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Advances in Pharmacology

Kim Brøsen, Per Damkier
No abstract text is available yet for this article.
2018: Advances in Pharmacology
Mikkel H Vendelbo, Lars C Gormsen, Niels Jessen
An increasing collection of imaging technologies makes it possible to differentiate treatment responders from nonresponders based on genetic variation. This chapter will review some of the imaging technologies currently available in nuclear medicine to visualize drug absorption, distribution, metabolism, and elimination. Some of the commonly used techniques to detect radiation-emitting compounds are the two-dimensional scintigraphy and the three-dimensional single-photon emission computed tomography (SPECT) which both detect photons using a gamma camera, and the three-dimensional positron emission tomography (PET), which detect the decay of positron-emitting radionuclides...
2018: Advances in Pharmacology
Deirdre P Cronin-Fenton, Per Damkier
Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy...
2018: Advances in Pharmacology
Shylaja Srinivasan, Sook Wah Yee, Kathleen M Giacomini
Pharmacogenetic studies of antidiabetic drugs have so far focused largely on response to metformin, which is the first-line therapy for treatment of type 2 diabetes (T2D). The first studies of metformin pharmacogenetics were focused on candidate genes that were implicated in metformin pharmacokinetics and transport. Since 2011, genome-wide association studies have been conducted in large cohorts of individuals with T2D identifying genes that are associated with glycemic response to metformin. There have been fewer pharmacogenetic studies of other antidiabetic drugs, and those have been largely limited to candidate gene studies with small sample sizes...
2018: Advances in Pharmacology
Peter E Weeke
Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit-risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient...
2018: Advances in Pharmacology
Ulrich M Zanger, Kathrin Klein, Nicole Kugler, Tamara Petrikat, Chang S Ryu
Germline pharmacogenetics has so far mainly studied common variants in "pharmacogenes," i.e., genes encoding drug metabolizing enzymes and transporters (DMET genes), certain auxiliary and regulatory genes, and drug target genes. Despite remarkable progress in understanding genetically determined differences in pharmacokinetics and pharmacodynamics of drugs, currently known common variants even in important pharmacogenes explain genetic variability only partially. This suggests "missing heritability" that may in part be due to rare variants in the classical pharmacogenes, but current evidence suggests that largely unexplored resources with potential for pharmacogenetics exist, both within already known pharmacogenes and in entirely new areas...
2018: Advances in Pharmacology
Aleksi Tornio, Janne T Backman
Interindividual variability in drug disposition is a major cause of lack of efficacy and adverse effects of drug therapies. The majority of hepatically cleared drugs are metabolized by cytochrome P450 (CYP) enzymes, mainly in families CYP1, CYP2, and CYP3. Genes encoding these enzymes are highly variable with allele distribution showing considerable differences between populations. Genetic variability of especially CYP2C9, CYP2C19, CYP2D6, and CYP3A5 is known to have clear clinical impact on drugs that are metabolized by these enzymes...
2018: Advances in Pharmacology
Filippo Corponi, Chiara Fabbri, Alessandro Serretti
Mental illness represents a major health issue both at the individual and at the socioeconomical level. This is partly due to the current suboptimal treatment options: existing psychotropic medications, including antidepressants, antipsychotics, and mood stabilizers, are effective only in a subset of patients or produce partial response and they are often associated with debilitating side effects that discourage adherence. Pharmacogenetics is the study of how genetic information impacts on drug response/side effects with the goal to provide tailored treatments, thereby maximizing efficacy and tolerability...
2018: Advances in Pharmacology
Ingolf Cascorbi
Immunosuppressive drugs are a prerequisite in organ transplantation to prevent rejection and are also widely used in inflammatory diseases such as inflammatory bowel disease (IBD) or also in some hematologic malignancies-depending on the mode of action. For thiopurine analogs the polymorphic thiopurine S-methyltransferase (TPMT) was early detected to be associated with thiopurine-induced leukopenia; recent studies identified also NUDT15 to be related to this severe side effect. For drugs like methotrexate and mycophenolate mofetil a number of ADME genes like UDP-glucuronosyltransferases (UGTs) and ABC efflux transporters were investigated, however, with partly contradicting results...
2018: Advances in Pharmacology
Ana M Peiró
Pain is an unpleasant feeling usually resulting from tissue damage that can persist along weeks, months, or even years after the injury, turning into pathological chronic pain, the leading cause of disability. Currently, pharmacology interventions are usually the first-line therapy but there is a highly variable analgesic drug response. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual analgesic response opening doors to precision medicine. PGx analyze the way in which the presence of variations in the DNA sequence (single-nucleotide polymorphisms, SNPs) could be responsible for portions of the population reaching different levels of pain relief (phenotype) due to gene interference in the drug mechanism of action (pharmacodynamics) and/or its concentration at the place of action (pharmacokinetics)...
2018: Advances in Pharmacology
Paul C D Bank, Jesse J Swen, Henk-Jan Guchelaar
Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations...
2018: Advances in Pharmacology
Tiphaine Adam de Beaumais, Evelyne Jacqz-Aigrain
Individual genomic differences may affect drug disposition and effects of many drugs, and identification of biomarkers are crucial to personalize dosage and optimize response. In children, developmental changes associated with growth and maturation translate into different relationships between genotype and phenotype and different responses to treatment compared to adults. This review aims to summarize some developmental aspects of pharmacogenetics, based on practical examples.
2018: Advances in Pharmacology
Orod Osanlou, Munir Pirmohamed, Ann K Daly
Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Genetic factors predispose to many ADRs, affecting susceptibility to both type A and type B reactions. The overall contribution of genetics will vary according to drug and ADR, and should be considered when attempting to predict and prevent ADRs. Genetic risk factors are considered in detail for a number of type A ADRs, especially those relating to warfarin and thiopurines, and type B ADRs affecting skin, the liver, and the heart...
2018: Advances in Pharmacology
Guilherme Suarez-Kurtz, Esteban J Parra
Pharmacogenetics/pharmacogenomics (PGx) relies on human genetic diversity. In this review we initially examine the PGx implications of human demographic history and genetic diversity, and highlight results from recent studies on the worldwide distribution of common and rare variants in pharmacogenes. The abundance of rare variants implies that a substantial effort will be required to identify their putative functional effects and to develop reliable algorithms for PGx-guided prescription. Furthermore, variants in all pharmacogenes relevant to a drug treatment must be considered...
2018: Advances in Pharmacology
Thomas P Ahern
Epidemiologic methods provide rigorous means by which to study the interplay between genetic factors and drug response. In this chapter, we describe the differences between experimental and observational study designs, and illustrate how to implement the highly efficient case-control study design. We discuss analytic approaches to evaluating gene-drug interactions within typical study designs and review sources of bias that must be assessed and accounted for in epidemiologic analyses.
2018: Advances in Pharmacology
Les Iversen
No abstract text is available yet for this article.
2018: Advances in Pharmacology
(no author information available yet)
No abstract text is available yet for this article.
2018: Advances in Pharmacology
Lloyd D Fricker
Peptides and small molecules that bind to peptide receptors are important classes of drugs that are used for a wide variety of different applications. The search for novel neuropeptides traditionally involved a time-consuming approach to purify each peptide to homogeneity and determine its amino acid sequence. The discovery in the 1980s of enkephalin convertase/carboxypeptidase E (CPE), and the observation that this enzyme was involved in the production of nearly every known neuropeptide led to the idea for a one-step affinity purification of CPE substrates...
2018: Advances in Pharmacology
Ted M Dawson, Valina L Dawson
In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative diseases...
2018: Advances in Pharmacology
Joseph T Coyle, Darrick T Balu
The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments...
2018: Advances in Pharmacology
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