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Yang L.,University of Cambridge | Cheriyan J.,University of Cambridge | Cheriyan J.,Clinical Unit Cambridge | Gutterman D.D.,Medical College of Wisconsin | And 7 more authors.
Chest | Year: 2017

Background Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo. Methods Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers. Results Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (–8.33 ± 0.172 logM vs –8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003). Conclusions GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD. Trial Registry ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov © 2016 The Authors


Worbe Y.,University of Cambridge | Irvine M.,University of Cambridge | Lange I.,University of Cambridge | Kundu P.,University of Cambridge | And 6 more authors.
Biological Psychiatry | Year: 2014

Background: Abnormal decision making under risk is associated with a number of psychiatric disorders. Here, we focus on binge drinkers (BD), characterized by repeated episodes of heavy alcohol intoxication. Previous studies suggest a decreased sensitivity to aversive conditioning in BD. Here, we asked whether BD might be characterized by enhanced risk seeking related to decreased sensitivity to the anticipation of negative outcomes. Methods: Using an anticipatory risk-taking task (40 BD and 70 healthy volunteers) and an adapted version of this task for functional magnetic resonance imaging (21 BD and 21 healthy volunteers), we assessed sensitivity to reward and loss across risk probabilities. Results: In the behavioral task, BD showed a higher number of risky choices in high-risk losses. In the neuroimaging task, the high-risk attitude in the loss condition was associated with greater activity in dorsolateral prefrontal, lateral orbitofrontal, and superior parietal cortices in BD. Explicit exposure of BD to the probability and magnitude of loss, via introduction of feedback, resulted in a subsequent decrease in risky choices. This change in risk attitude in BD was associated with greater activity in inferior frontal gyrus, which also correlated with the percentage of decrease in risky choices after feedback presentation, suggesting a possible role for cognitive control toward risk-seeking attitudes. Conclusions: Our findings suggest that a decrease in sensitivity to the anticipation of high-risk negative outcomes might underlie BD behavior. Presentation of explicit feedback of probability and loss in BD can potentially modify risk-taking attitudes, which have important public health implications and suggest possible therapeutic targets. © 2014 Society of Biological Psychiatry.


Nair S.C.,University Utrecht | Welsing P.M.J.,University Utrecht | Choi I.Y.K.,University of Amsterdam | Roth J.,University Hospital Muenster | And 9 more authors.
PLoS ONE | Year: 2016

Objectives: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods: Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. Results: The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. Conclusions: Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness. © 2016 Nair et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cambridge V.C.,University of Cambridge | Ziauddeen H.,University of Cambridge | Ziauddeen H.,Clinical Unit Cambridge | Ziauddeen H.,Cambridgeshire and Peterborough National Health Service Foundation Trust | And 18 more authors.
Biological Psychiatry | Year: 2013

Background: Binge eating is associated with obesity and has been conceptualized as food addiction. However, this view has received only inconsistent support in humans, and limited evidence relates key neurocircuitry to the disorder. Moreover, relatively few studies have used pharmacologic functional magnetic resonance imaging to probe the underlying basis of altered eating behaviors. Methods: In a double-blind, placebo-controlled, parallel group study, we explored the effects of a potent mu-opioid receptor antagonist, GSK1521498, in obese individuals with moderate binge eating. Subjects were tested during a baseline placebo run-in period and retested after 28-days of drug (n = 21) or placebo (n = 21) treatment. Using functional magnetic resonance imaging and behavioral measures, we determined the drug's effects on brain responses to food images and, separately, on motivation to expend energy to view comparable images. Results: Compared with placebo, GSK1521498 was associated with a significant reduction in pallidum/putamen responses to pictures of high-calorie food and a reduction in motivation to view images of high-calorie food. Intriguingly, although motivational responding was reduced, subjective liking for the same images actually increased following drug treatment. Conclusions: Stimulus-specific putamen/pallidal responses in obese people with binge eating are sensitive to altered mu-opioid function. This neuromodulation was accompanied by reductions in motivational responding, as measured by grip force, although subjective liking responses to the same stimuli actually increased. As well as providing evidence for a link between the opioid system and food-related behavior in binge-eating obese individuals, these results support a dissociation across measures of motivation and liking associated with food-related stimuli in these individuals. © 2013 Society of Biological Psychiatry.

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