# How will the futur IBS drug look like?



## 17014 (Apr 13, 2005)

Since we know that regulate serotonin in the colon of IBS patients is not the final answer for IBS, how will the futur IBS drug look like? Perhaps a combo of: - Serotonin-Agonist- Substance to reduce visceral hypersensibility- AntispasmodicNow the only thing that we need is a time machine.


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## eric (Jul 8, 1999)

FYI"Neuromuscular Dysfunction and IBS: Clinical Implications In This Article IntroductionPathophysiology of IBSTreatment Options for IBSConclusion--------------------------------------------------------------------------------ReferencesRelated Links Treatment Options for IBSThe preceding discussion lends itself to a review of the latest developments in the field of targeted pharmacotherapy for IBS.Serotonergic Agents5-HT3 Receptor Antagonist Therapy. The importance of 5-HT3 receptors in GI motor and sensory function led to the development of specific 5-HT3 antagonists, such as alosetron. In large, well-designed clinical trials, alosetron showed superiority in achieving the endpoint of global IBS symptom relief compared with both placebo and the antispasmodic medication mebeverine in women with IBS-D.[9,10] However, because of reports of ischemic colitis (a rare but serious side effect) in the clinical trials and early postmarketing surveillance of alosetron, this agent was voluntarily withdrawn from the US marketplace in December 2000. In 2002, it was re-released for monitored use in women with severe IBS-D who had failed to respond to conventional therapies.5-HT4 Receptor Agonist Therapy. Tegaserod, a highly selective partial 5-HT4 agonist that accelerates transit by increasing gut motility and augmenting gastrointestinal peristalsis, is approved by the US Food and Drug Administration (FDA) for the treatment of women with IBS-C as well as for the treatment of men and women younger than 65 years of age with chronic idiopathic constipation. Clinical trials have demonstrated that tegaserod is associated with significant improvement in the global assessment of IBS symptoms as well as individual symptoms, such as abdominal pain, bloating, and bowel habits, compared with placebo in women with IBS-C.[11,12] Tegaserod has not been associated with any significant drug interactions, changes in cardiac conduction, or the development of cardiac arrhythmias. The event rate for ischemic colitis in patients using tegaserod during postmarketing surveillance has been estimated to be 8/100,000 to 9/100,000 patient-years of use, a rate similar to that reported in the general population.[13]Mixed 5-HT4 Receptor Agonist/5-HT3 Receptor Antagonist Therapy. Renzapride is perhaps the most promising agent with combined 5-HT activities. In a recent dose-ranging study, renzapride was found to accelerate colonic transit and ascending colon emptying in a linear, dose-related fashion, as well as improve bowel function scores (stool form and ease of passage), but it did not significantly improve overall symptoms of IBS compared with placebo.[14] Phase 3 clinical trials with renzapride are currently under way in patients with IBS-C and IBS with mixed bowel pattern.Mosapride citrate is a 5-HT4 receptor agonist with weak 5-HT3 receptor antagonist activity that is used outside the United States as a therapy for upper GI motility disorders. A recent trial conducted in 14 patients with Parkinson's disease and constipation reported improvement in stool frequency, colonic transit time, and rectal contractile activity with mosapride administered at a dose of 15 mg/day for 3 months.[15] Mosapride has not been evaluated as a therapy for IBS.MelatoninMelatonin is a derivative of 5-HT and is known to be a primary mediator of the circadian cycle in humans. Although the exact mechanisms have not been fully elucidated, melatonin has been shown to play a role in the regulation of GI motility and sensation in animals, possibly serving to counterbalance the effects of endogenous 5-HT.[16] In a randomized trial evaluating melatonin in IBS patients, Song and colleagues[17] demonstrated that 2 weeks of melatonin (3 mg every night) resulted in diminished abdominal pain, less severe IBS symptoms, and increases in rectal balloon distention thresholds required for the perception of urgency and pain compared with placebo. Lu and colleagues[18] reported that 88% of IBS patients randomized to melatonin (3 mg every night) reported "mild-to-excellent" improvement in IBS symptoms compared with 47% of patients who received placebo. Of note, melatonin did not improve sleep parameters or psychological profiles in IBS patients.AntidepressantsAntidepressants have long been a treatment option in patients with moderate-to-severe IBS symptoms, but tolerability remains problematic. The highest-quality randomized trial performed to date comparing the efficacy of a tricyclic antidepressant (TCA) vs placebo was recently published.[19] The intention-to-treat analysis did not show a statistically significant improvement in a composite symptom scale between the TCA (desipramine) and placebo among patients with functional bowel disorders, largely due to 28% of patients not completing the trial (primarily because of adverse drug effects). Under a per-protocol analysis, however, desipramine resulted in a statistically significant benefit compared with placebo (73% vs 49%; P = .01; number needed to treat = 6). A recently published trial of 19 women with IBS who underwent fMRI studies of the brain during rectal distention while taking amitriptyline demonstrated reduced pain-related perigenual anterior cingulate cortex and parietal cortex activation during auditory stress, suggesting that TCA-mediated pain relief occurs via central rather than peripheral mechanisms.[20]In the largest study of selective serotonin reuptake inhibitor (SSRI) therapy for IBS conducted to date, 257 patients with severe IBS were randomized to paroxetine (20 mg/day), psychotherapy, or usual care (such as antispasmodics and stool form regulators).[21] After 12 weeks of treatment, the paroxetine group experienced a small but significant reduction in the number of days with abdominal pain compared with baseline (P = .014), as well as improvements in quality of life. Similar to trials with TCAs, only 50% of the SSRI group completed the 12-week treatment period. Another randomized trial involving 81 patients with IBS found that significant benefits for overall well-being, but not for gut-related symptoms, were associated with paroxetine vs placebo.[22]A randomized, double-blind, placebo-controlled trial involving 40 IBS patients found that fluoxetine (20 mg/day) did not significantly alter rectal sensation or reduce abdominal pain or global symptoms over a 6-week study period.[23] However, investigators from Iran observed a clinically significant improvement with fluoxetine in patients with IBS-C (as defined by Rome II criteria).[24] Masand and colleagues[25] reported the results of an open-label trial of citalopram in 15 patients fulfilling Rome I criteria for IBS. In this study, 12 weeks of treatment with citalopram (20-40 mg/day) improved abdominal pain, bowel-related symptom severity, and symptom frequency in approximately 80% of patients. Another recent cross-over trial found that citalopram was more effective than placebo in improving abdominal pain, bloating, and overall well-being in 23 nondepressed IBS patients referred to a tertiary-care center in Belgium.[26] From these studies, it is reasonable to conclude that SSRIs may offer benefit to a subset of patients with IBS, but it remains unclear how these agents exert their effects.Corticotrophin-Releasing Factor AntagonistsThe hypothalamic-pituitary-adrenal axis serves as the primary endocrine stress system in humans and provides an important interface between the brain and the gut immune system. The primary hypothalamic regulatory peptide, corticotrophin-releasing factor (CRF), is recognized as an important mediator of the behavioral, endocrinologic, autonomic, and visceral responses to a variety of different types of stimuli; evidence for a potential role of CRF in GI function has emerged through the identification of CRF receptors on myenteric neurons. In humans, CRF analogue administration has been observed to accentuate colonic motility and alter visceral pain responses,[27] and blockade of CRF receptors has been shown to blunt evoked motility and abdominal pain responses in IBS patients.[28] These data are clearly preliminary, and additional large-scale trials assessing the clinical effects and safety of CRF antagonists are needed.Opioid AntagonistsAmong the 5 different types of opioid receptors that have been found to modulate gut motor and sensory functions, mu and kappa receptor-avid agents have demonstrated the most promise to date as potential therapies in IBS.Stimulation of mu-opioid receptors results in the inhibition of gut neurotransmitter release; these receptors are thought to be the primary etiology of diminished colonic motility occurring in patients treated with opiates and in those with postoperative ileus. Alvimopan is a peripherally acting mu-opioid receptor antagonist that has been shown to selectively block the peripheral effects of morphine without appreciably decreasing its centrally mediated analgesic effects.[29] Moreover, alvimopan has been shown to accelerate colonic transit in healthy volunteers not taking opiates.[30] Several phase 3 studies have demonstrated a clinically significant promotility effect of alvimopan in patients with postoperative ileus.[31,32] A natural extension of the clinical indications for alvimopan may be IBS-C, although a recent abstract found that alvimopan had little effect on chronic idiopathic constipation in patients not taking opioids.[33]Kappa-opioid receptors appear to be important mediators of visceral sensation in humans. Fedotozine was one of the first compounds in this class to be studied, and although it was found to reduce the sensation of rectal balloon distention,[34] the development of this compound was halted after phase 3 clinical trials failed to show significant benefits in patients with IBS. A dose-ranging study of asimadoline conducted in healthy volunteers suggested attenuation of visceral hypersensitivity at low doses and also suggested a dose threshold beyond which the agent might enhance visceral sensation.[35] More recently, in a placebo-controlled, randomized, double-blind, crossover trial involving 20 IBS patients, a single 0.5-mg dose of asimadoline was shown to produce a statistically significant decrease in pain intensity elicited by stepwise descending colon distention without affecting pain threshold or colonic compliance.[36] Because this agent has not been found to affect bowel function, it may be necessary to combine asimadoline with agents that affect stool frequency and/or consistency to achieve satisfactory global benefit in IBS patients.Tachykinin Receptor AntagonistsThe tachykinins are a family of biologically active peptides, including SP and neurokinin A (NKA), that are thought to be important facilitators of communication between neurons and smooth muscle cells of the gut. Their release and subsequent activity are largely mediated by the activity of other ENS neurotransmitters, hormones, and local mechanical stimuli. The various tachykinin receptors differ with respect to their affinity for these endogenous peptides. For example, SP preferentially binds NK1 receptors in the GI muscle layers and myenteric plexus, where it appears to mediate gut motility. NKA binds avidly to NK2 receptors located in the muscle layers and seems to play more of a role in nociception. However, this selectivity is only relative, as the tachykinins can bind any of the receptor subtypes (NK1, NK2, and NK3) and thus can lead to a variety of physiologic effects.[37]Only limited data have been reported regarding the effects of NK1 receptor antagonists in the GI tract. NK2 receptors, which have been implicated as mediators of GI motility, visceral sensation, GI mucosal secretion, and intestinal inflammation, have received greater attention. Nepadutant, a potent NK2 receptor antagonist, was shown to antagonize the promotility effects as well as the frequency and amplitude of smooth muscle contractions induced by NKA in 30 healthy volunteers, suggesting a possible role for this antagonist in IBS.[38] Additional trials involving nepadutant and saredutant, another NK2 receptor antagonist, are currently under way.Autonomic ModulatorsWhereas the intrinsic activity of the ENS is the primary arbiter of GI function, input adrenergic neurons are involved in the maintenance of tonic inhibitory control of gut motility as well as the transmission of impulses from visceronociceptive pathways traversing the spinal cord. Abnormalities in the function of the ANS may be involved in the genesis of GI symptoms in patients with IBS.[39,40] The alpha2-adrenergic agonist clonidine has been shown to increase colonic compliance, reduce fasting colonic tone, and reduce visceral sensation in response to rectal distention in humans.[41] Camilleri and colleagues[42] reported the results of a dose-ranging study in 40 patients with IBS-D randomized to receive placebo or clonidine (0.05 mg or 0.1 mg, both twice daily) for 4 weeks. The global endpoint of satisfactory relief from IBS symptoms was not statistically significantly different (P = .39) among the 3 treatment groups, but clonidine 0.1 mg twice daily was associated with significantly less bowel dysfunction than placebo (P = .036). Clonidine was also significantly more likely to improve individual IBS symptoms, including stool passage, compared with placebo, but it did not significantly alter GI or colonic transit. Four patients withdrew from the study, 3 due to intolerable side effects associated with clonidine. Although the frequency of adverse events was greatest in the first week of treatment and decreased as the study progressed, it is unlikely that clonidine will become a standard therapy for IBS-D.Dextofisopam is a 2, 3 benzodiazepine that is structurally and functionally distinct from typical benzodiazepines. This drug is believed to act at a subcortical level via a non-GABA (gamma-aminobutyric acid)-ergic mechanism of action, possibly through the regulation of autonomic tone at the level of the hypothalamus; it has also been found to possess anti-inflammatory properties in animal models.[43] Results of a 12-week, double-blind, placebo-controlled phase 2 trial involving 140 (male and female) patients with IBS-D or IBS with mixed bowel pattern demonstrated that treatment with dextofisopam (200 mg twice daily) was associated with a significantly greater number of months of adequate relief from IBS symptoms compared with placebo (57% vs 43%; P = .033).[44] The most common side effect associated with dextofisopam was abdominal pain (reported in 12% of treated patients vs in 4% of placebo patients). Phase 3 clinical studies are currently being considered.Selective Chloride Channel Activator TherapyLubiprostone, a bicyclic fatty acid that selectively activates intestinal type-2 chloride channels, increases passive fluid secretion into the intestinal lumen; it is approved for the treatment of chronic idiopathic constipation. The results of a 4-week, placebo-controlled phase 3 study and of a 24-week open-label trial of lubiprostone treatment in patients with chronic constipation demonstrated that a dose of 24 mcg administered twice daily was associated with a greater number of weekly spontaneous bowel movements and improved constipation-related symptoms.[45,46] Phase 3 trials evaluating the efficacy of lubiprostone in patients with IBS-C are currently under way.Guanylate Cyclase-C AgonistsMD-1100 (linaclotide) is a potent guanylate cyclase-C agonist that acts peripherally to increase the production of cGMP in human colon cells, leading to the activation of the cystic fibrosis transmembrane conductance regulator and ultimately to increased intestinal chloride, bicarbonate, and water secretion, with a resultant acceleration in transit.[47] Results of a recent 7-day multidose phase 1 study involving 48 healthy volunteers reported significant changes in stool consistency, ease of stool passage, and that stool frequency and stool weight was associated with MD-1100.[48] Studies evaluating the clinical benefits of MD-1100 in patients with IBS-C are anticipated."http://www.medscape.com/viewarticle/548600_3


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