Drug Development for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common and chronic gastrointestinal disorder.  Symptoms include abdominal pain and cramping accompanied by diarrhea and/or constipation.  Estimated to effect 10 to 15% of the population, current drug treatment modalities are fail to relieve symptoms in many patients.  There is considerable interest in novel drugs that might more effectively control symptoms while producing limited side effects. 

A recent review of treatments for irritable bowel syndrome has been authored by Chang and Talley from the Mayo Clinic.  Dr. Chang works in a program identified as Enteric NeuroScience.  This designation highlights the importance of neuroscience issues in IBS.  Here are my notes from the review:

FDA Approved Drugs in the U.S.
Alosetron (Lotronex)--nerve receptor agonist initially approved for women with IBS and severe diarrhea and then removed from market due to risk of constipation, bowel obstruction and ischemic colitis.  Now re-approved but only by prescription from a limited number of physicians participating in monitoring program.
Lubiprostone (Amitiza)--chloride channel activator approved only in women with IBS accompanied by constipation

Nonapproved Drugs
Anticholinergic (antispasmodic)
    Scopoloamine also known as hyoscine is an alkaloid drug that has muscarinic antogist effects.  Effective in reducing cramping in some IBS patients.  May cause dry mouth and blurred vision especially at higher doses.
    Peppermint oil: a natural product that appears to have some scientific support for reducing cramping in IBS. 
Antidepressants
Tricyclic antidepressants: older antidepressants such as imipramine and doxepin reduce IBS symptoms in some individuals.  Effect may be due to anticholinergic effect seen with these older antidepressants.
Selective serotonin re-uptake inhibitors: new selective serotonin re-uptake inhibitors help some with IBS, but also can worsen diarrhea and cramping.
Serotonin norepinephrine re-uptake inhibitors--combine re-uptake blocking of both the serotonin and norepinephrine.  Limited study of these agents in IBS but may be promising as they appear to reduce pain in other clinical conditions.  Duloxetine (Cymbalta) clinical trial results pending

Drug development targets in IBS
Treatment of visceral hypersensitivity
    Kappa-opioid receptor agonists-k-opioid receptor stimulus reduces pain from the gut while not producing constipation characteristic of other opioid
    Endocannabinoids- cannabinoids receptors CB1 and CB2 potential targets as activation may reduce pain and hypermotility
    Transient receptor potential vanilloid type 1 (TRPV1)-a receptor that is located throughout nervous system and mediates sensation and pain
    Beta 3 adrenoreceptor agonists-activation inhibits cholinergic GI contractions and increases release of somatostation.  Potentially helpful for inhibiting diarrhea
    Neurokinin antagonists-Neurokinin 1 receptor antagonists reduce IBS subjects emotional response to rectosigmoid distention
Centrally acting agents
    Dextofisopam-benzodiazepine receptor binding agent that modulates autonomic function
Cholecystokinin (CCK) antagonists 
   CCK1 antagonism stimulates GI motility and may be helpful in treating IBS associated with constipation
Inflammatory drug targets
    Protease-activated receptors-Mast cells release serine proteases that stimulate GI receptors and may play role in visceral hypersensitivty and inflammatory bowel diseases and IBS

A review of clinical trials for IBS at ClinicalTrials.gov shows the following:
Completed trials: duloxetine, mosapride citrate, dextofisopam, crofelemer, itopride HCL, renzapride, asimadoline, alosetron, BMS-562086, mesalazine, St. Johns wort, talnetant
Recruiting: Saccharomyces boulardii, JNJ-27018966, Probaclac, Probiotic

Model of the chemical scopolamine shared under auspices of  Creative Commons Attribution-Share Alike 3.0 Unported by author Giorgiogp2

Chang JY, & Talley NJ (2010). Current and emerging therapies in irritable bowel syndrome: from pathophysiology to treatment. Trends in pharmacological sciences, 31 (7), 326-34 PMID: 20554042