Initial Pain Management in Pediatric Acute Pancreatitis: Opioid vs. Non-Opioid.

J Pediatr Gastroenterol Nutr. 2017 Oct 27;:

Authors: Grover AS, Mitchell PD, Manzi SF, Fox VL

Abstract
Nearly all patients with acute pancreatitis (AP) experience some degree of abdominal pain that is severe enough to prompt medical evaluation and necessitate analgesia. Effective analgesia is a priority in caring for such patients. Despite its importance, strategies for pain management in AP have been poorly studied, particularly in the field of pediatrics. Currently, no published data examine the management of pain due to acute pancreatitis in children at the time of initial presentation. Management approaches are often extrapolated from adult practice and based on anecdotal experience in the absence of objective data. The aim of our study was to examine the initial provision of analgesia to children who presented to a pediatric emergency department (ED) with acute pancreatitis.

PMID: 29077648 [PubMed - as supplied by publisher]

Pharmacogenomics of the Natriuretic Peptide System in Heart Failure.

Curr Heart Fail Rep. 2017 Oct 27;:

Authors: Abuzaanona A, Lanfear D

Abstract
PURPOSE OF REVIEW: Heart failure (HF) continues to be a public health burden despite advances in therapy, and the natriuretic peptide (NP) system is clearly of critical importance in this setting, spawning valuable diagnostic and prognostic testing, such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), as well as current and future therapeutics, including recombinant natriuretic peptides (e.g., carperitide, nesiritide) and recently sacubitril, which inhibits the key clearance mechanism for NPs. This article intends to summarize the existing evidence for the role of NP system genetic variation on cardiovascular phenotypes relevant to HF with particular focus on the potential impact on pharmacologic therapies.
RECENT FINDINGS: Several genes in NP system have been interrogated, in many cases genetic variation impacting protein quantity and function or related disease states. Recent data supports genetic variants potentially impacting pharmacokinetics or dynamics of medications targeting the pathway. Growing evidence indicates the importance of genetic variation to the functioning of the NP system and its pharmacologic manipulation.

PMID: 29075957 [PubMed - as supplied by publisher]

Pharmacogenomics DNA Biomarkers in Colorectal Cancer: Current Update.

Front Pharmacol. 2017;8:736

Authors: Ab Mutalib NS, Md Yusof NF, Abdul SN, Jamal R

Abstract
Colorectal cancer (CRC) remains as one of the most common cause of worldwide cancer morbidity and mortality. Improvements in surgical modalities and adjuvant chemotherapy have increased the cure rates in early stage disease, but a significant portion of the patients will develop recurrence or advanced disease. The efficacy of chemotherapy of recurrence and advanced CRC has improved significantly over the last decade. Previously, the historical drug 5-fluorouracil was used as single chemotherapeutic agent. Now with the addition of other drugs such as capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, vemurafenib, and dabrafenib, the median survival of patients with advanced CRC has significantly improved from less than a year to the current standard of almost 2 years. However, the side effects of systemic therapy such as toxicity may cause fatal complications and have a major consequences on the patients' quality of life. Hence, there is an urgent need for key biomarkers which will enable the selection of optimal drug singly or in combination for an individual patient. The application of personalized therapy based on DNA testing could aid the clinicians in providing the most effective chemotherapy agents and dose modifications for each patient. Yet, some of the current findings are controversial and the evidences are conflicting. This review aims at summarizing the current state of knowledge about germline pharmacogenomics DNA variants that are currently used to guide therapeutic decisions and variants that have the potential to be clinically useful in the future. In addition, current updates on germline variants conferring treatment sensitivity, drug resistance to existing chemotherapy agents and variants affecting prognosis and survival will also be emphasized. Different alteration in the same gene might confer resistance or enhanced sensitivity; and while most of other published reviews generally stated only the gene name and codon location, we will specifically discuss the exact variants to offer more accurate information in this mini review.

PMID: 29075194 [PubMed]

Schisandrol B protects against cholestatic liver injury through pregnane X receptors.

Br J Pharmacol. 2017 Apr;174(8):672-688

Authors: Zeng H, Jiang Y, Chen P, Fan X, Li D, Liu A, Ma X, Xie W, Liu P, Gonzalez FJ, Huang M, Bi H

Abstract
BACKGROUND AND PURPOSE: Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera.
EXPERIMENTAL APPROACH: Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB.
KEY RESULTS: SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent.
CONCLUSION AND IMPLICATIONS: These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.

PMID: 28128437 [PubMed - indexed for MEDLINE]

Association of PEAR1 rs12041331 polymorphism and pharmacodynamics of ticagrelor in healthy Chinese volunteers.

Xenobiotica. 2017 Dec;47(12):1130-1138

Authors: Li M, Hu Y, Wen Z, Li H, Hu X, Zhang Y, Zhang Z, Xiao J, Tang J, Chen X

Abstract
1. Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects. 2. The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180 mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed. 3. No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331 G allele carriers, AA homozygotes exhibited increased IPA after 15 μM ticagrelor incubation (p < 0.01), increased area under the time-effect curve of IPA and lower PRI at 2 h after ticagrelor administration (p < 0.05, respectively). Rs4661012 GG homozygotes showed increased IPA after 50 μM ticagrelor incubation as compared to T allele carriers (p < 0.01). 4. PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects.

PMID: 27937053 [PubMed - indexed for MEDLINE]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/10/27

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17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/10/25

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17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/10/25

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Identification of the genomic region under epigenetic regulation during nonalcoholic fatty liver disease progression.

Hepatol Res. 2017 Oct 23;:

Authors: Hotta K, Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Kessoku T, Yoneda M, Imajo K, Tomeno W, Saito S, Nakajima A

Abstract
AIM: The progression of nonalcoholic fatty liver disease (NAFLD) is affected by epigenetics. We performed co-methylation and differentially methylated region (DMR) analyses to identify the genomic region that is under epigenetic regulation during NAFLD progression.
METHODS: We collected liver biopsy specimens from 60 Japanese patients with NAFLD and classified these into mild (fibrosis stages 0-2) or advanced (fibrosis stages 3-4) NAFLD. We performed genome-wide DNA methylation analysis and identified the differentially methylated CpGs between mild and advanced NAFLD. DMRs having multiple consecutive differentially methylated CpGs between mild and advanced NAFLD were extracted.
RESULTS: Co-methylation analysis showed that individual differentially methylated CpG sites were clustered into three modules. The CpG sites clustered in one module were hypomethylated in advanced NAFLD and their annotated genes were enriched for "immune system" function. The CpG sites in another module were hypermethylated and their annotated genes were enriched for "mitochondria" or "lipid particle", and "lipid metabolism" or "oxidoreductase activity". Hypomethylated DMRs included tumorigenesis-related genes (FGFR2, PTGFRN, and ZBTB38), the expressions of which are upregulated in advanced NAFLD. Tumor suppressor MGMT had two DMRs and was downregulated. Conversely, FBLIM1 and CYR61, encoding proteins that reduce cell proliferation, exhibited hypomethylated DMRs and were upregulated. Expression of the antioxidant gene, NQO1, was upregulated, with a hypomethylated DMR. The DMR containing cancer-related MIR21 was hypomethylated in advanced NAFLD.
CONCLUSIONS: Co-methylation and DMR analyses suggest that the NAFLD liver undergoes mitochondrial dysfunction, decreased lipid metabolism, and impaired oxidoreductase activity, and acquires tumorigenic potential at the epigenetic level.

PMID: 29059699 [PubMed - as supplied by publisher]

Integrative cancer pharmacogenomics to establish drug mechanism of action: drug repurposing.

Pharmacogenomics. 2017 Oct 23;:

Authors: El-Hachem N, Ba-Alawi W, Smith I, Mer AS, Haibe-Kains B

PMID: 29057710 [PubMed - as supplied by publisher]

Medications for substance use disorders (SUD): Emerging approaches.

Expert Opin Emerg Drugs. 2017 Oct 21;:

Authors: Butelman ER, Kreek MJ

Abstract
INTRODUCTION: Substance use disorders are a group of chronic relapsing disorders of the brain, which have massive public health and societal impact. In some disorders (e.g., heroin/prescription opioid addictions) approved medications have a major long-term benefit. For other substances (e.g., cocaine, amphetamines and cannabis) there are no approved medications, and for alcohol there are approved treatments, which are not in wide usage. Approved treatments for tobacco use disorders are available, and novel medications are also under study. Areas covered: Medication-based approaches which are in advanced preclinical stages, or which have reached proof-of concept clinical laboratory studies, as well as clinical trials. Expert opinion: Current challenges involve optimizing translation between preclinical and clinical development, and between clinical laboratory studies to therapeutic clinical trials. Comorbidities including depression or anxiety are challenges for study design and analysis. Improved pharmacogenomics, biomarker and phenotyping approaches are areas of interest. Pharmacological mechanisms currently under investigation include modulation of glutamatergic, GABA, vasopressin and κ-receptor function, as well as inhibition of monoamine re-uptake. Other factors that affect potential market size for emerging medications include stigma, availability of treatment settings, adoption by clinicians, and the prevalence of persons with SUD who are not actively treatment-seeking.

PMID: 29057665 [PubMed - as supplied by publisher]

Cannabinoids concentration variability in cannabis olive oil galenic preparations.

J Pharm Pharmacol. 2017 Oct 23;:

Authors: Carcieri C, Tomasello C, Simiele M, De Nicolò A, Avataneo V, Canzoneri L, Cusato J, Di Perri G, D'Avolio A

Abstract
OBJECTIVES: Knowledge of the exact concentration of active compounds in galenic preparations is crucial to be able to ensure their quality and to properly administer the prescribed dose. Currently, the need for titration of extracts is still debated. Considering this, together with the absence of a standard preparation method, the aim of this study was to evaluate cannabinoids concentrations variability in galenic olive oil extracts, to evaluate the interlot and interlaboratory variability in the extraction yield and in the preparation composition.
METHODS: Two hundred and one extracts (123 (61.2%) from Bedrocan(®) , 54 (26.9%) from Bediol(®) , 11 (5.5%) from Bedrolite(®) , and 13 (6.5%) from mixed preparations) were analysed by liquid chromatography coupled with tandem mass spectrometry, quantifying cannabinoids (THC, CBD, THCA, CBDA and CBN) concentrations.
KEY FINDINGS: The RSD% of THC and CBD concentrations resulted higher than 50%. Specifically for Bedrocan(®) , Bediol(®) , Bedrolite(®) (5 g/50 ml), these were THC 82%, THC 53% and CBD 91%, THC 58% and CBD 59%, respectively. The median extraction yields were greater than 75% for all preparations.
CONCLUSIONS: Our results highlighted a wide variability in THC and CBD concentrations that justify the need for titration and opens further questions about other pharmaceutical preparations without regulatory indication for this procedure.

PMID: 29057480 [PubMed - as supplied by publisher]

Pharmacogenetics in Cardiovascular Medicine.

Curr Genet Med Rep. 2016 Sep;4(3):119-129

Authors: Tuteja S, Limdi N

Abstract
PURPOSE OF REVIEW: Pharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation- clopidogrel, warfarin and simvastatin.
RECENT FINDINGS: There is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing including the timing of testing, incorporation of test results into the electronic health record, reimbursement and ethical issues.
SUMMARY: Pharmacogenetics of clopidogrel, warfarin and simvastatin are three examples where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care.

PMID: 29057167 [PubMed]

Multiplexed quantification of proteins and transcripts in single cells.

Nat Biotechnol. 2017 Oct;35(10):936-939

Authors: Peterson VM, Zhang KX, Kumar N, Wong J, Li L, Wilson DC, Moore R, McClanahan TK, Sadekova S, Klappenbach JA

Abstract
We present a tool to measure gene and protein expression levels in single cells with DNA-labeled antibodies and droplet microfluidics. Using the RNA expression and protein sequencing assay (REAP-seq), we quantified proteins with 82 barcoded antibodies and >20,000 genes in a single workflow. We used REAP-seq to assess the costimulatory effects of a CD27 agonist on human CD8(+) lymphocytes and to identify and characterize an unknown cell type.

PMID: 28854175 [PubMed - indexed for MEDLINE]

CYP2B6 and OPRM1 Receptor Polymorphisms at Methadone Clinics And Novel OPRM1 Haplotypes: A Cross-Sectional Study.

Drug Metab Lett. 2016;10(3):213-218

Authors: AlMeman AA, Ismail R, Perola M

Abstract
INTRODUCTION: Methadone is accepted as an alternative therapy in opioid use disorders worldwide. Methadone responsiveness, however, is affected by a range of CYP450 enzymes and OPRM1 polymorphisms.
OBJECTIVE: This study sought to detect CYP2B6 and OPRM1 variants and their genotypes, as major contributors to inter-variability in methadone responsiveness and methadone dose requirements.
METHODS: We carried out a prospective experimental one-phase pharmacogenetic study in four addiction clinics in Malaysia. Patients on stable methadone maintenance therapy were recruited. The prevalence of the CYP2B6 and OPRM1 polymorphisms was determined using a nested polymerase chain reaction (PCR), followed by genotyping. A two-step multiplex PCR method was developed to simultaneously detect the 26 SNPs in these two genes.
RESULTS: 120 males were recruited for this study. The patients were between 21and 59 years old, although the majority of the patients were in their 30s. C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1 were found to be polymorphic, and the allelic frequencies of each were calculated. We further detected eight new haplotypes.
CONCLUSION: C64T and G15631T in CYP2B6and G31A, G691C, and A118G in OPRM1were found to be polymorphic. The new haplotypes may give a new insight on methadone clinics.

PMID: 27515451 [PubMed - indexed for MEDLINE]

Common genetic risk factors for coronary artery disease: new opportunities for prevention?

Clin Physiol Funct Imaging. 2017 May;37(3):243-254

Authors: Hamrefors V

Abstract
Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and morbidity worldwide, with coronary artery disease (CAD) being the single leading cause of death. Better control of risk factors, enhanced diagnostic techniques and improved medical therapies have all substantially decreased the mortality of CAD in developed countries. However, CAD and other forms of atherosclerotic CVD are projected to remain the leading cause of death by 2030 and we face a number of challenges if the outcomes of CAD are to be further improved. The fact that a substantial fraction of high-risk subjects do not reach treatment goals for important risk factors is one of these challenges. At the same time, there is also a non-negotiable fraction of 'concealed' high-risk subjects who are not detected by current risk algorithms and diagnostic modalities. In recent years, we have started to rapidly increase our knowledge of the framework of common genetics underlying CAD and atherosclerotic CVD in the population. In conjunction with modern diagnostic and therapeutic options, this new genetic knowledge may provide a valuable tool for further improvements in prevention. This review summarizes the recent findings from the search for common genetic risk factors for CAD. Furthermore, the author discusses how such recent findings could potentially be used in a number of clinical applications within CAD prevention, including in clinical risk stratification, in prediction of drug treatment response and in the search for targets for novel preventive therapies.

PMID: 26278888 [PubMed - indexed for MEDLINE]

Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants.

Pharmacol Ther. 2017 Oct 18;:

Authors: Mao XY, Jin MZ, Chen JF, Zhou HH, Jin WL

Abstract
Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric disorders and cancers, in addition to inherited factors. Currently, natural products or nutraceuticals (commonly called medical foods) are increasingly employed for adjunctive therapy of these patients. However, the potential molecular mechanisms of the nutrient efficacy remain elusive. In this review, we summarized the neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly through the differential modulations of redox homeostasis. In addition, the balance between reactive oxygen species (ROS) production and ROS elimination was manipulated by multiple molecular mechanisms, including cell signaling pathways, inflammation, transcriptional regulation and epigenetic modulation, which were involved in the therapeutic potential of nutraceutical antioxidants against neurological diseases and cancers. We specifically proposed that ROS scavenging was integral in the neuroprotective potential of nutraceuticals, while alternation of ROS level (either increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted the anti-cancer property of these compounds. We also hypothesized that ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death, was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting ferroptosis is advantageous to develop new nutraceuticals with more effective and lower adverse reactions for curing patients with neuropsychiatric diseases or carcinomas.

PMID: 29055715 [PubMed - as supplied by publisher]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/10/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/10/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Transcriptomic-Guided Drug Repositioning Supported by a New Bioinformatics Search Tool: geneXpharma.

OMICS. 2017 Oct;21(10):584-591

Authors: Turanli B, Gulfidan G, Arga KY

Abstract
Drug repositioning is an innovative approach to identify new therapeutic indications for existing drugs. Drug repositioning offers the promise of reducing drug development timeframes and costs, and because it involves drugs that are already in the clinic, it might remedy some of the drug safety challenges traditionally associated with drug candidates that are not yet available in the clinic. The gene-by-drug interactions are an important dimension of optimal drug repositioning and development strategies. While gene-by-drug interactions have been curated and presented in various databases, novel bioinformatics tools and approaches are timely, and required with a specific focus to support drug positioning. We report, in this study, the design of a public web-accessible transcriptomic-/gene expression-guided pharmaceuticals search tool, geneXpharma ( www.genexpharma.org ). GeneXpharma is a public platform with user-centric interface that provides statistically evaluated gene expressions and their drug interactions for 48 diseases under seven different disease categories. GeneXpharma is designed and organized to generate hypotheses on druggable genome within the disease-gene-drug triad and thus, help repositioning of drugs against diseases. The search system accommodates various entry points using drugs, genes, or diseases, which then enable researchers to extract drug repurposing candidates and readily export for further evaluation. Future developments aim to improve the geneXpharma algorithm, enrich its content, and enhance the website interface through addition of network visualizations and graphical display items. Bioinformatics search tools can help enable the convergence of drug repositioning and gene-by-drug interactions so as to further optimize drug development efforts in the future.

PMID: 29049014 [PubMed - in process]