinal tract of many mammalian organisms. In human body the highest concentration of MOR in the human body has been detected in the myenteric and submucosal plexuses, on immune cells in the lamina propria and ileal longitudi- nal muscle. DOR was detected in the enteric ganglia and fibers of esophagus, duodenum, ileum, cecum as well as in the proximal, and distal colon. KORs were localized on the myenteric and submucosal neurons, smooth muscle fibres as well as mucosa in rats [21]. Furthermore, opioid receptors were also found in high amounts on lymphocytes and macrophages, which suggest their involvement in the modulation of function of these cells [22]. EOS is crucially involved in numer- ous physiological processes, including pain signaling in the central and the peripheral nervous system, and respiration. In the GI tract opioid receptors play a major role in the regulation of GI transit, secretion and immune responses. The major effects of opioid receptor agonists in the GI tract are reduc- tion of intestinal contractility and impairment of peristalsis caused by blockade of neurotrans- mitter release [22]. Moreover opioids promote water and electrolyte absorption thus decreasing the volume of intestinal content and frequency of excretion. On the other hand, Moreover, both natural and synthetic opioid agonists exhibit potent analgesic effects and decrease abdominal pain in both physiological and pathophysiological conditions [23–25]. To date, several EOS-targeting compounds reached the market and found a place in the clinical treatment of GI-related condi- tions (e.g. loperamide, alvimopan, oxycodone, racecadotril; for comprehensive review please see Mosinska et al. [21]). Pharmacological Treatment of Diarrhea-Predominant IBS (IBS-D) Alosetron Alosetron is a 5-HT3 receptor antagonist is effective for the treatment of IBS-D in women. It is a therapeutic agent with a limited use and is available only for severe and unresponsive to other agents IBS-D cases. It improves pain and discomfort as well as stool frequency and urgency [7, 26]. Alosetron was approved by the U.S. Food and Drug Administration (FDA) in 2000, after a seven month review process. However, eight months later it was removed from the market fol- lowing reports of serious complications, such as severe constipation and ischemic colitis that, in several cases, lead to a surgery. In 2002 FDA reconsidered the case of alosetron and reintro- duced it to the market under a risk management plan with a lower recommended starting dose of 0.5 mg twice daily [7]. In 2005 and 2007 Chang et al. [27] and Krause et al. [28] respectively, have shown the effectiveness of alosetron in the treatment of IBS-D both in men (n = 662) and women (n = 705) reporting low incidence of serious adverse events. The recent 9-year evaluation of trends in alosetron postmarketing safety under the risk management program indicate that incidence of ischemic colitis and constipation remain rare and stable, at approximately 1 case/1000 patient- years [29]. The indications for alosetron in women with severe IBS-D include: (i) chronic IBS symptoms (generally lasting 6 months or longer), (ii) the absence of anatomic or biochemical