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Pharmacogenomics drugs metabolism

Andrew Kl Goey, Tristan M Sissung, Cody J Peer, William D Figg
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment...
October 21, 2016: Pharmacogenomics
Aharon Nachshon, Hanifa J Abu-Toamih Atamni, Yael Steuerman, Roa'a Sheikh-Hamed, Alexandra Dorman, Richard Mott, Juliane C Dohm, Hans Lehrach, Marc Sultan, Ron Shamir, Sascha Sauer, Heinz Himmelbauer, Fuad A Iraqi, Irit Gat-Viks
A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypically diverse, their genetic diversity in drug disposition processes, such as detoxification reactions, is still largely uncharacterized. Here we systematically measured RNA-sequencing expression profiles from livers of 29 CC lines under baseline conditions...
2016: Frontiers in Genetics
Julian A Michely, Sascha K Manier, Achim T Caspar, Simon D Brandt, Jason Wallach, Hans H Maurer
3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeO-PCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS)...
October 18, 2016: Current Neuropharmacology
Claudia Maria Hattinger, Elisa Tavanti, Marilù Fanelli, Serena Vella, Piero Picci, Massimo Serra
Antifolates are structural analogs of folates, which have been used as antitumor drugs for more than 60 years. The antifolate drug most commonly used for treating human tumors is methotrexate (MTX), which is utilized widely in first-line treatment protocols of high-grade osteosarcoma (HGOS). In addition to MTX, two other antifolates, trimetrexate and pemetrexed, have been tested in clinical settings for second-line treatment of recurrent HGOS with patients unfortunately showing modest activity. Areas covered: There is clinical evidence which suggsest that, like other chemotherapeutic agents, not all HGOS patients are equally responsive to antifolates and do not have the same susceptibility to experience adverse drug-related toxicities...
October 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
Joseph P Kitzmiller, Eduard B Mikulik, Anees M Dauki, Chandrama Murkherjee, Jasmine A Luzum
Statins are a cornerstone of the pharmacologic treatment and prevention of atherosclerotic cardiovascular disease. Atherosclerotic disease is a predominant cause of mortality and morbidity worldwide. Statins are among the most commonly prescribed classes of medications, and their prescribing indications and target patient populations have been significantly expanded in the official guidelines recently published by the American and European expert panels. Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy...
2016: Pharmacogenomics and Personalized Medicine
Meghan MacKenzie, Richard Hall
PURPOSE: Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. SOURCE: We selected relevant literature to illustrate the important concepts contained within. PRINCIPAL FINDINGS: Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach...
October 17, 2016: Canadian Journal of Anaesthesia, Journal Canadien D'anesthésie
Shabbir Ahmed, Zhan Zhou, Jie Zhou, Shu-Qing Chen
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual's particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters...
October 8, 2016: Genomics, Proteomics & Bioinformatics
Puneet Narang, Amy Johnson, Manasa Enja, Steven Lippmann
Many psychiatric patients experience pharmaceutical intolerances, and some of them do not derive optimal efficacy from their pharmacotherapies. Clinical problems such as these may result in prolonged dysfunction, adverse consequences, and repeated changes in medication treatment regimens. Pharmacogenomics is a laboratory method that aids individualized medication selection by predicting drug efficacy and adverse effect profiles. It is a technique that involves the testing of patients' genetic makeup to improve medicinal response and tolerance...
October 2016: Southern Medical Journal
Adriana Isvoran, Maxime Louet, Diana Larisa Vladoiu, Dana Craciun, Marie-Anne Loriot, Bruno O Villoutreix, Maria A Miteva
Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism...
September 28, 2016: Drug Discovery Today
Jeremy R Everett
Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalized medicine, that is the selection of medicines for subgroups of patients so as to maximize drug efficacy and minimize toxicity, is a key goal of twenty-first century healthcare. Currently, most personalized medicine paradigms rely on clinical judgment based on the patient's history, and on the analysis of the patients' genome to predict drug effects i.e., pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind...
2016: Frontiers in Pharmacology
T T Gao, Q Long
Stevens-Johnson syndrome(SJS)and toxic epidermal necrolysis(TEN)are life-threatening cutaneous adverse drug reactions that induce widespread epidermal necrosis. Ocular and cutaneous diseases are common chronic sequelae of SJS and TEN. Several concepts have been proposed to explain the pathogenesis of severe cutaneous adverse drug reactions. Recent advances in genetic, pharmacogenomics and immunologic studies have provided evidences of genetic predispositions, drug metabolism and cytokines related to SJS and TEN...
September 11, 2016: [Zhonghua Yan Ke za Zhi] Chinese Journal of Ophthalmology
Sundaramoorthy Revathidevi, Ravi Sudesh, Varadharajan Vaishnavi, Muthukrishnan Kaliyanasundaram, Kilyara George MaryHelen, Ganesan Sukanya, Arasambattu Kannan Munirajan
BACKGROUND: Breast cancer, the commonest cancer among women in the world, ranks top in India with an incidence rate of 1,45,000 new cases and mortality rate of 70,000 women every year. Chemotherapy outcome for breast cancer is hampered due to poor response and irreversible dose-dependent cardiotoxicity which is determined by genetic variations in drug metabolizing enzymes and transporters. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, induces expression of drug metabolizing enzymes (DMEs) and transporters leading to regulation of xenobiotic metabolism...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
Richard D Beger, Warwick Dunn, Michael A Schmidt, Steven S Gross, Jennifer A Kirwan, Marta Cascante, Lorraine Brennan, David S Wishart, Matej Oresic, Thomas Hankemeier, David I Broadhurst, Andrew N Lane, Karsten Suhre, Gabi Kastenmüller, Susan J Sumner, Ines Thiele, Oliver Fiehn, Rima Kaddurah-Daouk
INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status...
2016: Metabolomics: Official Journal of the Metabolomic Society
Andrea Calcagno, Jessica Cusato, Antonio D'Avolio, Stefano Bonora
BACKGROUND: Antiretroviral treatment is highly effective in enhancing HIV-positive patients' survival and quality of life. Despite an increased tolerability in recent years, a substantial amount of patients experience side effects. Antiretrovirals' efficacy and tolerability have been associated with plasma concentrations and single nucleotide polymorphisms in selected genes involved in drug disposition. OBJECTIVE: Our aim was to review the current knowledge in genetic polymorphisms affecting plasma, intracellular or compartmental concentrations of antiretrovirals...
September 19, 2016: Clinical Pharmacokinetics
Clint Mizzi, Eleni Dalabira, Judit Kumuthini, Nduna Dzimiri, Istvan Balogh, Nazli Başak, Ruwen Böhm, Joseph Borg, Paola Borgiani, Nada Bozina, Henrike Bruckmueller, Beata Burzynska, Angel Carracedo, Ingolf Cascorbi, Constantinos Deltas, Vita Dolzan, Anthony Fenech, Godfrey Grech, Vytautas Kasiulevicius, Ľudevít Kádaši, Vaidutis Kučinskas, Elza Khusnutdinova, Yiannis L Loukas, Milan Macek, Halyna Makukh, Ron Mathijssen, Konstantinos Mitropoulos, Christina Mitropoulou, Giuseppe Novelli, Ioanna Papantoni, Sonja Pavlovic, Giuseppe Saglio, Jadranka Setric, Maja Stojiljkovic, Andrew P Stubbs, Alessio Squassina, Maria Torres, Marek Turnovec, Ron H van Schaik, Konstantinos Voskarides, Salma M Wakil, Anneke Werk, Maria Del Zompo, Branka Zukic, Theodora Katsila, Ming Ta Michael Lee, Alison Motsinger-Rief, Howard L Mc Leod, Peter J van der Spek, George P Patrinos
Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes...
2016: PloS One
Kleanthi Lakiotaki, Evgenia Kartsaki, Alexandros Kanterakis, Theodora Katsila, George P Patrinos, George Potamias
One of the challenges that arise from the advent of personal genomics services is to efficiently couple individual data with state of the art Pharmacogenomics (PGx) knowledge. Existing services are limited to either providing static views of PGx variants or applying a simplistic match between individual genotypes and existing PGx variants. Moreover, there is a considerable amount of haplotype variation associated with drug metabolism that is currently insufficiently addressed. Here, we present a web-based electronic Pharmacogenomics Assistant (ePGA; http://www...
2016: PloS One
D L Hertz, K M Kidwell, N J Seewald, C L Gersch, Z Desta, D A Flockhart, A-M Storniolo, V Stearns, T C Skaar, D F Hayes, N L Henry, J M Rae
Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates...
August 23, 2016: Pharmacogenomics Journal
Drew Neavin, Rima Kaddurah-Daouk, Richard Weinshilboum
INTRODUCTION: The initial decades of the 21(st) century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject...
July 2016: Metabolomics: Official Journal of the Metabolomic Society
Zhaohui Liang, Jimmy Xiangji Huang, Xing Zeng, Gang Zhang
BACKGROUND: Genomic variations are associated with the metabolism and the occurrence of adverse reactions of many therapeutic agents. The polymorphisms on over 2000 locations of cytochrome P450 enzymes (CYP) due to many factors such as ethnicity, mutations, and inheritance attribute to the diversity of response and side effects of various drugs. The associations of the single nucleotide polymorphisms (SNPs), the internal pharmacokinetic patterns and the vulnerability of specific adverse reactions become one of the research interests of pharmacogenomics...
2016: BMC Medical Genomics
K T Hall, J Kossowsky, T F Oberlander, T J Kaptchuk, J P Saul, V B Wyller, E Fagermoen, D Sulheim, J Gjerstad, A Winger, K J Mukamal
Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104)...
October 2016: Pharmacogenomics Journal
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