Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

© 2015, BMJ Publishing Group. All rights reserved. Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies ( < 5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy

A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study proto

© Article author(s). Introduction Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended-release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-Arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. Methods and analysis The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics and dissemination Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. Trial registration number NCT02720822; Pre-results

Expanded Clinical Pharmacogenetics Implementation Consortium Guideline for Medication Use in the Context of G6PD Genotype

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in persons with G6PD deficiency, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in individuals with G6PD deficiency by one or more sources. We classify these medications as high, medium, or low to no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high-risk medications should be avoided, medium-risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at: www.cpicpgx.org)

Horse grimace scale does not detect pain in horses with equine gastric ulcer syndrome

Equine gastric ulcer syndrome (EGUS) is a highly prevalent and presumptively painful condition, although the amount of pain horses might experience is currently unknown. The aims of this study were to determine if the Horse Grimace Scale (HGS) could identify pain behaviours in horses with and without EGUS and if severity would be positively associated with the HGS score. Horse grimace scale scores were assessed blindly using facial photographs by seven observers and involved evaluation of 6 facial action units as 0 (not present), 1 (moderately present) and 2 (obviously present). Lameness examination, serum amyloid A (SAA) measurement and gastroscopy evaluation were performed on all horses. Horses (n = 61) were divided into two and three groups based on the presence (yes, no) and severity (none, mild, moderate-severe) of EGUS, respectively. Presence of lameness and elevated SAA (≥50 µg/mL) were used as exclusion criteria. Inter-observer reliability was analyzed by intra-class correlation coefficients (ICC). HGS scores between groups were compared using Welch’s and Brown Forsythe tests (p &lt; 0.05). Overall, HGS ICC was “excellent” (0.75). No significant differences (p = 0.566) were observed in HGS scores between horses with and without gastric lesions (mean, 95% CI; 3.36, 2.76–3.95 and 3, 1.79–4.20, respectively). HGS was not influenced by the presence or severity of EGUS in this current study. Further studies investigating the use of different pain scales in horses with EGUS are needed

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress

Special RepoRt Practical recommendations for pharmacogenomics- based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics

medical practice Oncology drugs A full day was dedicated to oncology covering germline as well as tumor pharmacogenomics. Three major examples were discussed. Response to tyrosine kinase inhibitors owing to activating EGFR mutations in non-small-cell lung cancer Miguel A Molina from Instituto Universitario USP Dexeus, Barcelona, presented the results of a national survey indicating the usefulness of tumor EGFR pharmacogenomics in order to define tumors that will respond (owing to activating mutations) to EGF receptor (EGFR) antagonists (tyrosine kinase inhibitors) [1]. Additional recent publications have confirmed the usefulness of EGFR pharmacogenomics in non-small-cell lung cancer (NSCLC) [2,3]. Tumor samples can be obtained from tumor biopsies, possibly followed by laser microdissection -or circulating blood tumor cells. Activating mutations are observed in 15% of The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6 -tamoxifen, TPMT-azathioprine -6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests. KEYWORDS: adverse drug reaction azathioprine cetuximab clopidogrel gefitinib genetic testing pharmacogenetics statins tacrolimus tamoxifen warfari

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example

Orally Active Multi-Functional Antioxidants Are Neuroprotective in a Rat Model of Light-Induced Retinal Damage

Progression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD.Proof of concept studies were conducted to evaluate the ability of 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8) to reduce retinal damage in 2-week dark adapted Wistar rats exposed to 1000 lx of light for 3 hours. Assessment of the oxidative stress markers 4- hydroxynonenal and nitrotyrosine modified proteins and Thioredoxin by ELISA and Western blots indicated that these compounds reduced the oxidative insult caused by light exposure. The beneficial antioxidant effects of these compounds in providing significant functional and structural protection were confirmed by electroretinography and quantitative histology of the retina.The present study suggests that multi-functional compounds may be effective candidates for preventive therapy of AMD