Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0000737 (abdominal pain)
 31,184 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin 4 receptors (5-HT(4)Rs) were discovered 15 years ago. They are coded by a very complex gene (700Kb, 38 exons) which generates eight carboxy-terminal variants (a, b, c, d, e, f, g, n). Their sequences differ after position L(358). Another variant is characterized by a 14 residue insertion within the extracellular loop 2. Highly selective potent 5-HT(4) receptor antagonists and partial agonists which cross the blood-brain barrier have been synthesized, but a specific full agonist for brain studies is still missing. Based on physiological and behavioral experiments, 5-HT(4)Rs may be targets to treat cognitive deficits, abdominal pain and feeding disorders. One 5-HT(4)R-directed drug (SL65.0155) is already in phase II to treat patients suffering from memory deficits or dementia.
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PMID:5-HT4 receptors. 1496 43

Tegaserod is a new partial agonist of serotonin 5-HT4 receptors specifically developed for the treatment of nondiarrhoeal forms of irritable bowel syndrome (IBS). Among its various effects is the stimulation of the peristaltic reflex with its promotility action appearing to affect the whole length of the gastrointestinal tract. Tegaserod has been assessed in a number of international multicentre trials and its use leads to an improvement in abdominal pain and bowel dysfunction as well as global well-being, at the expense of remarkably few adverse effects. It is noteworthy that it also appears to improve bloating, a benefit that has not been previously reported for a medication used in IBS. The optimal dose is 6 mg twice daily and the advantage of tegaserod over placebo in different trials varies from 5-20% with the number needed to treat ranging from 5-15 depending on the time at which this effect is calculated during the course of a trial. Recent experience with other drugs acting on 5-HT receptors has focused attention on possible safety issues such as prolongation of the QTc interval on the electrocardiogram and ischaemic colitis. However, data from efficacy trials and studies specifically designed to address the safety of tegaserod have not revealed any evidence of cardiotoxicity or the potential for causing ischaemic colitis. Furthermore, investigation of possible interactions with other drugs such as warfarin or the oral contraceptive have not resulted in any prescribing restrictions. Inappropriate prescription of tegaserod to a subgroup of IBS patients for which the drug was not designed, does not appear to have any serious consequences. Most of the efficacy data on tegaserod has been accumulated in females, simply as a result of the failure to recruit adequate numbers of males or restriction of trials to females. There is therefore insufficient information to assess whether there might be any potential gender differences in responsiveness. For this reason, the drug is currently only licensed for use in females.
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PMID:Benefit-risk assessment of tegaserod in irritable bowel syndrome. 1500 35

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts. In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod.
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PMID:Safety profile of tegaserod, a 5-HT4 receptor agonist, for the treatment of irritable bowel syndrome. 1523 Jun 44

Irritable bowel syndrome (IBS) is characterized by abdominal pain associated with disordered defecation, which may include urgency and altered stool frequency. Visceral pain syndromes, including IBS, may be effectively treated by a variety of therapies that modulate the interactions between the central and enteric nervous systems. Clinical observations and preliminary data suggest that antidepressants may be efficacious for the treatment of these syndromes. The tricyclic antidepressants (TCAs) have been utilized most extensively in this area, but there is a need for more rigorous efficacy data. Serotonin, an important neurotransmitter in both the central and enteric nervous systems, modifies both motility and sensation in the gut. Recognition of the importance of serotonin in digestive motility and sensation has sparked interest in the use of agents that modify serotonergic transmission in visceral pain syndromes. Pharmacological therapeutics that modulate the biological amines (serotonin, norepinephrine, dopamine and catecholamines) both peripherally and within the central nervous system may offer more effective therapies for these disorders. The selective serotonin reuptake inhibitors are commonly used in clinical practice, but more rigorous, controlled studies are needed to determine their effects beyond the treatment of psychiatric comorbidity. The newer generation antidepressants may provide additional insight into the pathophysiology of the brain-gut interactions and their relationship to functional bowel disorders, providing new therapeutic interventions.
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PMID:Antidepressants in the treatment of irritable bowel syndrome and visceral pain syndromes. 1529 70

The management of patients with irritable bowel syndrome (IBS) is a frequent, yet challenging task in both primary care and gastroenterology practice. A diagnostic strategy guided by keen clinical judgment should focus on positive symptom criteria and on the absence of alarm symptoms. In younger patients lacking alarm features, invasive testing has a low-yield. The presence of food intolerance and underlying celiac disease should be excluded. The usefulness of fecal tests such as calprotectin and lactoferrin to exclude organic bowel disease is not adequately established. In patients with moderate to severe symptoms who fail initial therapeutic trials, further tests can be performed in tertiary care settings, such as transit measurement and tests for diagnosing pelvic floor dysfunction. Treatment strategies for IBS are currently directed at the predominant symptoms. In diarrhea-predominant IBS, opioids (e.g. loperamide) and the 5-HT(3) receptor antagonist alosetron are efficacious. In constipation-predominant IBS, fiber and bulk laxatives are traditionally used, but their efficacy is variable and may worsen symptoms. The 5-HT(4) receptor agonist tegaserod is efficacious in female patients with IBS and constipation. In patients with IBS and abdominal pain, antispasmodics and antidepressants can be used, with the best evidence supporting the prescription of tricyclic antidepressants. The efficacy of psychological treatments in terms of relieving the symptoms of IBS is still uncertain. Limited evidence suggests that anti-enkephalinase agents, somatostatin analogues, alpha(2)-receptor agonists, opioid antagonists, selective serotonin reuptake inhibitors, probiotics and herbal treatments may be useful in IBS patients.
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PMID:Diagnostic and therapeutic strategies in the irritable bowel syndrome. 1546 18

Tegaserod is a drug in a new class of compounds called aminoguanidine indoles and is structurally similar to serotonin (5-HT) with modifications that make the drug selective for the 5-HT(4) receptor. Tegaserod has a stimulatory effect on gastrointestinal (GI) motility that has been demonstrated in animal studies and in healthy adults. Tegaserod also increases GI secretion and reduces rectal sensitivity. Tegaserod is currently approved by the FDA for the treatment of women with constipation-predominant irritable bowel syndrome (C-IBS). Eight large Phase III clinical trials involving > 5000 IBS patients support the clinical efficacy of tegaserod in this group of patients. Patients who were treated with tegaserod had an overall improvement in IBS symptoms (Subject's Assessment of Global Relief) as well as in secondary end points, such as abdominal pain and discomfort, stool consistency, change in bowel movements and relief of bloating. Tegaserod was well-tolerated. The most common adverse reaction in clinical trials was diarrhoea, which was usually temporary and mild, although severe diarrhoea requiring hospitalisation has been rarely (< 1%) reported.
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PMID:Review of tegaserod in the treatment of irritable bowel syndrome. 1550 Mar 84

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.
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PMID:Tegaserod: a serotonin 5-HT4 receptor agonist for treatment of constipation-predominant irritable bowel syndrome. 1564 12

Cilansetron is a novel serotonin type-3 (5-hydroxytryptamine; 5-HT) receptor subtype 3 (5-HT(3)) receptor antagonist currently being evaluated for the treatment of female and male patients with irritable bowel syndrome with diarrhoea predominance (IBS-D). 5-HT(3) receptor antagonists such as cilansetron have been shown to affect gastrointestinal motility. Whether cilansetron affects visceral sensation independent of effects on visceral compliance remains controversial. Results from two large, randomised, double-blind, placebo-controlled, parallel-group Phase III clinical trials of cilansetron in patients with IBS-D have recently been presented in abstract form. These studies found that cilansetron was more effective than placebo at improving overall, as well as individual symptoms, including abdominal pain and diarrhoea in female and male IBS-D patients. The most commonly reported side effect with cilansetron has been constipation and, in general, the drug has been well tolerated in clinical trials. Although rare, the most concerning side effect observed with cilansetron has been suspected ischaemic colitis. The event rate for suspected ischaemic colitis associated with cilansetron from clinical trials is 3.77 per 1000 person years of exposure. This rate appears to be greater than that expected in the IBS population and similar to that observed with alosetron, another 5--HT(3) receptor antagonist. All of the cases of suspected ischaemic colitis reported with cilansetron have resolved without serious sequelae. How issues surrounding the safety of cilansetron will affect the approval process in various countries remains to be determined. However, the risk-benefit of cilansetron is likely to be most favourable in patients with IBS-D who have failed to respond to conventional medical therapies. A detailed risk management plan and post-marketing surveillance programme will be required should this drug become available for the treatment of patients with IBS-D.
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PMID:Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhoea. 1575 94

Because of recurrent abdominal pain, jaundice and elevated liver function tests, a sixty-two-year old man had been referred to hospital several times within the preceding six months. By means of ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonant cholangiopancreatography, dilated extrahepatic bile ducts were diagnosed. Stones and a tumorous process were excluded. ERCP showed hypermotility of the upper gastrointestinal tract. Quantitative hepatobiliary scintigraphy demonstrated retention of activity in the intra- and extrahepatic bile ducts and delayed transit of activity to the duodenum as signs of papillary dysfunction. Drug anamnesis revealed that the patient had started migraine treatment with Zolmitiptan, a 5-HT (1B/1D)-receptor agonist of the second generation, six months before the beginning of the cholestasia syndrome. Because of the known increase in amplitudes of oesophageal motor waves and of lower oesophageal sphincter tone by Sumatriptan, a 5-HT (1B/1D)-receptor agonist of the first generation, Zolmitriptan treatment was stopped. Thereupon, laboratory findings normalised and the patient has been feeling well for more than one year. Serotonin is an important monamine neurotransmitter that acts both in the CNS and in the gastrointestinal tract on identical receptors and is transported by the same systems. Thus it is not surprising that therapeutic measures which influence the serotoninergic system in the CNS are also effective in the enteric nervous.
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PMID:[Extrahepatic cholestasia during therapy with Zolmitriptan (AscoTop)]. 1614 13

The association between migraine and functional gastrointestinal disorders has been confirmed by many clinical observations and epidemiological studies. In most patients during the attacks of migraine, apart from various neurological and vascular symptoms, gastrointestinal disturbances occur including nausea, vomiting, abdominal pain or diarrhea. Functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), are reported in migraine patients in periods between the attacks as well. On the other hand 23-53% of IBS patients have frequent headaches. Migraine and IBS often coexist with fibromyalgia and other chronic pain syndromes and functional disorders. Migraine and IBS affect approximately 10-20% of the general population, usually young adults. Both diseases are more prevalent in women, perhaps due to the role of estrogen in their pathogenesis. Looking for the common pathogenetic mechanisms of IBS and migraine the role of the brain-gut axis, neuroimmune and neuroendocrine interactions are being considered. The influence of stress on symptom occurrence and severity seems to be associated with hyperactivity of the hypothalamic-pituitary-adrenal axis. The enteric nervous system as a source of numerous neurotransmitters and visceral reflexes is a plausible common pathogenic link between IBS and migraine. In particular serotonin being the main neurotransmitter of the gastrointestinal tract plays a relevant role in the pathogenesis of IBS as well as migraine. Nowadays, agonists and antagonists of serotoninergic receptors are the most efficacious drugs for IBS and migraine therapy. Some side effects of triptans, 5-HT(1B/D) agonists, used in migraine treatment may be connected with the influence of triptans on the gastrointestinal functions. A better understanding of the relationship between migraine and IBS may result in more effective treatment of both diseases.
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PMID:[Migraine and irritable bowel syndrome]. 1641 71


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