European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 139-140 New therapeutic approaches in irritable bowel syndrome

M. CAMILLERI

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Mayo Clinic, Rochester, MN (USA)

Objective tagonists and there is no clear experimental To review advances in peripheral approaches basis for its occurrence in IBS patients ex- to treatment of irritable bowel syndrome, with posed to alosetron. Even with perfusion pres- special focus on serotonergic agents, antibacteri- sures of 60 mmHg, autoregulation in mucosal al agents, probiotics, secretion, opioid agents and blood flow increases oxygen extraction and others, specifically steroids and clonidine. maintains normal colonic mucosal oxygen up- take. There is no experimental basis for link- Serotonergic Agents for IBS ing severe constipation with the development Pharmacodynamic studies show that 5-HT3 an- of ischemic colitis. tagonists (e.g., alosetron) retard transit in the • The 5-HT4 agonist, tegaserod, was recently colon, increase colonic compliance, and may re- suspended. While no coronary ischemic events duce sensitivity, e.g. to distension. Alosetron is were observed in 7,031 placebo patients, there indicated for patients with severe diarrhea-pre- were event rates (5.5 per 1000 patient years) dominant IBS. The 5-HT4 agonists (e.g. with tegaserod (compared to general popula- tegaserod, ATI-7505) accelerate small bowel or tion rates of 4-5.1 for women and 10.6-12.5 colonic transit, and tegaserod may reduce colonic for men, per 1000 PY). There was no pattern sensitivity. Tegaserod used to be approved for C- to time to event (range 2-63 days/median 35) IBS and chronic constipation, but was recently and no dose relationship, and events occurred withdrawn because of possible cardiovascular primarily in patients with evidence of estab- toxicity. lished and/or symptomatic CV disease at base- Novel observations include: line.

•The novel 5-HT4 agonist, ATI-7505, is a deriv- •A combined 5-HT4 agonist/5-HT3 antagonist ative of cisapride. It accelerates gastric empty- (renzapride) also accelerates transit and ing and colon transit. Chemically, it is not me- loosens stool consistency. tabolized by CYP 3A4 (potentially reducing • Alosetron is also efficacious in men. risk of drug interactions), and early studies • Cilansetron results in adequate relief of IBS suggest it is safer from a cardiac arrhythmia symptoms in 3- or 6-month randomized con- perspective. trolled trials. • SSRIs or tricyclic antidepressants potentially • Alosetron was initially withdrawn from the act peripherally via SERT-inhibition in the market and is now available under restricted ENS (not demonstrated with paroxetine except conditions only in the U.S. Its side effects are for accelerated SB transit); venlafaxine re- constipation in 20-30% of patients and is- duces colonic tone and sensation, possibly via chemic colitis in 0.1 to 0.15% of patients. The a noradrenergic effect. causal relationship with ischemic colitis is un- clear, since there is an increased incidence of Antibacterial/Probiotics ischemic colitis in IBS. Nevertheless, the tim- A large randomized controlled trial of rifax- ing of events (26% of ischemic colitis within 7 imin suggests it provides greater benefit over days of alosetron treatment and 58% within 30 placebo in a 10-week follow-up period. Probi- days) suggests a causative relationship. Is- otics are promising, especially for flatulence,

chemic colitis is not a class effect of 5-HT3 an- bloating and borborygmi. Mechanisms of action

Corresponding Author: Michael Camilleri, MD; e-mail: [email protected] 139 M. Camilleri include improved immune function (e.g. IL- thresholds and improve abdominal pain in IBS. 10/IL-12 ratios are low at baseline in IBS; fol- Asimadoline, a new peripheral κ-agonist, had lowing therapy with L. salivarius UCC4331 and some pharmacodynamic efficacy, and it was test- B. infantis 35624, they increase to almost nor- ed in an on-demand randomized controlled trial mal). The combination probiotic VSL#3 is effec- versus placebo for pain episodes of moderate tive for relief of flatulence in IBS with significant severity in 100 females with IBS. The average bloating. Other potential mechanisms of action pain reduction 2 hours post-treatment was not of probiotics are effects on motility, secretion, significantly different between the groups. How- mucus secretion, sensation, and fermentation. ever, post-hoc analyses suggest it was effective in IBS-Alt. Further studies are needed. Alvimopan, Secretion a new peripheral µ-antagonist, has impressive ef- A chloride channel (ClC-2) activator (lubipro- fects on colonic transit, but recent imbalance in stone) and a guanylate cyclase C agonist (lina- the numbers of patients developing cardiac ad- clotide) induce enterocyte secretion by activating verse effects in trials of opiate bowel dysfunction surface mechanisms, accelerate colonic transit, has led to its suspension. and alter stool consistency. Lubiprostone has been approved for chronic constipation, and both Others: Steroids and Clonidine drugs show efficacy in phase IIB studies of C- Corticosteroids are no better than placebo in IBS. Lubiprostone is derived from prostones. the treatment of post-infectious IBS. Clonidine Linaclotide is a 14 AA peptide (similar to was efficacious in a small randomized controlled guanylin, 15 AAs, and uroguanylin, 16 AAs). trial versus placebo, with a 0.1 mg bid (but not 0.05 mg bid) dose being superior to placebo. Opioid Agents Three major opiate receptors (µ, δ, κ) have po- tential for use in IBS. The receptors are widely distributed in the central and peripheral nervous Conclusion system; µ-agonists (codeine, morphine) reduce nociception (central effect) and slow down GI Peripheral targets to therapy in IBS may be ef- transit (peripheral effect). The peripheral κ-ago- fective, and further studies are needed to more nist, fedotozine, was shown to increase pain fully understand their benefit: risk ratio.

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