Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tegaserod, a potent, partial serotonin 4 receptor (5-HT4) agonist, is an effective agent for the treatment of females with constipation-predominant irritable bowel syndrome. Tegaserod enhances gastric motility, stimulates peristaltic reflux and intestinal secretion, inhibits visceral sensitivity, and/or shortens colonic transit time. This agent may help women who have failed to respond to diet and exercise, laxatives, and other forms of therapy. The optimal dose of tegaserod is 6 mg twice daily and results in decreased number of days per month with pain, bloating, and days without bowel movements. Tegaserod is less effective in males than females in the treatment of constipation-predominant irritable bowel syndrome. Tegaserod is well tolerated. Diarrhea is the most frequent adverse effect. The diarrhea tends to occur most frequently during the first few months of therapy and decreases with continued administration.
 ...
PMID:Tegaserod for the treatment of constipation-predominant irritable bowel syndrome. 1212 Jan 85

Tegaserod (HTF 919), a selective 5-HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open-label, parallel-group study, the pharmacokinetics of a single 12-mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h-tz), ng.h/ml: 14.6 +/- 8.5 vs. 14.3 +/- 7.1; Cmax, ng/ml: 4.6 +/- 2.3 vs. 5.1 +/- 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.
 ...
PMID:Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects. 1272 56

Serotonin (5-hydroxytryptamine [5-HT])1 receptor agonists, such as those used for treating migraine, can cause coronary artery contraction, coronary spasm, and even myocardial infarction. Tegaserod maleate is a relatively new 5-HT4 receptor agonist with moderate affinity for the 5-HT1 receptor. Currently, it is approved only for treatment of irritable bowel syndrome in women who have constipation as the primary symptom. However, it is also being administered as a promotility agent in patients with gastroparesis. Since tegaserod has affinity for the 5-HT1 receptor, it is plausible that tegaserod could cause the same types of cardiovascular adverse events seen with agents prescribed for management of migraine. We report the first case of a man who experienced a myocardial infarction after receiving only two 6-mg doses of tegaserod; we also provide a hypothesis regarding this event. When considering prescribing a drug with 5-HT1 receptor agonist activity, clinicians should review the patient's medical history specifically for the presence of underlying cardiovascular risk factors.
 ...
PMID:Tegaserod-induced myocardial infarction: case report and hypothesis. 1553 69

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.
 ...
PMID:Delayed Gastric Emptying in Functional Dyspepsia. 1523

Using whole-cell patch-clamp methods, we examined the hypothesis that serotonin [5-hydroxytryptamine (5-HT)] receptor activation enhances TRPV1 function in mouse colon sensory neurons in lumbosacral dorsal root ganglia, which were identified by retrograde labeling with DiI (1,1'-dioctadecyl-3,3,3',3-tetramethlindocarbocyanine methanesulfonate) injected into multiple sites in the wall of the descending colon. 5-HT increased membrane excitability at a temperature below body temperature in response to thermal ramp stimuli in colon sensory neurons from wild-type mice, but not from TRPV1 knock-out mice. 5-HT significantly enhanced capsaicin-, heat-, and proton-evoked currents with an EC50 value of 2.2 microm. 5-HT (1 microm) significantly increased capsaicin-evoked (100 nm) and proton-evoked (pH 5.5) currents 1.6- and 4.7-fold, respectively, and significantly decreased the threshold temperature for heat current activation from 42 to 38 degrees C. The enhancement of TRPV1 by 5-HT was significantly attenuated by selective 5-HT2 and 5-HT4 receptor antagonists, but not by a 5-HT3 receptor antagonist. In support, 5-HT2 and 5-HT4 receptor agonists mimicked the facilitating effects of 5-HT on TRPV1 function. Downstream signaling required G-protein activation and phosphorylation as intracellularly administered GDP-beta-S [guanosine 5'-O-(2-thiodiphosphate], protein kinase A inhibitors, and an A-kinase anchoring protein inhibitor significantly blocked serotonergic facilitation of TRPV1 function; 5-HT2 receptor-mediated facilitation was also inhibited by a PKC inhibitor. We conclude that the facilitation of TRPV1 by metabotropic 5-HT receptor activation may contribute to hypersensitivity of primary afferent neurons in irritable bowel syndrome patients.
 ...
PMID:TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. 1550 39

Constipation is one of the most common gastrointestinal conditions with limited effective treatment options. Tegaserod, a 5-HT4 receptor agonist has demonstrated efficacy in relieving constipation-related symptoms in patients suffering from irritable bowel syndrome with constipation. This paper reviews two recent reports that have evaluated the efficacy and safety of tegaserod in patients with chronic constipation. Two double-blind, randomized, placebo-controlled trials have been reported; one in Europe and Asia (E2301) the other in North and South America (E2302). After a 2-week baseline period, patients were randomized to treatment with tegaserod 2 mg b.d., tegaserod 6 mg b.d. or placebo for 12 weeks. Two thousand, six hundred and twelve patients were randomized, the majority were white females. In both studies, responder rates during weeks 1-4 were significantly greater in the tegaserod groups compared with placebo. A similar trend was seen over weeks 1-12. Statistically significant improvements over placebo were seen across the majority of secondary efficacy variables. Tegaserod was safe with no consistent differences in the frequency of adverse events among the various groups. In conclusion, treatment of chronic constipation with tegaserod was associated with significant improvement in bowel frequency as well as other constipation symptoms. Tegaserod was also well tolerated in this patient population.
 ...
PMID:Review article: tegaserod for chronic constipation. 1552 51

This article reviews the efficacy and tolerability of traditional therapies for irritable bowel syndrome (IBS) and concludes that they are limited by both poor efficacy and adverse effects. Serotonin, a neurotransmitter found mainly in the gut, appears to represent a link in IBS pathophysiological processes -- altered gut motility, abnormal intestinal secretion and visceral hypersensitivity. Recently, available treatments for IBS have targeted serotonin receptors that are involved in motor, sensory and secretory functions of the gut. Serotonergic agents, such as alosetron (a 5-HT3 receptor antagonist) and tegaserod (a selective 5-HT4 receptor partial agonist), provide global relief of the multiple symptoms of IBS with diarrhoea and IBS with constipation, respectively, and represent important additions to the IBS treatment armamentarium.
 ...
PMID:Options for patients with irritable bowel syndrome: contrasting traditional and novel serotonergic therapies. 1560 19

Tegaserod, a potent partial agonist of the serotonin 5-HT4 receptor, is used to treat women with constipation-predominant irritable bowel syndrome. Since the drug's approval, the manufacturer has received infrequent although serious reports of diarrhea and ischemic colitis in patients taking the drug. These instances have led to a recent warning letter to physicians and a change in the prescription labeling of tegaserod. We describe the development of ischemic colitis in a woman who was treated with tegaserod and review the relationship among ischemic colitis, tegaserod use, and irritable bowel syndrome. Potential mechanisms involved in the occurrence of ischemic colitis in patients receiving tegaserod are also discussed.
 ...
PMID:Tegaserod-associated ischemic colitis. 1597 22

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.
 ...
PMID:Serotonergic modulation and irritable bowel syndrome. 1598 96

Novartis is developing Zelmac (SDZ-HTF-919), a 5-HT4 receptor partial agonist, which is in phase III clinical trials for the treatment of gastric motility disorders and irritable bowel syndrome (IBS). Warburg Dillon Read estimated (in January 1999) that Zelmac will achieve sales of 240 million Swiss Francs in 2001.
 ...
PMID:Zelmac (Novartis AG). 1616 Sep 39


<< Previous 1 2 3 4 Next >>