tegaserod and alosetron

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and it is characterized by episodes of abdominal pain and altered bowel functions. The specific bowel disturbances of diarrhea, constipation or an alternation between the two defines the IBS subtypes of diarrhea-predominant, constipation-predominant, and mixed or alternating IBS. Because of the abnormalities in bowel states associated with each IBS subtype, it is not likely that one agent would successfully treat all three subtypes. As a result, clinical trials have focused, for the most part, on one IBS subtype. Over the past 2 decades very few agents have achieved regulatory approval for the treatment of IBS. In the present article we review publications reporting on phase 2 and phase 3 studies evaluating agents to potentially be used in the treatment of patients with IBS.

Topics: Alprostadil; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbolines; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Lubiprostone; Peptides; Phenylalanine; Phloroglucinol; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin

Gut-acting therapies are common therapies for irritable bowel syndrome (IBS). Most of these peripheral acting agents are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in treating symptoms of IBS. The clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 antagonist alosetron in the treatment of women with severe IBS with diarrhea refractory to traditional therapy.

Topics: Alprostadil; Antidiarrheals; Carbolines; Dietary Fiber; Dietary Supplements; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Laxatives; Lubiprostone; Parasympatholytics; Serotonin Antagonists; Serotonin Receptor Agonists

Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT(3) receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT(3) receptor antagonist that is no longer in clinical development. In addition, the 5-HT(4) receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT(4) agonist/5-HT(3) antagonist. Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT(3) receptor antagonists or 5-HT(4) receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death. Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situatio

Topics: Animals; Carbolines; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT(3) antagonists and 5-HT(4) agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS.. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT(3) antagonists or 5-HT(4) agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.. The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT(3) antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT(3) antagonists/5-HT(4) agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT(3) antagonists vs. placebo was 0.78 (95% CI: 0.71-0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80-0.90). Renzapride and cisapride had no benefit in IBS.. Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.

Topics: Adult; Age Factors; Aged; Carbazoles; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Education, Medical, Continuing; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Treatment Outcome

Topics: Adult; Antidepressive Agents, Tricyclic; Carbolines; Cognitive Behavioral Therapy; Desipramine; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Parasympatholytics; Practice Guidelines as Topic

The treatment of irritable bowel syndrome due to the heterogeneous clinical symptoms and coexisting psychiatric disorders is still controversial. Although several agents with different mechanisms of action are widely used in clinical practice, there are only few drugs available with strong evidence of their efficacy, safety and tolerability at present. The etiology of irritable bowel syndrome is considered to be multifactorial: experimental and clinical research on visceral hypersensitivity, motility and brain-gut axis involving its neurotransmitters and receptors created the foundation of novel therapeutic approaches. Albeit nowadays several drugs (alosetron, tegaserod) have been registered in a few countries for the treatment of irritable bowel syndrome, further large clinical trials are required related to the new chemical entities.

Topics: Adrenergic alpha-Agonists; Analgesics, Opioid; Anti-Bacterial Agents; Antidepressive Agents; Carbolines; Chloride Channel Agonists; Cholecystokinin; Corticotropin-Releasing Hormone; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Muscarinic Antagonists; Neurokinin-1 Receptor Antagonists; Neurotrophin 3; Parasympatholytics; Probiotics; Receptors, Neurokinin-2; Serotonin Agents; Somatostatin

Pharmacogenomics of serotonin are potentially relevant in research and clinical practice. There are few proven examples of the importance of pharmacogenetics of serotonin-modifying agents used in functional gastrointestinal or motility disorders. Drug metabolism is dependent on function of the cytochrome P450 enzymes, such as 2D6 and 3A4. Genetic variations in transporters and translation mechanisms have been associated with responses to treatment in irritable bowel syndrome and in obesity. Research on the impact of polymorphisms of key proteins on the pharmacokinetics and pharmacodynamics of drugs that alter serotonin-mediated signalling will assist in explaining diverse responses to those drugs and ultimately improve clinical practice, individualizing medicine.

Topics: Appetite Depressants; Carbolines; Cyclobutanes; Dyspepsia; Gastrointestinal Agents; Genetic Variation; Humans; Indoles; Obesity; Pharmacogenetics; Polymorphism, Genetic; Receptors, Serotonin; Serotonin; Serotonin Agents; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists

The epidemiology and current understanding of the pathophysiology of irritable bowel syndrome is reviewed, beginning with a historical perspective. The roles of genetics, environment, allergy, infection and inflammation, bacterial overgrowth, hormones and motility abnormalities are discussed. Using the current evidence-based literature, the practical approach of diagnosis and treatment is outlined, including traditional modalities and newer therapeutic agents such as serotonin modulators.

Topics: Antidepressive Agents; Carbolines; Dietary Fiber; Food Hypersensitivity; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome; Parasympatholytics; Prevalence; Retrospective Studies; Serotonin Antagonists; United States

Although irritable bowel syndrome (IBS) is a common disorder, IBS is traditionally considered to be a condition that primarily affects young and middle-aged adults. However, increasing evidence suggests that prevalence of IBS in older adults may be similar to that in younger adults; therefore, the diagnosis should be considered when a geriatric patient presents with unexplained abdominal symptoms. Because incidences of other conditions with similar symptoms are higher in the geriatric population, use of certain diagnostic tests (eg, colonoscopy) is warranted in this patient population. In addition, because older adults are more likely than younger adults to suffer from comorbid conditions, polypharmacy is common in this patient population, and this should be considered when diagnosing and treating these patients.

Topics: Aged; Carbolines; Diagnosis, Differential; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Risk Factors

Topics: Anti-Bacterial Agents; Benzyl Compounds; Carbolines; Clonidine; Humans; Indoles; Inflammatory Bowel Diseases; Neostigmine; Probiotics; Propylamines

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.

Topics: Animals; Antidepressive Agents; Antidiarrheals; Carbolines; Cathartics; Humans; Indoles; Intestines; Irritable Bowel Syndrome; Parasympatholytics; Serotonin; Serotonin Agents

Topics: Adult; Aged; Antidepressive Agents; Carbolines; Dietary Fiber; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin Antagonists; Serotonin Receptor Agonists

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.

Topics: Carbolines; Colonic Diseases, Functional; Humans; Indoles; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Antidepressive Agents; Benzofurans; Carbazoles; Carbolines; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Physical Examination; Pyridines

Irritable bowel syndrome (IBS) is a commonly encountered condition seen in multiple medical specialties. Recent research has brought dramatic advances in our understanding of the epidemiology, burden of illness, diagnosis, and management of IBS. It is now widely accepted that the prevalence of IBS is between 10% and 20% of the US population and that the direct and indirect costs associated with IBS are significant. The processes required for diagnosis of IBS remain controversial. Scant evidence exists to support exhaustive diagnostic evaluations, and IBS is no longer considered a diagnosis of exclusion. The use of standardized symptom-based criteria remains to be perfected, and the diagnosis is often arrived at only after multiple laboratory, endoscopic, and radiologic examinations. The effects of treatment for IBS mirror the heterogeneous nature of the condition. No single medication has proven to be universally effective, and multiple therapeutic approaches exist. Greater understanding of gastrointestinal neurophysiology has led to promising advances in medical and nonmedical approaches to IBS.

Topics: Antidepressive Agents, Tricyclic; Carbolines; Cost of Illness; Desipramine; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Psychotherapy; Serotonin Antagonists; United States

Irritable bowel syndrome (IBS) is a common disorder with major health status and economic effects. Symptom criteria are of paramount importance in diagnosis, but differences among the Manning, Rome I, and Rome II criteria may lead to variable identification of people with the disorder. Practice guidelines are based on evidence and, to a greater degree, on consensus; therefore, experts vary on the specifics of ordering particular diagnostic tests. There is an overlap of IBS symptoms with those of celiac sprue, and selected patients should be tested for the latter disease. Symptom confusion with biliary pain and overlap with chronic pelvic pain could contribute to the predisposition of IBS patients to undergo cholecystectomy and hysterectomy. Development and documentation of effective therapy has been difficult, but depending on the selection of subgroups, there is evidence for usefulness of smooth muscle relaxants, loperamide, and antidepressants. Various forms of psychological therapy and new serotonin-modulating agents seem especially promising. The placebo effect of the physician-patient relationship has important therapeutic benefit.

Topics: Anti-Bacterial Agents; Carbolines; Celiac Disease; Clinical Trials as Topic; Colonic Diseases, Functional; Diagnosis, Differential; Female; Forecasting; Gastrointestinal Agents; Humans; Indoles; Male; Prognosis; Risk Assessment; Severity of Illness Index

Topics: Antidepressive Agents, Tricyclic; Antidiarrheals; Behavior Therapy; Carbolines; Cathartics; Colonic Diseases, Functional; Diagnosis, Differential; Humans; Indoles; Loperamide; North America; Parasympatholytics; Randomized Controlled Trials as Topic; Research Design; Serotonin Antagonists; Serotonin Receptor Agonists; Severity of Illness Index; Treatment Outcome

Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.

Topics: Antidepressive Agents; Benzofurans; Carbolines; Cisapride; Constipation; Drug Industry; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

The most important component of the treatment of irritable bowel syndrome (IBS) is to establish a therapeutic physician-patient relationship, coupled with patient education. We describe a stepwise approach to management, including judicious use of invasive tests, and setting realistic treatment goals that address the dominant symptoms, their severity, and psychosocial factors.

Topics: Abdominal Pain; Antidepressive Agents; Antidiarrheals; Carbolines; Cholinergic Antagonists; Colonic Diseases, Functional; Constipation; Diagnosis, Differential; Diarrhea; Diet; Follow-Up Studies; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Middle Aged; Parasympatholytics; Patient Education as Topic; Physician-Patient Relations; Psychotherapy; Randomized Controlled Trials as Topic; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Topics: Abdominal Pain; Animals; Carbolines; Colonic Diseases, Functional; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors

Topics: Adult; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Diagnosis, Differential; Diet; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Psychotherapy; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Topics: Benzofurans; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Female; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Abdominal Pain; Animals; Benzyl Compounds; Carbolines; Central Nervous System; Colitis, Ulcerative; Colon; Colonic Diseases, Functional; Colonoscopy; Controlled Clinical Trials as Topic; Diarrhea; Digestion; Electromyography; Female; Follow-Up Studies; Gastric Emptying; Gastroenteritis; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Myenteric Plexus; Neurons; Neurotransmitter Agents; Placebos; Pressure; Propylamines; Receptors, Opioid, kappa; Rectum; Risk Factors; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Time Factors

More than one decade ago, rising cases of ischemic colitis (IC) prompted the Federal Drug Administration to revoke alosetron's approval as treatment of irritable bowel syndrome (IBS). The aim of this study was to identify medical therapies associated with development of IC.. The Federal Adverse Event Reporting System was queried for the time between January 2004 and September 2015. We identified reports listing IC as treatment complication and extracted suspected causative and concomitantly administered drugs, indications for their use and outcomes.. After eliminating duplicates, we found 2811 cases of IC (68.4 % women; 59.4 ± 0.4 years). Patients with IBS accounted for 3.9 % of the cases, mostly attributed to tegaserod or alosetron. Chemotherapeutic and immunosuppressive drugs, sex hormones, and anticoagulants were the most commonly suspected causes. Bisphosphonates, nonsteroidal anti-inflammatory drugs, antipsychotics, triptans, interferon therapy, and laxative use prior to colonoscopy were among the more commonly listed treatments. In 8 %, the adverse event contributed to the patient's death with male sex and older age predicting fatal outcomes.. Beyond confirming known risks of IC, the results identified several potential culprits of ischemic colitis. This information may not only explain the development of this serious adverse event, but could also guide treatment decisions, cautioning healthcare providers when considering these agents in persons with known risk factors or other drugs that may increase their risk of IC.

Topics: Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antineoplastic Agents; Antipsychotic Agents; Autoimmune Diseases; Bone Density Conservation Agents; Carbolines; Colitis, Ischemic; Colonoscopy; Databases, Factual; Diphosphonates; Estrogens; Female; Gonadal Steroid Hormones; Humans; Immunosuppressive Agents; Indoles; Interferons; Irritable Bowel Syndrome; Laxatives; Male; Mental Disorders; Middle Aged; Neoplasms; Osteoporosis; Preoperative Care; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Tryptamines; United States

Topics: Anti-Bacterial Agents; Biofeedback, Psychology; Carbolines; Colitis; Diet; Dysentery; Dyspepsia; Egypt; Female; Firmicutes; Greece; Helicobacter pylori; History, 17th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Humans; Indoles; Intestines; Irritable Bowel Syndrome; Marketing; NAV1.5 Voltage-Gated Sodium Channel; Penicillins; Phenethylamines; Practice Guidelines as Topic; Rifamycins; Rifaximin; Serotonin; Social Support; Spirit Possession

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

As the use of the 5-HT(3) receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT(4) receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated.. Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance.. Intravenous alosetron (0.03-0.3 mg.kg(-1)) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15-20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT(3) receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3-1.0 mg.kg(-1)) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon.. Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.

Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Carbazoles; Carbolines; Clonidine; Colitis; Colon; Fasting; Female; Heart Rate; Indoles; Mesenteric Artery, Superior; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyridines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Splanchnic Circulation; Vasoconstrictor Agents; Vasodilator Agents

Several high-profile drug withdrawals for safety issues have brought into focus the FDA's process for approving drugs and monitoring adverse experiences with those agents after marketing has begun. Gastroenterologists and their patients have been affected adversely by removal from the marketplace of two licensed agents for irritable bowel syndrome (IBS): alosetron and tegaserod. The criteria used by the FDA for assessment of the risks and benefits of drugs used for functional bowel problems seem to be different than those used for the treatment of other conditions and have resulted in drastic limitation of access to these drugs rather than just warnings about risks as they are discovered. Decisions that affect the availability of drugs for patients with functional bowel disease should be discussed with clinicians who take care of those patients before going into effect. The absence of this sort of consultation leaves physicians with serious limitations on their abilities to take care of patients.

Topics: Adverse Drug Reaction Reporting Systems; Carbolines; Clinical Trials as Topic; Drug Approval; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Product Surveillance, Postmarketing; Risk; Serotonin Receptor Agonists; United States; United States Food and Drug Administration

A mathematical model of a segment of the gut with an enclosed pellet is constructed. The gut is represented as a thin deformable soft biological shell with the pellet modeled as a non-deformable solid. Mechanical properties of the gut wall were represented as longitudinal and circular smooth muscle layers embedded in stroma that satisfies the general type of nonlinear orthotropy. Deformations of the wall are finite. Bolus propulsion is numerically simulated by generation and propagation of an electromechanical wave along the syncytia. Pharmacological manipulation is applied to model 5-HT type 3 antagonist (Lotronex, GlaxoSmithKline) and 5-HT type 4 agonist (Zelnorm, Novartis, AB) drugs on the dynamics of bolus progression. The results lead to new quantitative insights into the complex spatio-temporal patterns of gastrointestinal transit. It is demonstrated that the reciprocal relationship in contraction of the longitudinal and circular smooth muscle syncytia is necessary to provide the "mixing" type of movements during the preparatory phase of propulsion. Strong simultaneous contractions of the both smooth muscle layers are required to expel the "mixed" pellet from the segment. The model is implemented as an interactive software system, Gut Discovery(www.aincompany.com), and accurately predicts the effects of drugs on gut motility.

Topics: Algorithms; Biomechanical Phenomena; Carbolines; Electrophysiology; Gastrointestinal Motility; Humans; Indoles; Intestines; Models, Biological; Muscle Contraction; Muscle, Smooth; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Carbolines; Double-Blind Method; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Carbolines; Diet; Dietary Fiber; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Probiotics; Psychotherapy; Serotonin Receptor Agonists

Topics: Carbolines; Humans; Indoles; Irritable Bowel Syndrome; Polypharmacy; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Carbolines; Colonic Diseases, Functional; Diagnosis, Differential; Drug Approval; Female; Gastrointestinal Agents; Humans; Indoles; Male; United States; United States Food and Drug Administration

Topics: Antidepressive Agents, Tricyclic; Antidiarrheals; Behavior Therapy; Carbolines; Cathartics; Colonic Diseases, Functional; Diagnosis, Differential; Evidence-Based Medicine; Humans; Indoles; Loperamide; North America; Parasympatholytics; Randomized Controlled Trials as Topic; Serotonin Antagonists; Serotonin Receptor Agonists; Severity of Illness Index

Topics: Benzofurans; Carbolines; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Guanidines; Humans; Indoles; Male; Serotonin Antagonists