REVIEW Novel strategies and future landmarks in the treatment of irritable bowel syndrome Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by continuous or remittent abdominal pain, bloating and altered defecation. The population-based prevalence of IBS has been reported to be approximately 3–20%, depending on the diagnostic criteria. Despite intense research in recent decades, the pathogenesis of IBS remains only partially understood, and thus no specific and universally effective patient management has been developed so far. Current therapy for IBS focuses on the major symptoms, while a novel approach in the treatment is based on targeting specific receptors in the gastrointestinal tract that are known to be involved in the pathogenesis of the disease. In view of the severe side effects of early serotonin receptor modulators, a good safety profile is of primary importance in the treatment of functional gastrointestinal disorders. This article provides a pathogenesis-based overview of recently developed pharmaceutics and future perspectives on the therapy of IBS. † KEYWORDS: chloride channel n guanilate cyclase‑C n irritable bowel syndrome Richárd Róka , n neuropeptide n opioid n probiotics n serotonin Krisztina Gecse & Tibor Wittmann Irritable bowel syndrome (IBS) is a chronic func- neural transmission within the gut and altera- †Author for correspondence: tional gastrointestinal disorder characterized by tions of the sensory afferent system at the spinal First Department of Internal continuous or remittent abdominal pain, bloat- cord or CNS may play a role in the development Medicine, University of Szeged, ing and altered defecation. Depending on the of IBS symptoms. Psychological and psychiatric Korányi fasor 8, Szeged, diagnostic criteria, the population-based preva- comorbidity is common among patients with 6720, Hungary lence of IBS has been reported to be approxi- IBS, and psychosocial factors may exacerbate Tel.: +36 62 545 186 mately 3–20% of the general population, and symptoms and affect clinical outcome of IBS Fax: +36 62 545 185 IBS symptoms are major reasons for primary care patients [3,5]. The effect of gonadal hormones on [email protected] visits and consultations with gastro enterologists. visceral pain perception, gastrointestinal motil- The first presentation of patients to a physician ity and central pain processing, and gender- is typically between the ages of 30 and 50 years, related differences in psychosocial factors, may and the prevalence of the disease is greater in induce differences in response to psychological women [1–3]. The diagnosis of IBS relies on a and pharmacologic therapy between female and symptom-based classification system known as male patients [6,7]. Rome criteria, Rome III being the most recent. Current therapy of IBS focuses on the major It defines IBS as recurrent abdominal pain or symptoms experienced by patients. The therapies discomfort lasting for at least 3 days per month include: antispasmodic (anticholinergic) medi- over 3 months, and which is associated with cation; smooth-muscle relaxants (cimetropium two or more of the following characteristics: bromide, pinaverimun bromide and octylonium improvement with defecation, onset associated bromide and mebeverine); prokinetic agents (tri- with change in stool frequency or onset associ- mebutine), which are recommended for pain and ated with change in stool form. The Rome III bloating; and low-dose tricyclic anti depressants, criteria classifies IBS patients based on their which may be useful in the treatment of constant bowel habits into three subgroups, namely and disabling pain. On one hand, increased die- diarrhea predominant (IBS-D), constipation tary fiber intake and osmotic laxatives may reduce predominant (IBS-C) and subjects with mixed constipation, and on the other hand loperamide pattern (IBS-M) [4]. Despite intense research in and diphenoxylate can decrease the number of recent decades, the pathogenesis of IBS remains loose stools, urgency and fecal soiling in diarrheic only partially understood, and thus no specific patients. The treatment strategy is based on the and universally effective patient management nature and severity of the symptoms. Milder has been developed so far. Altered colonic motor symptoms are commonly treated symptomati- function, visceral hypersensitivity, minimal cally with pharmacological agents directed at the inflammation of intestinal mucosa, changes in gut, whereas more severe symptoms are associated 10.2217/THY.09.22 © 2009 Future Medicine Ltd Therapy (2009) 6(4), 603–613 ISSN 1475-0708 603 REVIEW Róka, Gecse & Wittmann Novel strategies & future landmarks in the treatment of irritable bowel syndrome REVIEW with higher levels of psychosocial difficulties and However, based on severe side effects (serious illness behaviors, and often require psychological constipation, ischemic colitis and bowel per- and antidepressant medications [3]. foration), alosetron had been withdrawn from A novel approach in the treatment of IBS is the market and was later re-introduced under a based either on targeting specific receptors in restricted program only, while cilansetron did the gastrointestinal tract that are known to be not receive US FDA approval due to similar side involved in the pathogenesis of the disease, or effects [13]. A novel, potent 5-HT3 antagonist modification of disturbed gastrointestinal bacte- (ramosetron) seems to be effective and well toler- rial flora. These potential therapeutical modalities ated, demonstrating no gender difference in the will be discussed in detail in this article. treatment of abdominal pain, discomfort and altered bowel habits in patients with diarrhea- Serotonin receptor modulation predominant IBS according to a Phase II trial n Serotonin in the pathogenesis in Japan [14,15]. of IBS Approximately 95% of the serotonin (5-hydroxy- n 5-HT4 agonists tryptamine [5-HT]) in the human body is 5-HT4 receptor agonists potentiate peristalsis found in the gastrointestinal tract: 90% is in initiated by 5-HT1 receptor stimulation in the the secretory granules of enterochromaffin cells gut. Therefore tegaserod (a partial agonist of throughout the gut, and the remaining 5% is the 5-HT4 receptor) accelerates gastrointestinal located in enteric neurons. Serotonin is one of transit and also intestinal secretion, thus being the most investigated neurotransmitters in the beneficial in the treatment of IBS patients with patho genesis of IBS, since it plays a key role in constipation [16,17]. However, tegaserod is now the initiation of peristaltic and secretory reflexes, only available via a restricted access program and in the modulation of visceral sensations. owing to concerns of a possible risk of cardio- The 5-HT release from enterochromaffin cells vascular and cerebrovascular mortality [17]. is triggered by luminal mechanic and chemical Prucalopride is a more selective 5-HT4 agonist stimuli, which activate intrinsic primary afferent and a potential pharmaceutical in the treatment neurons, and thus the information is transmit- of IBS-C. It proved to be effective in the treat- ted to interneurons, motor and secretomotor ment of severe chronic constipation with only neurons. The action of 5-HT is rapidly termi- mild side effects, such as headache and abdomi- nated by the activation of the serotonin reuptake nal pain [18,19], although carcinogenicity proven transporter (SERT) to avoid receptor desensitiza- by animal studies may limit its clinical use [20]. tion [8]. Several serotonin receptor subtypes have been characterized, of which 5-HT3, 5-HT4 n Mixed 5-HT4 agonist/ and 5-HT1b are the most important for gastro- 5-HT3 antagonist intestinal function. The 5-HT1b receptors are Renzapride is a mixed 5-HT4 receptor agonist responsible for initialization of peristalsis, 5-HT4 and 5-HT3 receptor antagonist with a stimula- receptors play a role in augmenting the release tory effect on gastrointestinal motility and tran- of neurotransmitters and 5-HT3 receptors are sit [21]. It has been demonstrated to have a ben- responsible for transmitting sensory stimuli to eficial effect on abdominal pain and discomfort the CNS [9]. Several studies demonstrated the in IBS-C and IBS-M patients, and on colonic possible role of increased release of 5-HT, abnor- transit in IBS-C patients [22,23]. malities of SERT and SERT polymorphisms in the pathogenesis of IBS [10]. n Tryptophan hydroxylase inhibitors Serotonin is synthesized from tryptophan by n 5-HT3 receptor antagonists the sequential actions of tryptophan hydroxy- The 5-HT3 receptor antagonists (alosetron and lase (TPH) and the aromatic amino acid decar- cilansetron) prevent the activation of 5-HT3 boxylase. Two isoforms of TPH have been dis- receptors on extrinsic afferent neurons and covered. TPH1 is primarily expressed in the decrease visceral pain in IBS. They also decrease enterochromaffin cells of the gastrointestinal small intestinal and colonic motility (this lat- tract, while TPH2 is expressed exclusively in ter effect being more prominent in females), neuronal cells. In an animal model, TPH inhibi- and therefore are effective in the treatment of tors (LP-533401 and LP-615819) selectively the subgroup of IBS-D patients. Alosetron and inhibited gastro intestinal 5-HT biosynthesis, cilansetron proved to be effective in symptom leaving the brain 5-HT levels unaffected. These relief of female diarrheic IBS patients [11,12]. compounds reduce emesis in an experimental 604 Therapy