(Laurie Barclay, MD, Jan., 2004)

Irritable bowel syndrome (IBS) is a gastrointestinal syndrome characterized by abdominal pain or cramping, bloating, and altered bowel habits. It affects about one in five Americans, or up to 55 million people, making it the most prevalent gastrointestinal complaint in the U.S. Rather than being a well-defined disease, this collection of symptoms is considered to be a functional disorder because no underlying pathology has been identified.

Although IBS can strike otherwise healthy individuals of either sex and of all ages, typically it first appears in the second to fifth decades. It affects three times as many women as men, or nearly one-quarter of U.S. women.

The pain associated with IBS may localize to a single abdominal region, or it can be a more diffuse, dull ache involving multiple areas. Fewer than 5% of IBS cases are considered severe, but some patients have intractable, unbearable pain. Either constipation or diarrhea may predominate, or patients may have fluctuating bouts of both symptoms.

These symptoms may be intermittent and fluctuating, at times occurring daily and then remitting for weeks or months. During flares, some individuals find it difficult to work, to attend school or social activities, or even to travel short distances. While IBS may reduce quality of life or rarely be debilitating, it does not lead to permanent gastrointestinal sequelae such as intestinal bleeding, cancer or inflammatory bowel disease, nor does it shorten life expectancy.

The abdominal discomfort in IBS may relate to increased sensitivity of the nerves in the colon, whereas changes in bowel habits are attributed to abnormalities in colonic muscular action and disordered motility. Although the colonic epithelium appears to work properly, rapid movement of colonic contents can result in watery stool, or decreased motility can lead to overabsorption of colonic fluid and constipation.

Despite the lack of well-defined pathophysiology, biological, psychological, and social factors may all exacerbate the manifestations of IBS. Because symptoms of IBS in women often worsen during their periods, some researchers believe that reproductive hormones may influence the manifestations of this disorder.

Caffeine, chocolate, high-fat foods, dairy products, large meals, alcohol, and some medications may induce attacks. The immune system may be involved in the pathogenesis of IBS. In a small subset of individuals with symptoms that mimic IBS, occult celiac disease with gluten intolerance is the culprit.

Stress, fatigue and depression may aggravate IBS, and conversely, IBS may predispose to or worsen depression, fatigue and anxiety disorders. A history of abuse in childhood may be a risk factor for IBS. This overlap of IBS with psychological conditions may be explained by overactivity of the autonomic nervous system, or by abnormal serotonin levels. This neurotransmitter regulates gastrointestinal motility and sensitivity, and it has also been implicated in depression.

Diagnostic criteria for IBS include at least three months of abdominal pain or discomfort relieved by defecation or associated with a change in bowel habits, plus two or more of the following symptoms occurring at least 25% of the time: change in stool frequency or form, altered stool passage, mucus in the stool, and/or bloating. Diagnostic tests to rule out other diseases may include stool or blood tests, barium enema, or endoscopy.

Although there is currently no cure for IBS, there are many options available to treat the symptoms, including fiber supplements, laxatives, antidiarrheal agents, tranquilizers, antidepressants or drugs that control colonic spasms. Alosetron hydrochloride (Lotronex) is approved for women with severe, diarrhea-predominant IBS refractory to conventional therapy. However, it may cause severe constipation or colonic ischemia. Tegaserod maleate (Zelnorm) is approved for short-term treatment of women with constipation-predominant IBS.

CenterWatch has identified a pipeline of 12 drugs in various phases of development for IBS, including primarily gastrointestinal receptor antagonists, as well as tranquilizers and probiotics.

Pain Therapeutics is planning phase III testing of the opioid antagonist PTI-901, or low dose naltrexone. This small molecule with a novel mechanism of action is intended to treat both men and women with IBS. In a phase I/II trial, 50 patients of both genders reported a 75% positive response rate to PTI-901, as well as improved abdominal pain and bowel habits. There were no drug-related adverse events.

Dexloxiglumide is a selective cholecystokinin type A (CCKA) receptor antagonist in phase III testing by Rottapharm in Europe only, as U.S. trials have been discontinued. As the D-isomer of loxiglumide, it retains all pharmacological properties of loxiglumide but is more potent.

In animal models, dexloxiglumide inhibits exogenous CCK activity on gallbladder contraction, pancreatic secretion, gastric emptying, intestinal motility, and satiety, and it antagonizes CCK-1 binding to rat pancreatic acini with good selectivity (170-fold) over the CCK-2 receptor.

In healthy volunteers with constipation, oral dexloxiglumide 200 mg twice daily or three times daily was well tolerated, only partially inhibiting gallbladder motility while accelerating colon transit. Preliminary clinical trials in constipation-predominant IBS suggest that it is significantly more effective than placebo in relieving symptoms and is well tolerated.

Although Forest Laboratories, Inc. had licensed U.S rights for dexloxiglumide in constipation-predominant IBS from Rotta Research Laboratorium of Italy, it announced in October of 2003 that it had discontinued development for this indication. Two placebo-controlled Phase III clinical studies involving 12 weeks of dexloxiglumide treatment in 1,400 women with constipation-predominant IBS showed a trend in favor of dexloxiglumide. However, the difference in Subject Global Assessment, which measures overall patient evaluation of abdominal discomfort, pain and altered bowel habit, was not statistically significant compared with placebo. There were limited side effects and no effect on gallstone formation.

Solvay Pharmaceuticals' drug cilansetron targets a different gastrointestinal receptor. In two Phase II placebo- controlled trials and in two Phase III placebo-controlled trials in the US, Europe and other countries, this 5- hydroxytriptamine(HT)-3 receptor antagonist was effective for diarrhea-predominant IBS in both men and women. More than 4,000 patients have been enrolled in phase III studies.

Like cilansetron, renzapride is a 5-HT3 receptor antagonist, but it is also a potent agonist of the serotonin-4 and 5-HT4 receptors influencing intestinal motility and sensitivity. Alizyme is in Phase II development of this novel benzamide derivative for mixed-symptom and constipation-predominant IBS. Renzapride's dual mechanism of action has been tested in a 510-patient, Phase IIb clinical trial in constipation- predominant IBS, and in a separate, 160-patient Phase IIb clinical trial in mixed-symptom IBS. A pharmacokinetic/ pharmacodynamic study in 48 patients with constipation- predominant IBS is ongoing at the Mayo Clinic.

In a Phase IIa clinical trial completed in 2000, both men and women with constipation-predominant IBS had acceptable safety and symptom improvements similar to that seen with tegaserod (ZelmacŪ/ZelnormŪ). Efficacy was even better in women.

Because they are involved in the processing of nociceptive information, neurokinin (NK) receptors activated by substance P are a potential target for treatment of visceral pain, such as the pain produced by colonic distension. Talnetant, or SB 223412, is a tachykinin (NK3) receptor antagonist in Phase II testing by GlaxoSmithKline. Animal models demonstrate that this compound crosses the blood- brain barrier and reduces the nociceptive response to colorectal distension.

Similarly, saredutant is an NK2 receptor antagonist in Phase II testing by Sanofi-Synthelabo Pharmaceuticals. TAK-637 is an NK1 receptor antagonist in Phase II testing by Takeda Chemical Industries, but this drug is currently on clinical hold. Testing in guinea pigs suggests that NK1 receptor- mediated mechanisms regulate colonic hypersensitivity induced by sensitization of visceral afferent nerves of gastrointestinal origin or by acute psychosomatic stress.

Other IBS drugs in the pipeline involve different mechanisms of action. BNP-166, in Phase II testing by IVAX, is a novel soft corticosteroid which undergoes rapid conversion to inactive metabolites when it is absorbed into the blood stream.

Sucampo Pharmaceuticals is in Phase II development of SPI- 0211, a novel chloride channel activator. In September 2003, Sucampo completed the first of three open-label safety studies to support the New Drug Application for treating constipation-predominant IBS. This study enrolled 308 subjects at 22 U.S. sites and showed that SPI-0211, 24 micrograms twice daily, was significantly more effective than placebo for all constipation variables tested.

A novel tranquilizer in Phase II development by Vela Pharmaceuticals is dextofisopam, the R-enantiomer of the 2,3-benzodiazepine tofisopam. Racemic tofisopam comprising both R- and L-enantiomers has been marketed and used safely in Europe and Asia for anxiety disorders for over two decades. In Phase I trials, dextofisopam was non-sedating and very well tolerated. After obtaining acceptance of its IND in June 2003, VelaPharm has begun a Phase II trial of dextofisopam in IBS.

Still in Phase I testing is Probactrix, a BioBalance Corporation product formerly known as "Bio-Cocktail." Although this M-17 form of Escherichia coli is currently being pursued as a medical food product, the company may pursue prescription drug status for this probiotic in the future. Open randomized studies suggest that intake of this indigenous human gastrointestinal flora may be effective in diarrhea related to antibiotic use, malabsorption syndrome, acute infectious diarrhea, or other causes.

Until the mechanisms of IBS are better understood, experimental therapies for IBS will most likely continue to target the symptoms rather than the cause. Because medications specific for IBS are currently limited, this should be an incentive for further development, especially for medications suitable for use in both sexes.