Irritable Bowel Syndrome (IBS)
Irritable bowel syndrome (IBS) is a chronic disorder characterized by recurrent symptoms of lower abdominal pain with disturbed defecation and bloating. The disorder affects up to 20% of the population and is the most common gastrointestinal (GI) ailment diagnosed by general practitioners. Although it is estimated that only one in five patients with IBS seeks medical attention, direct medical costs account for an estimated $8 billion each year within the United States.
Corticotropin-releasing factor (CRF) is a peptide that functions as a neurotransmitter in the brain. It plays a critical role in coordinating the body’s overall response to stress, and it interacts with two known receptor subtypes, CRF1 and CRF2.
The initial presentation of irritable bowel syndrome (IBS) occurs between the ages of 30 and 50 in over one-half of patients diagnosed with the condition. The classic symptoms reported include abdominal pain, constipation, and/or diarrhea.
Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) analogue, has been investigated as a treatment for irritable bowel syndrome (IBS) because of the predominance of IBS in women and the exacerbation of symptoms reported during menses. Symptoms of abdominal pain, nausea, vomiting, bloating, and early satiety were improved with the administration of the drug.
The investigation of novel compounds for the treatment of irritable bowel syndrome remains a challenging area of R&D for both the biotechnology and pharmaceutical industries. The problem stems from the lack of understanding of the etiology and pathophysiology of this common functional gastrointestinal (gastrointestinal) disorder. Because the majority of current therapies for irritable bowel syndrome address abnormal motility more effectively than they do pain, most irritable bowel syndrome drug development in recent years has focused on therapies for visceral hypersensitivity.
Diarrhea is one of the most socially restrictive symptoms associated with irritable bowel syndrome. Also, chronic diarrhea carries the possibility of dehydration, which, in severe cases, may lead to a patient being hospitalized for intravenous fluid and electrolyte replenishment. In general, patients suffering from D-irritable bowel syndrome use antidiarrheal agents on an as-needed basis; only in cases of severe D-irritable bowel syndrome are antidiarrheals used on a consistent dosage schedule.
Clinical research has shown that modulation of 5-HT3 and 5-HT4 receptors affects visceral pain sensation and intestinal transit. The serotonin (5-HT) receptor modulator drug class has received the majority of irritable bowel syndrome researchers’ attention for nearly a decade. However, early agents in this class — alosetron (GlaxoSmithKline’s Lotronex) and tegaserod (Novartis’s Zelnorm/Zelmac) — have encountered considerable opposition during the approval process as a result of safety concerns revealed during clinical trials and postmarketing studies.
Irritable bowel syndrome (IBS) is common, occurring worldwide in males and females of all age-groups. Prevalence figures vary, owing partly to the lack of definitive diagnostic criteria. On the basis of information compiled from diagnostic and symptom-associated surveys, prevalence ranges from 2.9% to 20%.
It is estimated that the typical patient visits an average of three different physicians over a three-year span before receiving the diagnosis of irritable bowel syndrome (IBS). Because there is an absence of distinguishing physical or laboratory markers in IBS, the diagnosis is based on patient symptoms. The diagnosis must be confirmed by the exclusion of other conditions, such as malabsorptive disorders, metabolic disorders, dietary factors, infection, inflammatory bowel disease, psychological disorders, or gynecological disorders.
Like the currently marketed alosetron, the agent antagonizes 5-HT3 receptors, thereby slowing gastric motility and providing relief for patients with D-irritable bowel syndrome. The agent also reduces the transmission of afferent signals from the gut to the brain. In the United States, clinical data supporting a new drug application (NDA) for cilansetron were based on efficacy and safety studies in approximately 4,000 D-irritable bowel syndrome patients, and Solvay reports that its NDA submission included an appropriate-use program — not unlike that of alosetron in the United States — that is based on collaboration with physicians, pharmacists, patients, and risk-minimization experts.
Activation of 5-HT3 receptors on enteric neurons in the gastrointestinal (GI) tract is critical for regulation of visceral pain and GI transit. Alosetron is a 5-HT3 receptor antagonist that delays whole gut transit time, increases colonic transit time, and alters the colon’s reaction to distension (Table 6).
The diagnosis of irritable bowel syndrome (IBS) is one of exclusion of organic disease. Diagnosis should be based on patient history, physical examination, symptoms, and laboratory tests. Symptoms should have been present for at least 12 weeks, such that acute onset of pain, diarrhea, or any other symptoms should initially be presumed to be organic and not IBS until sufficient testing or history is obtained to rule out other causes.
Irritable bowel syndrome (IBS) is both a physiologic and psychological syndrome. Thus, pharmacological treatment may be geared towards alleviating gastrointestinal symptoms; concurrently, medications may be prescribed to temper the pain component of IBS or modify underlying affective disorders and psychosocial factors that may be contributing to or resulting from symptom severity.
Patients with irritable bowel syndrome typically complain of crampy abdominal pain and constipation. In some patients, chronic constipation is punctuated by brief episodes of diarrhea.
The American Digestive Health Foundation recommends that the most cost-effective and beneficial treatment for patients with irritable bowel syndrome (IBS) is probably establishment of an effective clinical relationship. They suggest a series of steps, including 1) acknowledgment of the patient’s pain, 2) development of an empathetic, nonjudgmental point of view, 3) education and reassurance, 4) goal setting, 5) helping the patient take responsibility, and 6) referral to a specialist when necessary. Treatment for irritable bowel syndrome (IBS) is based on the symptom characteristics, the extent of physiologic disturbance, and the psychosocial condition of the patient.
Loperamide, an opioid agonist, is commonly used for patients with diarrhea-predominant irritable bowel syndrome (IBS). The drug increases gastrointestinal (GI) transit time, enhances water and ion absorption, and increases rectal sphincter tone.
Unknown but patients show some gut motility abnormalities with increased response to stress and stimulants, and increase in the 3 cycles/ minute smooth muscle contractions. Up to 1/3 of patients develop IBS after an episode of gastroenteritis.
Antimuscarinic agents such as hyoscyamine and dicyclomine, a nonspecific smooth muscle relaxant with antimuscarinic activity, have been used to treat symptoms associated with irritable bowel syndrome (IBS). Controlled studies assessing the efficacy of these medications are lacking.
Irritable bowel syndrome (IBS) was historically described using the terminology spastic colon, nervous stomach, and colitis, among others. These descriptions are no longer considered accurate or acceptable.
Cholecystokinin (CCK), a neurohormonal peptide found in both the central and enteric nervous systems, is involved in the regulation of gastrointestinal motility and secretion. Development activity with regard to antagonists at CCK receptors is limited. The only compound in the later stages of development is RottaPharm’ s dexloxiglumide, which recently encountered problems with respect to efficacy in clinical trials.