Summary
Background
Treatment of IBS and functional lower gastrointestinal disorders is still based predominantly on symptoms; biomarkers that reflect the mechanism or pathophysiology have been ...identified. Given the diverse mechanisms that result in the same clinical phenotype of IBS, it is hypothesised that identification of biomarkers may lead to individualisation of medical therapy.
Aim
To review the biomarkers that have been appraised in IBS.
Methods
A single author reviewed the published literature on biomarkers appraised in IBS.
Results
The current literature suggests that these biomarkers are insufficiently sensitive or specific to differentiate IBS from health or from other diseases causing similar symptoms, such as coeliac disease or inflammatory bowel disease. Most of the proposed biomarkers are not actionable, that is, they do not lead to an efficacious therapy based on the biological inference of the biomarker itself. However, among proposed biomarkers in IBS, some are actionable, as they specifically reflect a quantitative difference in a mediator of dysfunction or result in a quantifiable disturbance of function that can be specifically treated. Such biomarkers may potentially identify relevant subgroups that respond to specific therapy. The most promising actionable biomarkers are measurement of colonic transit (leading to treatments that reverse the abnormal transit) and measurements of bile acid diarrhoea to identify responders to bile acid sequestrants.
Conclusions
Therefore, although biomarkers are not ready for prime time as diagnostic tests in IBS, some biomarkers could identify subgroups of patients with IBS for inclusion in clinical trials that target specific dysfunctions. Such an approach may enhance treatment efficacy, and may ultimately help reduce costs in drug development and in the management of patients in clinical practice.
Background
Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.
Purpose
The objective of this article is to increase the awareness of ...gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms. The non‐selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity. In addition to the well‐recognized manifestations of cannabinoid hyperemesis, cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. Decreased enteric FAAH activity is associated with colonic inertia in slow transit constipation and, conversely, the orphan G protein‐coupled receptor, GPR55, is overexpressed in streptozotocin‐induced gastroparesis, suggesting it is involved in inhibition of antral motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.
Cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. These clinical measurements of gastric emptying and antroduodenal manometry were obtained in a patient with prior use of cannabinoids. This article addresses effects of cannabinoids on gastrointestinal motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. Cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.
It is of major importance to measure the validity of self-reported dietary intake using web-based instruments before applying them in large-scale studies.
This study aimed to validate self-reported ...intake of fish, fruit and vegetables, and selected micronutrient intakes assessed by a web-based self-administered dietary record tool used in the NutriNet-Santé prospective cohort study, against the following concentration biomarkers: plasma beta carotene, vitamin C, and n-3 polyunsaturated fatty acids.
One hundred ninety-eight adult volunteers (103 men and 95 women, mean age=50.5 years) were included in the protocol: they completed 3 nonconsecutive-day dietary records and two blood samples were drawn 3 weeks apart. The study was conducted in the area of Paris, France, between October 2012 and May 2013.
Reported fish, fruit and vegetables, and selected micronutrient intakes and plasma beta carotene, vitamin C, and n-3 polyunsaturated fatty acid levels were compared.
Simple and adjusted Spearman's rank correlation coefficients were estimated after de-attenuation for intra-individual variation.
Regarding food groups in men, adjusted correlations ranged from 0.20 for vegetables and plasma vitamin C to 0.49 for fruits and plasma vitamin C, and from 0.40 for fish and plasma c20:5 n-3 (eicosapentaenoic acid EPA) to 0.55 for fish and plasma c22:6 n-3 (docosahexaenoic acid). In women, correlations ranged from 0.13 (nonsignificant) for vegetables and plasma vitamin C to 0.41 for fruits and vegetables and plasma beta carotene, and from 0.27 for fatty fish and EPA to 0.54 for fish and EPA+docosahexaenoic acid. Regarding micronutrients, adjusted correlations ranged from 0.36 (EPA) to 0.58 (vitamin C) in men and from 0.32 (vitamin C) to 0.38 (EPA) in women.
The findings suggest that three nonconsecutive web-based dietary records provide reasonable estimates of true intake of fruits, vegetables, fish, beta carotene, vitamin C, and n-3 fatty acids. Along with other validation studies, this study shows acceptable validity of using such diet-assessment methods in large epidemiologic surveys and broadens new perspectives for epidemiology.
Background
Opioids are effective for acute and chronic pain conditions, but their use is associated with often difficult‐to‐manage constipation and other gastrointestinal (GI) effects due to effects ...on peripheral μ‐opioid receptors in the gut. The mechanism of opioid‐induced constipation (OIC) differs from that of functional constipation (FC), and OIC may not respond as well to most first‐line treatments for FC. The impact of OIC on quality of life (QoL) induces some patients to decrease or stop their opioid therapy to relieve or avoid constipation.
Purpose
At a roundtable meeting on OIC, a working group developed a consensus definition for OIC diagnosis across disciplines and reviewed current OIC treatments and the potential of treatments in development. By consensus, OIC is defined as follows: ‘A change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency’. The working group noted the prior validation of a patient response outcome and end point for clinical trials and recommended future efforts to create treatment guidelines and QoL measures specific for OIC. Details from the working group's discussion and consensus recommendations for patient care and research are presented in this article.
Summary
Background Metoclopramide is a dopamine receptor antagonist which has been used for treatment of a variety of gastrointestinal symptoms over the last thirty years. In 2009, the FDA issued a ...black box warning regarding long‐term or high‐dose use of this medication because of the risk of developing tardive dyskinesia.
Aims To review the mechanism of action and pharmacokinetic properties of metoclopramide, the risk of metoclopramide‐induced tardive dyskinesia, potential mechanisms that may alter and to summarize the clinical context for appropriate use of the drug.
Methods We conducted a PubMed search using the following key words and combined searches: metoclopramide, neuroleptics, tardive dyskinesia, incidence, prevalence, dopamine, receptors, pharmacokinetic, pharmacology, pharmacogenetics, DRD3 Ser9Gly polymorphism, cytochrome P450, p‐glycoprotein, risk factors, gastroparesis, outcome, natural history.
Results Available data show that risk of tardive dyskinesia from metoclopramide use is likely to be <1%, much less than the estimated 1–10% risk previously suggested in national guidelines. Tardive dyskinesia may represent an idiosyncratic response to metoclopramide; pharmacogenetics affect pharmacokinetic and dopamine receptor pharmacodynamics in response to neuroleptic agents that cause similar neurological complications.
Conclusion Community prevalence and pharmacogenetic mechanisms involved in metoclopramide‐induced tardive dyskinesia require further study to define the benefit‐risk ratio more clearly.
Summary
Background Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have ...enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities.
Aims To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin‐releasing hormone), the efficacy and safety of new 5‐HT4 agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase‐C agonists), bile acid modulation, anti‐inflammatory agents and visceral analgesics.
Methods Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy.
Results The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5‐HT4 agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents ‘borrowed’ from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study.
Conclusions There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal.
The objective of this study is to examine the association between impulsivity and weight status in a large sample of the adult general population in France, and the influence of gender on this ...relationship. A total of 11,929 men and 39,114 women participating in the NutriNet-Santé cohort were selected in this cross-sectional analysis. The Barratt Impulsiveness Scale (BIS-11) was used to assess impulsivity. Weight and height were self-reported. The association between impulsivity and BMI was estimated using logistic regressions adjusted for socio-demographic and lifestyle factors. Individuals with high impulsivity levels (BIS-11 total score >71) were more likely to be obese (Odds Ratio (OR) = 1.80, 95% Confidence Interval (CI): 1.39, 2.33 in men; OR = 1.30, 95% CI: 1.15, 1.48 in women) compared to individuals in the average range of impulsivity. The strongest associations between impulsivity and obesity were observed in men, where highly impulsive participants were more likely to be class III obese (BMI > 40 kg/m²) (OR = 3.57, 95% CI: 1.86, 6.85). This large sample analysis supports the existence of a relationship between impulsivity and weight status and the importance of psychological factors in the prevention of obesity.
Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in ...diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…
Scintigraphic colonic transit measurement has emerged as a unique disease‐related biomarker pertinent to drug development and personalized therapy. This surrogate offers reproducible and accurate ...performance across a spectrum of common colonic motility disorders, linking colonic transit measurements to biological processes and clinical end points. The pathobiologic validity, prognostic utility, performance characteristics, evidence‐based linkage of therapeutic intervention with outcome, applicability across distinct pharmacodynamic profiles, and potential for individualizing patient management are all attributes of this gastrointestinal imaging paradigm. The cumulative evidence suggests that the integration of colonic transit measurement as a biomarker would accelerate the development and regulatory approval of therapeutic agents for the treatment of colonic dysmotility.
Clinical Pharmacology & Therapeutics (2010) 87 6, 748–753. doi: 10.1038/clpt.2010.23
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