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

We investigated the possible involvement of 5-HT3 receptors in the colonic motor alterations and abdominal pain evoked by rectal distension (RD) in rats, under normal and inflammatory conditions. Responses to RD were evaluated by electromyography in rats treated with 5-HT3 antagonists (ondansetron and cilansetron, 0.1 and 1 mg/kg, intraperitoneally), before and 3 days after intrarectal administration of TNB/ethanol. RD evoked a significant (P < 0.05) and gradual inhibition of the occurrence of colonic spike bursts (SB) and a gradual increase in abdominal SB from 11 mm in diameter on wards. Ondansetron and cilansetron (0.1 mg/kg) significantly reduced both the colonic (62 and 66%, respectively) and the abdominal response (28 and 61%, respectively) for an 11 mm diameter of RD. After TNB/ethanol, both colonic and abdominal responses to RD were significantly (P < 0.05) enhanced and appeared for a lower diameter (9 mm) (colon: 4.8 +/- 0.9 vs 8.4 +/- 1.1, abdomen: 7.7 +/- 1.5 vs 0.5 +/- 0.4). Cilansetron (0.1, 1 mg/kg) significantly (P < 0.05) attenuated the TNB-induced colonic motor inhibition, while ondansetron and cilansetron (0.1, 1 mg/kg) reduced the TNB-induced increase in abdominal response. We conclude that 5-HT and 5-HT3 receptors mediate RD-induced viscerosensitive alterations in rats, both in normal conditions and during TNB-induced rectocolitis. However, the relative efficacy of the 5-HT3 receptor antagonists depends on the experimental conditions (intact or inflamed bowel) and does not appear to increase with the dose.
 ...
PMID:Influence of 5-HT3 receptor antagonists in visceromotor and nociceptive responses to rectal distension before and during experimental colitis in rats. 772 Dec 33

There is evidence from studies, in both animals and humans, that 5-HT3 receptor blockade has potential value in the treatment of irritable bowel syndrome, particularly in those patients with diarrhoea-predominant bowel habits. New findings suggest that 5-HT3 receptors exist on gut afferent neurones and that their activation by locally released 5-HT leads to visceral nociceptive stimulation, in addition to increased neuronally-mediated motor and secretory activity. If this concept is validated, it will provide a rationale for the use of 5-HT3 receptor antagonists in patients with increased gut motility, reduced fluid absorption and low nociceptive thresholds leading to abdominal pain. Alosetron is a highly selective, potent 5-HT3 receptor antagonist which is well absorbed with a long pharmacodynamic half-life. Its ability to provide long-lasting blockade of 5-HT3 receptors throughout the body make it an ideal candidate within its class to evaluate the clinical hypothesis that sustained and ubiquitous 5-HT3 receptor blockade is of value in the treatment of IBS.
 ...
PMID:Review article: the therapeutic potential of 5-HT3 receptor antagonists in the treatment of irritable bowel syndrome. 1042 38

Alosetron (Lotronex) is a potent, highly selective 5-HT(3) antagonist. Animal models have shown it to be active in anxiety, psychosis, cognitive impairment, emesis and drug withdrawal, though its application in humans has been almost entirely restricted to irritable bowel syndrome (IBS). Alosetron does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and is widely distributed throughout tissues after oral or iv. dosing in animals. Its metabolism is rapid and extensive with N-demethylation, hydroxylation and oxidation. The drug, or its two principal metabolites, is equally excreted through the biliary tract and kidneys. Alosetron has proved safe in a range of toxicity studies; at high repeated dosing, clinical signs were transient and repeated administration produced no significant adverse effects on fertility, reproductive performance or fetal development. In pharmacokinetic studies, bioavailability of alosetron in healthy volunteers is approximately 60% and the plasma half-life is about 1.5 h. There are some gender differences in the pharmacokinetic profile, with 30 - 50% higher alosetron concentrations in females. No consistent differences in alosetron serum concentrations between the young and elderly were observed. The pharmacokinetics of single, oral doses of alosetron are linear up to 8 mg. In human pharmacodynamic studies, alosetron increased basal jejunal water and electrolyte absorption, increased colonic transit time and, consequently, whole gut transit time. Alosetron has been evaluated in two large Phase II trials (randomised, double-blinded, placebo-controlled) and in Phase III trials which included a four-week observation period after cessation. Dose response studies suggested that the effective dosages could be between 1 and 2 mg, twice-daily. In Phase II trials, alosetron, 1 mg b.i.d., resulted in a greater proportion of non-constipated IBS patients reporting adequate relief of pain and discomfort, as well as improvement of bowel symptoms, frequency, urgency and stool consistency when compared with placebo. However, this beneficial effect was seen exclusively among females. Phase III studies evaluated exclusively females with non-constipated IBS and confirmed the results of the Phase II studies. Alosetron was well-tolerated in all studies, with the most frequently recorded adverse event being constipation. Thus, alosetron appears promising in the treatment of abdominal pain and discomfort and normalising of bowel function in patients with non-constipated IBS. It also improves quality of life, has a high degree of tolerability and has an excellent safety profile to date.
 ...
PMID:Pharmacology and clinical experience with alosetron. 1106 Jun 67

Tegaserod (Zelmac), an aminoguanidine indole derivative of serotonin, is a selective partial agonist highly selective for 5-HT(4) receptor with an affinity constant in the nanomolar range. Tegaserod does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and distributes widely into tissues. Pharmacokinetics of oral tegaserod are linear in the 2--12 mg dose range. After oral administration tegaserod is metabolized mainly pre-systemically; when absorbed, intact tegaserod is excreted as N-glucuronides mainly via the bile. No clinically relevant drug--drug interactions were identified. Tegaserod has proven safe in toxicity studies. In pharmacodynamic studies, tegaserod stimulated the peristaltic reflex in vitro, increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension in animals, and accelerated gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome. Three large phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (approximately 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject's global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well-tolerated; the most frequent adverse event was transient diarrhoea.
 ...
PMID:Review article: tegaserod. 1120 4

Irritable bowel syndrome (IBS) is a common functional bowel disorder of unknown aetiology. It is defined by the presence of gastrointestinal (GI) symptoms including abdominal pain/discomfort, bloating and bowel motor dysfunction. No available therapy is yet effective against all the symptoms of the disorder. Current treatments therefore target individual symptoms but may be accompanied by unpleasant side-effects. Tegaserod is a novel selective serotonin receptor type-4 (5-HT4) partial agonist with structural similarity to 5-HT Tegaserod stimulates small bowel and colonic motility and helps to normalise GI function. Clinical trials using a patient's assessment of efficacy demonstrate that tegaserod significantly improves key symptoms of IBS: abdominal pain/discomfort, bloating and constipation. Tegaserod is well tolerated with an excellent safety profile and represents a significant treatment advance in this difficult-to-treat disorder.
 ...
PMID:Tegaserod: a novel, selective 5-HT4 receptor partial agonist for irritable bowel syndrome. 1183 35

Irritable bowel syndrome (IBS) comprises a major proportion of gastrointestinal and primary care practice worldwide. The past several years have seen the rapid evolution of a new and comprehensive model of IBS based on alterations in brain-gut interactions. Alterations in the bidirectional communication between the enteric nervous system and the central nervous system are implicated in the pathogenesis of IBS. 5-Hydroxytryptamine (5-HT; serotonin), a major neurotransmitter in the gastrointestinal tract, and its receptors 5-HT3 and 5-HT4 are involved in the control of gastrointestinal function. A number of abnormal motor and sensory patterns have been reported in patients with IBS. However, it is not known whether these abnormalities are related to symptoms or have a role in establishing a diagnosis of functional gastrointestinal disorders. Visceral hyperalgesia in IBS patients can be secondary to altered receptor sensitivity at the viscus itself and altered central modulation of sensation involving psychological influences in the interpretation of these sensations. The development of diagnostic criteria for IBS helps to avoid unnecessary and costly investigations. A detailed history allows us to diagnose IBS and search for another cause if warning symptoms are present. The Rome criteria are presently used to define IBS and are currently the most widely applied criteria used in clinical diagnosis and research purposes. Abdominal pain or discomfort associated with chronic altered bowel habits are the mainstay in diagnosis, while the supportive criteria may be used to further classify IBS patients into diarrhea-predominant or constipation-predominant subgroups. Minimal diagnostic tests have been advocated in the initial diagnostic approach to patients with suspected IBS, depending on the predominant symptom. The therapeutic goals in IBS must focus on the overall well-being of the patient, including abdominal symptoms and the accompanying nonbowel symptoms and affective disorders. It is important to establish an effective physician-patient relationship and to reassure the patient once the diagnosis of IBS is made. Dietary modification may be of value in some patients with IBS. Dietary fiber is frequently recommended for patients with constipation-predominant IBS. Two novel serotonin agonists are currently under development for constipated IBS patients, tegaserod and prucalopride. Antidiarrheal agents, including loperamide and diphenoxylate, may help patients with diarrhea-predominant IBS. 5-HT3 receptor antagonists may play a role in the management of such patients in the future. Psychological treatment and antidepressants should be considered when IBS symptoms are severe or refractory or associated with psychological distress and impaired quality of life.
 ...
PMID:Irritable bowel syndrome: update on pathogenesis and management. 1211 90

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.
 ...
PMID:Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome. 1215 Jun 98

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (C(max)) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L. Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4) receptors and is devoid of promotile activity. The second is direct glucuronidation which leads to generation of three isomeric N-glucuronides. The plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half-life of 11 +/- 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment. No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfarin and oral contraceptives have indicated no clinically relevant interactions and no requirement for dosage adjustment.
 ...
PMID:Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity. 1240 41

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterised by recurrent abdominal pain and altered bowel habits in the absence of any discernible structural, biochemical and physiological abnormalities. Although there is no specific biological marker for the diagnosis of this disorder, recently developed symptom-based criteria provide the tools necessary to make a diagnosis. The precise underlying pathophysiology of IBS remains unknown. However, disturbances in the brain-gut axis involving the central nervous system and the enteric nervous system have emerged as an underlying concept for IBS. In this regard, conventional treatment has been recognised as unsatisfactory for many patients with IBS and novel, neuroenteric modulatory compounds have been introduced for use by clinicians. Specifically, compounds interacting with the 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT3 and 5-HT4 subtype have been demonstrated of benefit in some patients for the treatment of IBS. In this leading article, we present the current data on the pharmacology, clinical trials, indications and adverse effects of alosetron, a potent and selective 5-HT3 antagonist. As a result of the recognition of serious adverse effects, the indication for alosetron has been restricted and it is now indicated only for women with severe diarrhoea-predominant IBS who have symptoms for at least 6 months and who have failed to respond to conventional therapy. Prescribing restrictions and the risk-management programme implemented as required by the US FDA is reviewed along with a summary of the studies to be performed after reintroduction of alosetron to monitor safety.
 ...
PMID:Alosetron in irritable bowel syndrome: strategies for its use in a common gastrointestinal disorder. 1293 Jan 62

Alosetron (Lotronex, GlaxoSmithKline) is a potent and selective 5-HT(3)-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT(3) receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.
 ...
PMID:Alosetron and irritable bowel syndrome. 1459 62


1 2 3 4 5 6 7 Next >>