Clinical trial: protective effect of a commercial fish protein hydrolysate against indomethacin (NSAID)-induced small intestinal injury

Background A partially hydrolysed and dried product of pacific whiting fish is marketed as a health food supplement supporting 'intestinal health'.Aim To examine whether the partially hydrolysed and dried product of pacific whiting fish influenced the small intestinal damaging side effects of the nonsteroidal anti-inflammatory drug, indomethacin.Methods Eight human volunteers completed a double-blind, placebo-controlled, crossover protocol of clinically relevant dose of indomethacin (50 mg t.d.s. p.o. for 5 days) with 7 days of fish hydrolysate or placebo starting 2 days prior to indomethacin. Changes in gut permeability were assessed using 5 h urinary lactulose:rhamnose (L/R) ratios.Results Fish hydrolysate given alone did not affect permeability. In the main study (n = 8), baseline values were similar for both arms (0.28 +/- 0.05 and 0.35 +/- 0.07). Administration of indomethacin (+placebo) caused a fivefold rise in L/R ratios (increasing to 1.54 +/- 0.35), whereas L/R ratios in the same subjects ingesting indomethacin + fish hydrolysate was only 0.59 +/- 0.14 (P < 0.01 vs. indomethacin alone). Dyspeptic symptoms occurred in four of eight subjects taking indomethacin alone, but zero of eight when hydrolysate was co-administered.Conclusion Natural bioactive products (nutriceuticals), such as fish hydrolysates, may provide a novel approach to the prevention and treatment of NSAID-induced and other gastrointestinal injurious conditions

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry

Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Background Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value

UK National Survey of Gastroenterologists’ attitudes and barriers toward therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease

Background Evidence supports use of therapeutic drug monitoring (TDM) in improving efficacy and cost-effectiveness of anti-tumour necrosis factor (TNF) therapy in inflammatory bowel disease (IBD). Our objective was to assess attitudes and barriers towards TDM use with anti-TNF’s in the UK. Methods A 17-question survey was distributed to members of the British Society of Gastroenterology by email. Results Of 243 respondents (51.6% male), 237 respondents met inclusion criteria. Of these, 46% were consultants (gastroenterologist, GI), 39.2% IBD nurse specialists (clinical nurse specialists, CNS), 14.8% registrars. TDM is used by 96.9% for secondary loss of response; 72.5% for primary non-response and 54.1% used TDM proactively. Barriers were time lag in receiving results (49.8%), lack of awareness of guidelines (46.4%) and cost (29.9%). Clinicians working at a teaching hospital (OR 2.6, 95% CI 0.71 to 9.8), IBD CNS and GI registrars (OR 2.6, 95% CI 0.7 to 10 and OR 1.5, 95% CI 0.3 to 7.2, respectively) were more likely to use TDM. Clinicians practising for &gt;20 years (OR 4.1, 95% CI 0.4 to 41.8) and a large volume IBD practice (&gt;50% IBD patients per month) were more likely to use TDM (OR 45.7, 95% CI 7.5 to 275). Proactive TDM, was more likely to be used in tertiary care (OR 2.25, 95% CI 0.84 to 6.1), IBD CNS (OR 1.2, 95% CI 0.7 to 2.1) and clinicians managing &gt;50% IBD patients per month (OR 10.8, 95% CI 1.3 to 90.3). Clinicians with 5–9 years of experience in practice were more likely to use proactive TDM (OR 2.6 and CI 1.04 to 6.4). Conclusion Validation of point of care and lower cost assays, reduced time lag from test to result, lower cost of testing and dissemination of current recommendations may further optimise treatment strategies