Motility Disorders Irritable Bowel Syndrome New Therapies for Functional Lower Bowel Disease Michael Camilleri, MD Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, Minnesota
Abstract Aim: To review new medications for treatment of irritable bowel syndrome: the new 5-HT4 agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics. Methods: Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics, and efficacy. Results and Conclusions: The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS, and these effects are associated with pain relief. The new 5-HT4 agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability, and efficacy. The potential benefits and risks of agents ‘borrowed’ from other indications (like hyperlipidemia, allergic diseases, inflammatory bowel disease or somatic pain) deserve further study.
Keywords Serotonin, bile acid, colesevelam, anti-inflammatory, visceral analgesic
Disclosure: Michael Camilleri, MD, has received research grants from Microbia, Theravance, Takeda and ARYx. He has performed consulting for Ironwood, Theravance and ARYx. His employer, Mayo Clinic, has a provisional patent application regarding bile acid modulation for chronic diarrhea. Acknowledgments: The excellent secretarial support of Mrs Cindy Stanislav is gratefully acknowledged. Dr Camilleri’s work on IBS is supported by NIH grants R01-DK079866 and 1RC1-DK086182. Received: August 10, 2010 Accepted: September 30, 2010 Citation: US Gastroenterology & Hepatology Review, 2010;6:33–7 Correspondence: Michael Camilleri, MD, Mayo Clinic, Charlton 8-110, 200 First St. S.W., Rochester, MN 55905. E:
camilleri.michael@mayo.edu
Despite claims based on meta-analyses1
that there are several
treatments, such as peppermint oil, antidepressants, and probiotics based on Bifidobacteria that are efficacious for the treatment of irritable bowel syndrome (IBS), patients and clinicians question their effectiveness. Though the pipeline of medical treatments in IBS is significant,2
potassium channel) and shown to be safe through studies of effects on QTc interval and arrhythmogenic potential in clinical trials.4
Three 5-HT4
agonists in development fulfill these criteria for selectivity and safety, and have advanced to human trials.
many candidate medications are still at a very early stage of development. Some targets for therapy are not new, but new pharmaceutical compounds promise to produce safer restoration of normal bowel function by modulating motility and secretion. There are still no robust targets or proven therapies directed at visceral pain.
This review addresses the efficacy and safety of new 5-HT4 agonists, a new 5-HT3 antagonist, tryptophan hydroxylase (TPH) inhibitor, intestinal secretagogues (chloride channel activators, guanylate cyclase C
agonists), bile acid modulation, anti-inflammatory agents, κ-opioid agonist, pregabalin and gabapentin, benzodiazepine modulators, and centrally acting agents.
5-HT4 Agonists
Since the withdrawal of cisapride and tegaserod because of cardiac or potential vascular adverse events, any new drugs in this class have been required to be highly selective3
for the 5-HT4 receptor over other receptors (e.g. 5-HT2B, 5-HT7) and channels (e.g. delayed rectifier © TOUCH BRIEFINGS 2010 Prucalopride accelerates colonic transit5 and is efficacious in treating
severe chronic constipation unresponsive to laxative treatment.6–8 Continued efficacy in a two-year open-label study of patients recruited from seven prior randomized controlled trials suggests prucalopride effectiveness. Reports on cardiovascular safety include a study in 100 elderly constipated patients (of whom ~80% had history of or current cardiovascular disease) in a dose-escalation study of prucalopride. Vital signs, electrocardiogram (ECG), and Holter monitor data were not different from placebo, and no patients had QTcF >500 milliseconds.9,10
ATI-7505 is a benzamide whose chemical structure was modified from
that of cisapride so that it is a full and selective 5-HT4 receptor agonist in the gastrointestinal (GI) tract, a partial agonist in the heart, has negligible inhibitory activity at the human ether-a-go-go related gene (hERG) channel, and undergoes hydrolytic metabolism by esterase independent of cytochrome P450 (CYP) 3A4. Therefore, drug interactions with agents that affect or are metabolized by CYP 3A4 are unlikely. The affinity ratio between IKr and 5-HT4 receptors for both
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