Irritable Bowel Syndrome: Camilleri M

Camilleri M. · No affiliation provided · Am J Gastroenterol. · Pubmed #19293789 No free full text.

Abstract: There is controversy on the validity of binary end points used in irritable bowel syndrome (IBS) clinical trials. In a usual-care observational study, baseline severity influenced the response measured as satisfactory relief. This editorial reviews the observations from a non-pharmacological study to assess the effect of baseline severity on the performance of binary end points in large drug trials. The pivotal finding is that once the patients who reported adequate relief at baseline were excluded from the analysis, baseline severity no longer affected the proportion of patients reporting adequate relief of IBS with treatment. As large drug trials enriched the study cohorts for at least moderate severity after a no-treatment, run-in period, it seems likely that the precaution of excluding mild disease de facto resolved the hypothetical weakness of the adequate relief end point. Given the high responsiveness and longitudinal construct validity demonstrated with adequate relief end point, it should be accepted as a trial end point.

Camilleri M. · No affiliation provided · Neurogastroenterol Motil. · Pubmed #15916617 No free full text.

This publication has no abstract.

Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota 55905, USA. · Curr Opin Endocrinol Diabetes Obes. · Pubmed #19115522 No free full text.

Abstract: PURPOSE OF REVIEW: To assess the role of serotonin and its control in the manifestations and treatment of lower functional gastrointestinal disorders. RECENT FINDINGS: Recent literature has explored several novel concepts in the association of serotonin and symptoms, alterations in tissue levels of serotonin and its reuptake protein, aspects of the genetic determinants of serotonergic function (particularly 5-HTTLPR) and its relationship to gastrointestinal motor and sensory functions, and novel serotonergic agents used in therapy of lower functional gastrointestinal disorders. The most consistent findings are the increase in plasma 5-hydroxytryptamine (5-HT) in diarrheal diseases and reduction in constipation. The serotonin transporter in platelets has an impact on the circulating level of 5-HT. Meta-analysis shows that 5-HTTLPR genotype is not significantly associated with irritable bowel syndrome in Whites or Asians. New 5-HT3 antagonists and 5-HT4 agonists are efficacious and promise to provide relief for patients if they can pass regulatory hurdles. SUMMARY: Although the most relevant implication for clinical practice remains the evidence that serotonergic agents are efficacious in the treatment of chronic constipation, chronic diarrhea and irritable bowel syndrome, the role of genetic control of 5-HT and its receptors is the subject of ongoing research, and is likely to enhance understanding of the mechanisms and treatment of these diseases.

Camilleri M, Chang L. · Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Gastroenterology. · Pubmed #18848833 No free full text.

Abstract: Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic, or rectal sensitivity and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system: antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics, and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients' reported outcomes and associated quality of life. After a decade of experience with different end points that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global end points to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals.

Camilleri M. · Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. · J Clin Gastroenterol. · Pubmed #18806702 No free full text.

Abstract: To review the rationale and current evidence for the efficacy of probiotics in the treatment of irritable bowel syndrome (IBS), the following specific questions are addressed from a review of the published literature: Are bacterial flora altered in IBS? Is infection a significant risk factor for IBS? How prominent is the inflammation in IBS? Do probiotics change bacterial flora? Do probiotics adhere to mucosa? What are the potential mechanisms of action of probiotics in IBS: immune function, motor, secretory, sensory, and fermentation? What is the efficacy of probiotics in IBS?

Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #18715494 links to  free full text

Abstract: Asimadoline is a potent kappa-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the kappa receptor, with IC(50) of 5.6 nmol L(-1) (guinea pig) and 1.2 nmol L(-1) (human recombinant), and high selectively with kappa : micro : delta binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post-on-demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain-free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.

Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Mayo Clinic, Rochester, MN 55905, USA. · Curr Opin Pharmacol. · Pubmed #18588997 No free full text.

Abstract: Over the past decade, the failed promise of animal models and preclinical pharmacology, and a changing landscape in the regulatory perspectives have impacted the development of drugs for the treatment of irritable bowel syndrome (IBS). In general, animal models have failed to predict efficacy of medications developed for visceral pain. On the contrary, extensive experience with different endpoints in large, randomized, and controlled trials has generated some data on psychometric validation and unprecedented information about responsiveness of binary or global endpoints. However, it has now become necessary to pursue further validation studies in the run-up to or during pivotal trials. Guidance documents from regulatory agencies in Europe and the United States have focused on patient response outcomes (PROs) and associated impact on quality of life. These extra validation steps will undoubtedly result in delays in drug development. Providing relief to patients should galvanize all parties to achieve effective and fair strategies for regulatory approval.

Camilleri M, Saito YA. · Clinical Enteric Neuroscience Translational and Epidemiological Research Program, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Methods Mol Biol. · Pubmed #18370239 No free full text.

Abstract: It is anticipated that unraveling the human genome will have a direct impact on the management of specific diseases. Variations or mutations in genes involved in drug metabolism or disease pathophysiology in gastroenterology and hepatology are expected to have effect on response to therapy. The spectrum of diseases is vast. Thus, we focus this review on clinical pharmacogenetics of inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, liver transplantation, and colon cancer. Although only a few genotyping tests are used regularly in clinical practice, we anticipate that in the future there will be more routine use of many of the tests described in this review.

Andresen V, Montori VM, Keller J, West CP, Layer P, Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. · Clin Gastroenterol Hepatol. · Pubmed #18242143 links to  free full text

Abstract: BACKGROUND & AIMS: We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS). METHODS: Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently. RESULTS: We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups. CONCLUSIONS: 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.

Camilleri M. · CENTER Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #17620087 No free full text.

Abstract: 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.

Camilleri M, Gorman H. · Clinical Enteric Neuroscience Translational and Epidemiological Research Group, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #17593135 No free full text.

Abstract: Based on a systematic PubMed search, this short review addresses why intestinal permeability may be important in the pathobiology of irritable bowel syndrome (IBS), the evidence of abnormal permeability in patients with IBS, and the pros and cons of the different probe molecules available to assess intestinal permeability. While a subgroup of patients with IBS appears to have evidence of increased intestinal permeability, improvements in the methods and validation are key to further research in this field in order to better understand intestinal barrier functions in IBS.

Camilleri M, Mangel AW, Fehnel SE, Drossman DA, Mayer EA, Talley NJ. · CENTER Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Clin Gastroenterol Hepatol. · Pubmed #17428741 No free full text.

Abstract: The choice of primary endpoint for a clinical trial is one of the most important determinants of the ability of a clinical trial to demonstrate efficacy of therapeutic agents. Although there are still no clear, universally accepted guidelines on the definition of clinical benefit for irritable bowel syndrome (IBS), consensus guidelines stress the importance of using validated endpoints. This article reviews the evidence available in the literature on the psychometric validation and performance of the 3 endpoints recommended by the Rome III Committee for use as primary endpoints in treatment trials of IBS. The Rome III Committee recommends 2 types of measures: binary endpoints addressing the construct of relief (that is, adequate relief and satisfactory relief) and an integrative symptom questionnaire that addresses the change in severity of a representative group of symptoms of IBS (that is, the IBS Severity Scale). The current evidence suggests that at present, adequate relief should be recognized by regulatory authorities as an acceptable primary endpoint in clinical trials. This analysis also suggests that data from individual clinical trials should be pooled and undergo meta-analysis, and that prospective studies should be considered to further characterize the performance of available endpoints as outcome measures in pharmacotherapeutic trials in IBS.

Azpiroz F, Bouin M, Camilleri M, Mayer EA, Poitras P, Serra J, Spiller RC. · Digestive System Research Unit, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain. · Neurogastroenterol Motil. · Pubmed #17280586 No free full text.

Abstract: General introduction The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.

Camilleri M. · Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Dig Liver Dis. · Pubmed #17259088 No free full text.

Abstract: This brief review appraises the current evidence of the efficacy of probiotics, including lactobacilli, bifidobacteria, and VSL#3, in the treatment of irritable bowel syndrome (IBS). The mechanisms potentially important will be evaluated, with specific reference to immune function, effects on motility and intraluminal milieu. These experimental and clinical observations suggest that probiotics may play a role in the management of IBS.

Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research Group, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #17244161 No free full text.

Abstract: 5-HT(3) antagonists are effective treatments for chemotherapy-induced emesis and diarrhoea and urgency and pain associated with irritable bowel syndrome. Reports of ischaemic colitis led to restricted use of the approved drug, alosetron. This article briefly reviews the controversial information from epidemiology and adverse reaction reports and addresses the experimental basis for the development of ischaemic colitis as a result of 5-HT(3) antagonist treatment. The author reviews the potential factors based involved in the ischaemic colitis and ways in which this class of compound may influence those factors based on experimental evidence, including the literature on any vascular effects of these agents. Finally, the article addresses the theoretical basis for the constipation as a predisposing factor for the development of ischaemic colitis. The evidence reviewed suggests that further studies are needed to explore the principles to prove or disprove the association.

Saito YA, Camilleri M. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Clinical Enteric Neuroscience Translational and Epidemiological Research, Charlton 8-110, 200 First Street SW, Rochester, MN 55905, USA. · Expert Opin Pharmacother. · Pubmed #17020413 No free full text.

Abstract: As knowledge of the human genome grows, there will be a direct impact on the management of specific diseases. Within gastroenterology and hepatology, there has been a change in the understanding of how variations or mutations in genes involved in drug metabolism or disease pathophysiology affect response to therapy. This review discusses the application of clinical pharmacogenetics to the following diseases and disorders: inflammatory bowel disease, Helicobacter pylori infections, gastroesophageal reflux disease, irritable bowel syndrome, functional dyspepsia, liver transplantation and colon cancer. Although only a few genotyping tests are regularly used in clinical practice, it is anticipated that studies will propel the routine use of many of the tests described in this review, in the future.

Park MI, Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Group, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #16918724 No free full text.

Abstract: A significant proportion of adults believe they suffer from food allergy, and 20-65% of patients with irritable bowel syndrome (IBS) attribute their symptoms to something in food that activates an abnormal response. This systematic review evaluates the role of food allergy in aetiology and management of these disorders. Activation of gastrointestinal mucosal immune system may be one of the causative factors in the pathogenesis of functional dyspepsia and IBS. This activation may result from effects of bacterial infection or other luminal factors including commensal microbial flora and food antigens. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients. Further well-controlled studies are needed to establish whether food allergy plays a role in the pathophysiology of functional dyspepsia and IBS.

Andresen V, Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Drugs. · Pubmed #16789793 No free full text.

Abstract: Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder affecting up to 3-15% of the general population in Western countries. It is characterised by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits. The pathophysiology of IBS is considered to be multifactorial, involving disturbances of the brain-gut-axis: IBS has been associated with abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Hence, there is a need for new treatment strategies. Increasing knowledge of brain-gut physiology, mechanisms, and neurotransmitters and receptors involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches. This article provides a systematic overview of recently approved or novel medications that show promise for the treatment of IBS; classification is based on the physiological systems targeted by the medication. The article includes agents acting on the serotonin receptor or serotonin transporter system, novel selective anticholinergics, alpha-adrenergic agonists, opioid agents, cholecystokinin antagonists, neurokinin antagonists, somatostatin receptor agonists, neurotrophin-3, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin and atypical benzodiazepines. Finally, the role of probiotics and antibacterials in the treatment of IBS is summarised.

Floch MH, Madsen KK, Jenkins DJ, Guandalini S, Katz JA, Onderdonk A, Walker WA, Fedorak RN, Camilleri M. · Yale University School of Medicine, New Haven, CT 06520-8019, USA. · J Clin Gastroenterol. · Pubmed #16633136 No free full text.

Abstract: Probiotics are live microbial organisms that are administrated as supplements or in foods to benefit the host. It is the recommendation that they may be helpful in the prevention and treatment of acute diarrhea in adults and children, the prevention of antibiotic-associated diarrhea in adults and children, and the maintenance of remission and prevention of pouchitis. Although early results indicate that probiotics may also be useful in immunologic modulation to prevent atopy, treatment of radiation intestinal disease, vaginosis, ulcerative colitis, and the irritable bowel syndrome, the studies available are not sufficient to say they are definitely helpful. Even fewer data are available to recommend probiotics for the treatment of H pylori and Crohn disease and for the prevention of cardiovascular risk factors or other degenerative diseases. Clearly, larger and better-designed studies of probiotics are necessary, including comparative and dose-ranging trials.

Camilleri M. · Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. · J Clin Gastroenterol. · Pubmed #16633134 No free full text.

Abstract: The irritable bowel syndrome (IBS) follows an acute, presumably infectious diarrheal illness in approximately 15% of patients. There may be a persistent, mild inflammatory state with changes in mucosal function or structure. Changes in the colonic bacterial flora reported in IBS seem related to predominant bowel. Colonic bacteria normally metabolize nutrients with the formation of gas and short chain fatty acids. The latter may induce propulsive contractions and accelerate colonic transit or they may enhance fluid and sodium absorption in the colon. This review addresses the mechanisms, rationale and current evidence for the efficacy of probiotics, including Lactobacilli, Bifidobacteria, and VSL#3, in the treatment of IBS. The mechanisms influenced by probiotics include immune function, motility, and the intraluminal milieu. Probiotics may suppress the low-grade inflammation associated with IBS or restore normal local immune function. Lactobacilli and Bifidobacteria subspecies are able to deconjugate and absorb bile acids, potentially reducing the colonic mucosal secretion of mucin and fluids that may contribute to functional diarrhea or IBS with diarrhea. Therapeutic trials show the potential benefit of Bifidobacteria or Lactobacilli species alone or in the specific probiotic combination, VSL#3, on symptoms in IBS. Colonic transit was retarded in IBS patients treated with VSL#3 without induction of significant changes in bowel function. In summary, probiotics are promising therapies in IBS.

Camilleri M. · Mayo Clinic College of Medicine, Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Gastroenterology Research Unit, Charlton 8-110200 First Street S.W., Rochester, MN 55905, USA. · Pharmacogenomics. · Pubmed #16013999 No free full text.

Abstract: Functional gastrointestinal disorders, including irritable bowel syndrome and functional dyspepsia, are highly prevalent disorders affecting approximately one in four people in Western societies. This article reviews examples of the role of pharmacogenomics in the safety and efficacy of medications used in the management of such disorders. These include variations in the effects of medications metabolized by cytochrome P450 enzymes (e.g., 2D6 and 2C19), and the effects of genetic polymorphisms in the promoter of the serotonin transporter protein, which influence the response to alosetron in patients with diarrhea-predominant irritable bowel syndrome. These observations suggest that pharmacogenomics will introduce a new era in pharmacotherapeutics in gastroenterology.

Park MI, Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Charlton 8-110 200 First Street Southwest, Rochester, MI 55905, USA. · Gastroenterol Clin North Am. · Pubmed #15862937 No free full text.

Abstract: Several twin studies and familial aggregation studies in IBS are consistent with either a genetic or a social learning hypothesis, and it is possible that both play a role. The prospect of identifying a genetic cause for IBS may be very important, because it raises the possibility of confirming that IBS isa disease entity, suggests new insight into the pathophysiology of the disorder, and provides new targets for drug development. Several candidate genetic markers including: those related to cytokines such as IL-10, TNF-alpha and TGF beta1; SERT-P; alpha-adrenergic receptors; and G proteins have been associated with certain aspects of IBS. Genetic polymorphisms,however, are common and may have no etiological or pathogenetic relevance. Searching for the genes in IBS is of potentially great relevance.Such studies may identify more specific phenotypes in IBS or potentially predict increased disease vulnerability, but it is unlikely that this strategy will lead to a diagnostic test, given the limited component of IBS that is likely to be genetically determined. Pharmaco genomic studies have potential to be important in the future. For this potential to be realized, it will be necessary to formally include genetic studies in trials of experimental drugs.This would enhance understanding of one of the roles of genetics for treating IBS.

Camilleri M. · CENTER, Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester, MN 55905, USA. · Gut. · Pubmed #15361483 links to  free full text

This publication has no abstract.

Camilleri M, Talley NJ. · Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Neurogastroenterol Motil. · Pubmed #15086867 No free full text.

Abstract: Sensorimotor disorders of the stomach, small intestine and colon have a limited repertoire of clinical manifestations, and there is the potential for more than one mechanism to lead to symptoms. In many recent clinical trial programs of novel agents in neurogastroenterology, the emphasis has been primarily on symptom assessment of broad groups of patients identified by the Rome criteria. Drugs of potential value have fallen by the wayside with this approach. We propose the current paradigm is partly to blame; physiological testing should provide the basis for identifying more homogeneous populations and therapeutic targets within functional bowel disease, and this applies to the upper and lower gut. Here we summarize the evidence that certain biomarkers can, in a limited fashion, be used to predict the success of an experimental medicine in common disorders of gastrointestinal function, including the irritable bowel syndrome and functional dyspepsia. Although the current evidence is limited and is most convincingly demonstrated with examples of transit measurements (for loperamide, alosetron, tegaserod and piboserod), we perceive this paradigm that studies using validated and responsive biomarkers have an important role to play in drug development.

Camilleri M. · Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R) Program, Mayo Clinic College of Medicine, Charlton 8-110, 200 First Street SW, Rochester, MN 55905, U.S.A. · Br J Pharmacol. · Pubmed #15037521 links to  free full text

Abstract: This article summarizes the ongoing challenges in irritable bowel syndrome and the exciting opportunities for development of novel therapies for this common, enigmatic condition. The challenges include insufficient understanding of mechanisms, lack of specificity of symptoms, differentiation from other conditions, and lack of availability of noninvasive tests to identify dysfunctions. However, significant opportunities are reflected by the advances in clinical trial design and, particularly, clinically relevant end points for such trials, and the increasing understanding of basic neuroenteric science. The latter has delivered two new medications to the practice (alosetron and tegaserod), and other candidate therapies (other serotonergic, tachykininergic, opioid, cannabinoid modulators) are being carefully appraised as potential drugs for the future.