http://adaptivepharmacogenomics.com/ 2010-07-25T03:23:17Z Adaptive Pharmacogenomics, LLC esau.issaks@adaptivepharmacogenomics.com 2010-07-25T03:23:17Z PubMed:20419428

<p>Methods Mol Biol. 2010;637:23-45</p> <p>Authors: Yan Q</p> <p>Bioinformatics is the rational study at an abstract level that can influence the way we understand biomedical facts and the way we apply the biomedical knowledge. Bioinformatics is facing challenges in helping with finding the relationships between genetic structures and functions, analyzing genotype-phenotype associations, and understanding gene-environment interactions at the systems level. One of the most important issues in bioinformatics is data integration. The data integration methods introduced here can be used to organize and integrate both public and in-house data. With the volume of data and the high complexity, computational decision support is essential for integrative transporter studies in pharmacogenomics, nutrigenomics, epigenetics, and systems biology. For the development of such a decision support system, object-oriented (OO) models can be constructed using the Unified Modeling Language (UML). A methodology is developed to build biomedical models at different system levels and construct corresponding UML diagrams, including use case diagrams, class diagrams, and sequence diagrams. By OO modeling using UML, the problems of transporter pharmacogenomics and systems biology can be approached from different angles with a more complete view, which may greatly enhance the efforts in effective drug discovery and development. Bioinformatics resources of membrane transporters and general bioinformatics databases and tools that are frequently used in transporter studies are also collected here. An informatics decision support system based on the models presented here is available at http://www.pharmtao.com/transporter . The methodology developed here can also be used for other biomedical fields.</p> <p>PMID: 20419428 [PubMed - indexed for MEDLINE]</p>

2010-07-25T03:23:17Z PubMed:20502164

<p>Crit Care Med. 2010 Jun;38(6 Suppl):S106-16</p> <p>Authors: Empey PE</p> <p>Adverse drug reactions are a significant public health problem that leads to mortality, hospital admissions, an increased length of stay, increasing healthcare costs, and withdrawal of drugs from market. Intensive care unit patients are particularly vulnerable and are at an elevated risk. Critical care practitioners, regulatory agencies, and the pharmaceutical industry aggressively seek biomarkers to mitigate patient risk. The rapidly expanding field of pharmacogenomics focuses on the genetic contributions to the variability in drug response. Polymorphisms may explain why some groups of patients have the expected response to pharmacotherapy whereas others experience adverse drug reactions. Historically, genetic association studies have focused on characterizing the effects of variation in drug metabolizing enzymes on pharmacokinetics. Recent work has investigated drug transporters and the variants of genes encoding drug targets, both intended and unintended, that comprise pharmacodynamics. This has led to an appreciation of the role that genetics plays in adverse drug reactions that are either predictable extensions of a drug's known therapeutic effect or idiosyncratic.This review presents the evidence for a genetic predisposition to adverse drug reactions, focusing on gene variants producing alterations in drug pharmacokinetics and pharmacodynamics in intensive care unit patients. Genetic biomarkers with the strongest associations to adverse drug reaction risk in the intensive care unit are presented along with the medications involved. Variant genotypes and phenotypes, allelic frequencies in different populations, and clinical studies are discussed. The article also presents the current recommendations for pharmacogenetic testing in clinical practice and explores the drug, patient, research study design, regulatory, and practical issues that presently limit more widespread implementation.</p> <p>PMID: 20502164 [PubMed - indexed for MEDLINE]</p>

2010-07-25T03:23:14Z PubMed:20419427

<p>Methods Mol Biol. 2010;637:1-21</p> <p>Authors: Yan Q</p> <p>The study of membrane transporters may result in breakthroughs in the discovery of new drugs and the development of safer drugs. Membrane transporters are essential for fundamental cellular functions and normal physiological processes. These molecules influence drug absorption and distribution and play key roles in drug therapeutic effects. A primary goal of current research in drug discovery and development is to fully understand the interactions between transporters and drugs at both the system levels in the human body and the individual level for personalized therapy. Systematic studies of membrane transporters will help in not only better understanding of diseases from the systems biology point of view but also better drug design and development. The exploration of both pharmacogenomics and systems biology in transporters is necessary to connect individuals' genetic profiles with systematic drug responses in the human body. Understanding of gene-diet interactions and the effects of epigenetic changes on transporter gene expression may help improve clinical drug efficacy. The integration of pharmacogenomics, nutrigenomics, epigenetics, and systems biology may enable us to move from disease treatment to disease prevention and optimal health. The key issues in such integrative understanding include the correlations between structure and function, genotype and phenotype, and systematic interactions among transporters, other proteins, nutrients, drugs, and the environment. The exploration in these key issues may ultimately contribute to personalized medicine with high efficacy but less toxicity.</p> <p>PMID: 20419427 [PubMed - indexed for MEDLINE]</p>

2010-07-11T03:23:08Z PubMed:20153366

<p>Pharmacol Ther. 2010 May;126(2):146-58</p> <p>Authors: Xie HG</p> <p>The use of the immunosuppressants has revolutionized organ transplantation, including pediatric heart transplantation (PHTx). Recent evidence has shown that pharmacogenomics holds the promise to maximize the likelihood of drug safety and efficacy after the drug and dose are tailored individually based on the translation of pharmacogenomics to patient care. In this review, the immunosuppressants used for the PHTx are introduced, including their similarities and differences in immunosuppressive mechanisms of action, and their unique clinical efficacy and safety issues in relation to genetic polymorphisms in the genes that encode drug-metabolizing enzymes, drug transporters and drug targets. In addition, genetic susceptibility to severe drug-associated complications and strategies for their prevention and treatment are discussed. Moreover, clinically important drug-drug, drug-herb, or drug-food interactions and the effects of demographic and clinical covariates of recipients and donors on clinical endpoints of the PHTx are summarized, respectively. All relevant data are focused mainly on the PHTx. Information provided in this review would be useful for pediatric patient care, in particular for personalized medication, because each and every valuable piece could be fitted to the big picture of how organ rejection would be delayed and even avoided after personalized immunosuppressive therapy.</p> <p>PMID: 20153366 [PubMed - indexed for MEDLINE]</p>

2010-07-10T13:07:22Z http://www.rxpgnews.com/neurosciences/Study_finds_brain_imaging_and_biomarker_assessments_helpful_in_early_identification_of_Alzheimer_s_disease_411481.shtml

( from http://www.rxpgnews.com ) Abnormal brain images combined with examination of the composition of the fluid that surrounds the spine may offer the earliest signs identifying healthy older adults at risk of developing Alzheimer’s disease, well before cognitive problems emerge, a study by researchers at UC Davis has found.<br /><br /> “Our findings indicate that a distinctive pattern of imaging and biomarker deviations from typical adults may be an early warning sign of neurobiological pathology and an early sign of Alzheimer’s disease,” said Laurel Beckett, a professor of public health sciences at UC Davis and the lead study author. "By the time people get diagnosed with Alzheimer’s using cognitive tests, there’s already a lot of brain damage. We hope that in the future methods that combine brain imaging and biomarker assessments can push the diagnosis back, while learning more about the mechanisms causing Alzheimer’s disease, so we can develop better treatments.”<br /><br /> Published in the journal Neurobiology of Aging in June, the study analysis picked out a subgroup of healthy adults who later would experience a decline in memory performance typical of early Alzheimer’s disease long before other study participants.<br /><br /> For the study, Beckett and her team used data from the Alzheimer’s Disease Neuroimaging Initiative, which provides researchers with access to brain scans, clinical data and other laboratory results from spinal fluid and blood tests from more than 800 older adults. Some study participants began with a clean slate of cognitive health, some with mild cognitive impairment — a condition that often presages Alzheimer’s — and others with mild or moderate Alzheimer’s disease.<br /><br /> The researchers analyzed data from 220 normal older adults who had undergone structural magnetic resonance imaging (MRI) and clinical examinations. About half also provided spinal fluid samples. Among the 96 participants, cluster analysis identified three distinct subgroups of individuals based solely on their baseline imaging and laboratory measures. During the next three years, few of these healthy people showed any cognitive change. But cognitive tests for people in one of the subgroups — about 10 percent of the sample — declined at nearly five times the rate as healthy older adults. The researchers believe this group, which had the most extreme MRI and spinal fluid measurements, may represent the earliest stages of subclinical cognitive decline and Alzheimer’s disease.<br /><br /> Beckett said that the finding is an important step toward discovering the constellation of imaging and fluid biomarkers that foreshadow cognitive decline, as well as a means of determining whether new treatments are effective.<br /><br /> “The problem with current clinical trials is that we don’t know who is on the edge of experiencing dementia. And even if we did, how would we know if a treatment was working, since they haven’t shown any clinical problems?” Beckett said. “This method could improve clinical trials for prevention and reduce the numbers of study participants necessary to speed drug discovery — and eventually change how the pharmaceutical industry and National Institutes of Health conduct Alzheimer's disease clinical trials."

2010-07-10T03:23:18Z PubMed:20367534

<p>Expert Opin Drug Metab Toxicol. 2010 May;6(5):621-32</p> <p>Authors: Rodrigues AC</p> <p>IMPORTANCE OF THE FIELD: The important role of drug transporters in drug absorption and disposition has been well documented. Statins are subjected to active transport of membrane proteins of the superfamilies ATP-binding cassette and solute carrier, and there is limited understanding of the mechanisms by which differences in transporter expression and activity contributes to variability of pharmacokinetics (PKs)/pharmacodynamics (PDs) of statins. AREAS COVERED IN THIS REVIEW: This review aims to discuss the roles of drug transporters in the PKs and PDs of statins, and in drug interactions with statins. WHAT THE READER WILL GAIN: A comprehensive summary of the literature on this subject including in vitro and in vivo observations. TAKE HOME MESSAGE: In vivo and in vitro studies have shown that efflux and uptake transporters modulate the PKs/PDs of statins. Until now organic anion transporting polypeptides (OATP)1B1 variants have been considered major factors in limiting the uptake of statins and increasing statin exposure, and, consequently, increasing risk of myopathy. Further studies in pharmacogenetics and in vitro models to assess statin disposition and toxicity are required to understand the contribution of others transporters, such as multidrug resistance-associated protein (MRP)1, MRP2, breast cancer resistance protein, OATP2B1, OAT1B3 and OATP1A2, in interindividual variability to statins efficacy and safety.</p> <p>PMID: 20367534 [PubMed - indexed for MEDLINE]</p>

2010-07-10T03:23:17Z PubMed:18850266

<p>Heart Fail Rev. 2010 May;15(3):219-28</p> <p>Authors: Lanfear DE</p> <p>Heart failure (HF) is a modern epidemic and is one of the few cardiovascular diseases which is increasing in prevalence. The growing importance of the Natriuretic Peptide (NP) system in HF is well recognized. Laboratory tests for B-type Natriuretic Peptide (BNP) have proven value as diagnostic and prognostic tools in HF and are now part of routine clinical care. Furthermore, recombinant atrial natriuretic peptide (ANP) (carperitide) and BNP (nesiritide) and are approved HF therapies in Japan and the US, respectively and additional natriuretic peptides (e.g., CNP, urodilatin, and designer NPs) are under investigation for use in HF. Common genetic sequence variants are increasingly being recognized as determinants of disease risk or drug response and may help explain a portion of the inter-individual variation in the human NP system. This review describes current knowledge of NP system genetic variation as it pertains to HF as well as ongoing studies and where the field is expected to progress in the near future. To briefly summarize, NP system genetic variants have been associated with alterations in gene expression, NP levels, and cardiovascular disease. The next step forward will include specific investigations into how this genetic variation can advance 'Personalized Medicine', such as whether they impact the utility of diagnostic BNP testing or effectiveness of therapeutic NP infusion. This is already in progress, with pharmacogenetic studies of nesiritide currently underway. We expect that within 5 years there should be a reasonable idea of whether NP system genetic variation will have important clinical implications.</p> <p>PMID: 18850266 [PubMed - indexed for MEDLINE]</p>

2010-07-10T03:23:16Z PubMed:18437562

<p>Heart Fail Rev. 2010 May;15(3):187-96</p> <p>Authors: Shin J, Johnson JA</p> <p>Beta-blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a beta-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a beta-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for beta-blockers in patients with HF and discusses the potential implications of beta-blocker pharmacogenetics for HF patients.</p> <p>PMID: 18437562 [PubMed - indexed for MEDLINE]</p>

2010-07-10T03:23:16Z PubMed:18351457

<p>Heart Fail Rev. 2010 May;15(3):209-17</p> <p>Authors: Beitelshees AL, Zineh I</p> <p>Blockade of the renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors has been a cornerstone of heart failure therapy for over 15 years. More recently, further blockade of RAAS with aldosterone antagonists and angiotensin receptor blockers (ARBs) has been studied. While these therapies have certainly improved outcomes in the treatment of heart failure, morbidity and mortality remain extremely high. Furthermore, polypharmacy and complex regimens of seven medications on average is the norm for management of heart failure. This results in increased costs, patient burden, and uncertainty as to the best course of therapy. The ability to personalize patients' therapeutic regimens using pharmacogenomics has the potential of providing more effective and efficient use of RAAS-modulating medications. This review highlights the implications of major RAAS pharmacogenetic studies, while outlining future directions for translation to practice.</p> <p>PMID: 18351457 [PubMed - indexed for MEDLINE]</p>

2010-07-09T03:23:04Z PubMed:20607838

<p><b>Pharmacogenetics of drug-induced liver injury.</b></p> <p>Hepatology. 2010 Apr 19;</p> <p>Authors: Russmann S, Jetter A, Kullak-Ublick GA</p> <p>Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI. (HEPATOLOGY 2010).</p> <p>PMID: 20607838 [PubMed - as supplied by publisher]</p>