Review article: current and emerging therapies for functional dyspepsia

Functional dyspepsia represents a heterogeneous group of gastrointestinal disorders marked by the presence of upper abdominal pain or discomfort. Although its precise definition has evolved over the last several decades, this disorder remains shrouded in controversy. The symptoms of functional dyspepsia may overlap with those of other functional bowel disorders including irritable bowel syndrome and non-erosive reflux disease. There may be coexistent psychological distress or disease complicating its presentation and response to therapy. Given the prevalence and chronicity of functional dyspepsia, it remains a great burden to society. Suspected physiological mechanisms underlying functional dyspepsia include altered motility, altered visceral sensation, inflammation, nervous system dysregulation and psychological distress. Yet the exact pathophysiological mechanisms that cause symptoms in an individual patient remain difficult to delineate. Numerous treatment modalities have been employed including dietary modifications, pharmacological agents directed at various targets within the gastrointestinal tract and central nervous system, psychological therapies and more recently, complementary and alternative treatments. Unfortunately, to date, all of these therapies have yielded only marginal results. A variety of emerging therapies are being developed for functional dyspepsia. Most of these therapies are intended to normalize pain perception and gastrointestinal motor and reflex function in this group of patients.     

CRF1 receptors as a therapeutic target for irritable bowel syndrome

The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.     

Review article: the hypersensitive gut—peripheral kappa agonists as a new pharmacological approach

Hypersensitivity to pain is a common component of functional bowel disorders. Hyperalgesia may be induced by various stimuli which produce a cocktail of inflammatory mediators that decrease the pain threshold. Drugs able to block these peripheral events within the gut may offer a new pharmacological approach for treating functional bowel disorders. Kappa opioids have been shown to inhibit somatic pain through a peripheral mechanism of action, acting directly on receptors located on peripheral sensory endings. They can block both the nociceptive messages as well as the release of sensory peptides. This paper reviews the effects of opioid agonists on gut visceral pain and motility anomalies induced by visceral pain. Kappa opioids have strong effects on all models tested, with a peripheral mechanism of action allowing the design of drugs acting only in the periphery and having no central nervous system side-effects. This contrasts with mu agonists which are centrally active on pain and worsen the subsequent transit and motility anomalies.     

Modulation of visceral pain and inflammation by protease-activated receptors

The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, particularly in the domains of inflammation and pain mechanisms. Activation of PARs by selective peptidic agonists in the intestine or the pancreas leads to inflammatory events and changes in visceral nociception, suggesting that PARs could be involved in the modulation of visceral pain and inflammation. PARs are present in most of the cells that are potentially actors in the generation of irritable bowel syndrome (IBS) symptoms. Activation of PARs interferes with several pathophysiological factors that are involved in the generation of IBS symptoms, such as altered motility patterns, inflammatory mediator release, altered epithelial functions (immune, permeability and secretory) and altered visceral nociceptive functions. Although definitive studies using genetically modified animals, and, when available, pharmacological tools, in different IBS and inflammatory models have not yet confirmed a role for PARs in those pathologies, PARs appear as promising targets for therapeutic intervention in visceral pain and inflammation processes.     

Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder, characterized by abdominal pain/discomfort, bloating and altered bowel habit. AIM: To conduct a systematic evidence-based review of pharmacological therapies currently used, or in clinical development, for the treatment of IBS in Europe. The safety and tolerability of these therapies are the subject of an accompanying review. METHODS: A literature search was completed for randomized controlled studies which included adult patients with IBS and an active or placebo control, assessed IBS symptoms, and were published in English between January 1980 and June 2005. The level of evidence for efficacy was graded according to the quality of the trial design and the study outcome. RESULTS: There is some evidence for improvement of individual IBS symptoms with antidiarrhoeals (diarrhoea), antispasmodics (abdominal pain/discomfort), bulking agents (constipation), tricyclic antidepressants (abdominal pain/discomfort) and behavioural therapy. In contrast, there is strong evidence for the improvement of global IBS symptoms with two new serotonergic agents: the 5-HT4 selective agonist tegaserod (IBS with constipation) and the 5-HT3 antagonist alosetron (IBS with diarrhoea). Further data are required for the 5-HT3 antagonist, cilansetron, and the mixed 5-HT3 antagonist/5-HT4 agonist renzapride before their utility in IBS can be appraised. CONCLUSIONS: There is limited evidence for the efficacy, safety and tolerability of therapies currently available in Europe for the treatment of IBS. Overall, there is an absence of pharmacological agents licensed specifically for the treatment of IBS subtypes, and new agents are awaited in Europe that will allow changes in clinical practice to focus on and improve global IBS symptoms.     

Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting

Background  Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required.
Aim  To identify an appropriate dosage of renzapride (a 5-HT₄ receptor full agonist/5-HT₃ receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome.
Methods  In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5–12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life.
Results  Although there were no statistically significant differences between renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses.
Conclusions  This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.     

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea—two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu‐enkephalin and Met‐enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu‐enkephalin, Met‐enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.     

Anti-hyperalgesic effect of octreotide in patients with irritable bowel syndrome

BACKGROUND: Octreotide has been found to be beneficial in the treatment of chronic pain, although the mechanisms underlying its therapeutic effect are incompletely understood. AIMS: To assess the effect of octreotide on perceptual responses to rectal distension in irritable bowel syndrome patients and healthy controls at baseline and following the experimental induction of rectal hyperalgesia. METHODS: In study 1, rectal perception thresholds for discomfort were determined in seven irritable bowel syndrome patients and eight healthy controls on three separate days using a computer-controlled barostat. Subjects received saline, low-dose and high-dose octreotide in a random double-blind fashion. In study 2, perceptual responses to rectal distension were obtained in nine irritable bowel syndrome patients and seven controls before and after repetitive high-pressure mechanical sigmoid stimulation. RESULTS: Octreotide increased the discomfort thresholds in irritable bowel syndrome patients, but not in controls, without changing rectal compliance. Repetitive sigmoid stimulation resulted in decreased rectal discomfort thresholds in the patient group only. In irritable bowel syndrome patients, octreotide prevented the sensitizing effect of repetitive sigmoid stimulation on rectal discomfort thresholds. CONCLUSIONS: Octreotide effectively increased discomfort thresholds in irritable bowel syndrome patients, but not in controls, at baseline and during experimentally induced rectal hyperalgesia. These findings suggest that octreotide exerts primarily an anti-hyperalgesic rather than analgesic effect on visceral perception.     

Effect of long-term treatment with octreotide on rectal sensitivity in patients with non-constipated irritable bowel syndrome

BACKGROUND: Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. AIM: To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. METHODS: Forty-six non-constipated irritable bowel syndrome patients (52% female, 19-63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. RESULTS: Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. CONCLUSIONS: Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms.     

Review article: visceral hypersensitivity

Visceral hypersensitivity is highly prevalent in all functional bowel disorders. Most also demonstrate wider patterns of somatic referral of intestinal pain or discomfort. This hypersensitivity may explain the symptoms as the sensitive gut can be more easily provoked by normal or abnormal motor events in the gut. Visceral hypersensitivity may increase during psychosocial stress and during periods of symptom exacerbation, although this requires confirmation. Pharmacological therapy to reduce visceral hypersensitivity is now possible using antagonists to neurotransmitters, opening up an exciting new era for the treatment of functional gastrointestinal disorders.     

Review article: drugs interfering with visceral sensitivity for the treatment of functional gastrointestinal disorders--the clinical evidence

At present, the concept of visceral hypersensitivity provides the leading hypothesis regarding the generation of symptoms in functional gastrointestinal disorders. This paper discusses the current clinical evidence for drugs that have been proposed to interfere with visceral sensitivity in functional gastrointestinal disorders. Several possible pharmacological targets have been identified to reduce visceral pain and to reverse the processes underlying the persistence of visceral hypersensitivity. However, most of the available evidence comes from experimental animal models and cannot simply be extrapolated to patients with functional gastrointestinal disorders. In this review, we selected five drug classes that have been shown to exhibit visceral analgesic properties in experimental studies, and of which data were available regarding their clinical efficacy. These included opioid substances, serotonergic agents, antidepressants, somatostatin analogues and alpha(2)-adrenergic agonists. Although clinical trials show a limited benefit, in particular for serotonergic agents, the evidence illustrating that these effects result from normalization of visceral sensation is currently lacking. Therefore, we conclude that the concept of targeting visceral hypersensitivity as a treatment for functional gastrointestinal disorders is still controversial. Future evaluations require patient selection based on the presence of visceral hypersensitivity and application of compounds that exhibit 'true' viscerosensory effects.     

Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model

Analgesia from most opioids is mediated by mu receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic/pharmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty-four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood samples and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic/pharmacodynamic profiles were modeled using a 2-stage, nonlinear, mixed-effects approach with an effect compartment to represent the concentration-analgesia delay. Morphine kinetics was best described by a 2-compartment model, whereas oxycodone kinetics was best described with a 1-compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic/pharmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.     

Evoked Human Oesophageal Hyperalgesia: A Potential Tool for Analgesic Evaluation?

Abstract: Hypersensitivity is a common finding in visceral disorders. Therefore, in the development and testing of analgesics for the treatment of visceral pain, it is important to establish an experimental pain model of visceral hypersensitivity. Such a model will mimic the clinical situation to a higher degree than pain models where the receptors and peripheral afferents are briefly activated as with, for example, electrical, thermal, and mechanical stimulations. In this study, a model to evoke experimental hyperalgesia of the oesophagus with a combination of acid and capsaicin was introduced. The study was a randomised, double‐blind, cross‐over study. Fifteen healthy volunteers were included. Sensory assessments to mechanical, heat, and electrical stimulations were done in the distal oesophagus, before and after perfusion with a 200 ml solution of acid+capsaicin (180 ml HCL 0.1 M and 2 mg capsaicin in 20 ml solvent) or saline. Oesophageal pain assessment and referred pain areas were evaluated. There were reproducible pain assessments between repetitions within the same day and between days (all P > 0.05). Acid+capsaicin perfusion induced 56% reduction of the pain threshold to heat (P = 0.04), 19% reduction of the pain threshold to electrical stimuli (P < 0.001), 78% increase of the referred pain areas to mechanical stimulation (P < 0.001) and 52% increase of the referred pain areas to electrical stimulus (P = 0.045). All volunteers were sensitised to one or more modalities by acid+capsaicin. The model was able to evoke consistent hyperalgesia and may be useful in future pharmacological studies.     

Disturbed upper gastrointestinal sensation: an important abnormality?

The relationship between disturbed upper gastro-intestinal motility and symptoms of heartburn and dyspepsia varies. For example, in some symptomatic patients abnormal motor events are not detected, whereas, conversely, impaired motor patterns may be recorded in patients who are asymptomatic. Nociceptive visceral afferents arising in the gut transmit peripheral sensations to the brain. It has been postulated that variations in sensory afferent activity are responsible for the inconsistent expression of disturbed upper gastrointestinal motility. Several studies have demonstrated that patients with so-called functional symptoms, which appear to arise from normal gut regions, exhibit a lower perception threshold to stimuli that distend the gut. Such visceral hypersensitivity could explain the occurrence of symptoms in the absence of demonstrable physiological or morphological abnormalities. Evidence that variations in visceral sensory afferent activity constitute an important disease mechanism is not conclusive. In certain conditions such as non-cardiac chest pain and functional dyspepsia, visceral hypersensitivity provides a useful hypothetical framework. Not only has this framework established a basis for previously unexplained symptoms, but perhaps more importantly it has stimulated research to develop novel pharmacological agents to modulate nociception. The challenge is now to establish putative pathogenetic links between aberrant sensory activity and disturbed upper gastrointestinal motility, and also to locate the neural abnormalities along the gut-brain axis.     

New therapeutical approaches for treatment of irritable bowel syndrome

Irritable bowel syndrome is a common functional disorder of the gut. The cause is not known. Symptoms can be quite variable and include abdominal pain, bloating, and sometimes bouts of diarrhea and/or constipation. It causes a great deal of discomfort and distress, but it does not permanently harm the intestine and does not lead to a serious disease, such as cancer. There are numerous treatment options in functional gastrointestinal disorders acting peripherally by influencing motility and visceral sensitivity. However, older 5-HT4 receptor agonists had limited clinical success because they were associated with changes in the cardiac function. New generation 5-HT4 receptor agonists, 5-HT, antagonists or partial antagonists are promising approaches to treat gastrointestinal dysmotility, particularly colonic diseases. A further new approach is the activation of chloride cannels within the gastrointestinal wall by the prostaglandin E metabolite lubiprostone. In patients with chronic constipation, lubiprostone produced a bowel movement, with sustained improvement in frequency as well as other constipation symptoms. Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase C (GC-C) receptor agonist and intestinal secretagogue is also an effective treatment for chronic constipation. The pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from of constipation-predominant irritable bowel syndrome and chronic constipation. Data are emerging, but the efficacy and safety profile of these agents in the treatment irritable bowel disease appears encouraging. Further randomized controlled trials are warranted.     

TRP channels in neurogastroenterology: opportunities for therapeutic intervention

The members of the superfamily of transient receptor potential (TRP) cation channels are involved in a plethora of cellular functions. During the last decade, a vast amount of evidence is accumulating that attributes an important role to these cation channels in different regulatory aspects of the alimentary tract. In this review we discuss the expression patterns and roles of TRP channels in the regulation of gastrointestinal motility, enteric nervous system signalling and visceral sensation, and provide our perspectives on pharmacological targeting of TRPs as a strategy to treat various gastrointestinal disorders. We found that the current knowledge about the role of some members of the TRP superfamily in neurogastroenterology is rather limited, whereas the function of other TRP channels, especially of those implicated in smooth muscle cell contractility (TRPC4, TRPC6), visceral sensitivity and hypersensitivity (TRPV1, TRPV4, TRPA1), tends to be well established. Compared with expression data, mechanistic information about TRP channels in intestinal pacemaking (TRPC4, TRPC6, TRPM7), enteric nervous system signalling (TRPCs) and enteroendocrine cells (TRPM5) is lacking. It is clear that several different TRP channels play important roles in the cellular apparatus that controls gastrointestinal function. They are involved in the regulation of gastrointestinal motility and absorption, visceral sensation and visceral hypersensitivity. TRP channels can be considered as interesting targets to tackle digestive diseases, motility disorders and visceral pain. At present, TRPV1 antagonists are under development for the treatment of heartburn and visceral hypersensitivity, but interference with other TRP channels is also tempting. However, their role in gastrointestinal pathophysiology first needs to be further elucidated.     

Randomised clinical trial: the clinical effects of a novel neurokinin receptor antagonist, DNK333, in women with diarrhoea-predominant irritable bowel syndrome

Background Neurokinin receptors may play an important role in the visceral hypersensitivity and exaggerated motor/secretory activity associated with diarrhoea‐predominant irritable bowel syndrome (IBS‐D). Aim To evaluate the effects of DNK333, a novel neurokinin antagonist, in women with IBS‐D. Methods In two consecutive phase II studies, women with IBS‐D were randomised to twice‐daily (b.d.) DNK333 25 mg, DNK333 100 mg or placebo for 2 weeks (Trial 1), or DNK333 25 mg b.d. or placebo for 4 weeks (Trial 2). Primary efficacy variables studied were change from baseline of stool form at week 2, and satisfactory relief of IBS‐related abdominal pain/discomfort and global IBS‐D symptoms. Secondary efficacy variables, pharmacokinetics and safety were also evaluated. Results In total, 315 subjects were randomised. There were no statistically significant differences between treatment groups for the primary efficacy variables. However, analysis of combined data from both trials revealed significant differences favouring DNK333 25 mg over placebo for satisfactory relief of IBS‐related abdominal pain/discomfort and global IBS‐D symptoms. Trends favouring improvement with DNK333 25 mg vs. placebo were seen for all secondary efficacy variables. DNK333 had a safety profile similar to placebo. Conclusions DNK333 25 mg b.d. appears to be effective and well tolerated in women with IBS‐D. Further studies with neurokinin antagonists are warranted.     

Pleural effusions: pathophysiology and management with intrapleural tetracycline

Chronic or recurrent pleural effusions are a consequence of a variety of disease states and may produce significant pain or discomfort in a patient. Both surgical and pharmacological attempts to control pleural effusions have been tried, with moderate success. This article reviews the pathophysiology of pleural effusion and the role of intrapleural tetracycline in its management. Irritating chemicals, when instilled into the pleural space, are known to produce adhesion of the pleural membranes. Tetracycline has been shown in both animal and human studies to be effective in preventing the recurrence of a pleural effusion while producing only minor side effects, such as fever and pleuritic pain. Studies involving tetracycline in treating pleural effusions are reviewed, and guidelines for the preparation and administration of intrapleural tetracycline are presented. Because of its efficacy, low toxicity, ease of preparation, ready availability, and low cost, tetracycline deserves strong consideration as a first-line agent in the management of recurrent pleural effusions.     

Impact of advertisement and clinic populations in symptoms and perception of irritable bowel syndrome

BACKGROUND: This study assessed the impact of recruitment on irritable bowel syndrome clinical trials, by determining whether irritable bowel syndrome patients recruited from advertisement or a specialty clinic differ in clinical and physiologic measures. METHODS: We prospectively surveyed 657 irritable bowel syndrome patients who either: (i) were referred from a functional bowel disease clinic (52%); or (ii) responded to advertisement for clinical trials (48%), using questionnaires about bowel and psychological symptoms, and quality of life. In a subset of 42 irritable bowel syndrome patients (29 advertisement and 15 clinic patients), rectal discomfort thresholds were measured before and after repetitive sigmoid stimulation. RESULTS: While the advertisement population more commonly consulted primary care physicians, the clinic population more commonly consulted gastroenterologists. The clinic population reported more prevalent and severe abdominal pain, and higher psychological symptom scores, while the advertisement population had greater quality of life. In the visceral perception studies, both subgroups were hypersensitive to rectal distension. CONCLUSION: Compared to the clinic population, the advertisement population had less severe abdominal pain and psychological symptoms, better quality of life but similar visceral perception. The differences in clinical self-reports may have consequences for enrolment of these different patient populations into clinical trials.     

Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome

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.