Pharmacogenomics and global precision medicine in the context of adverse drug reactions : top 10 opportunities and challenges for the next decade

In a move indicative of the enthusiastic support of precision medicine, the U.S. President Barack Obama announced the Precision Medicine Initiative in January 2015. The global precision medicine ecosystem is, thus, receiving generous support from the United States ($215 million), and numerous other governments have followed suit. In the context of precision medicine, drug treatment and prediction of its outcomes have been important for nearly six decades in the field of pharmacogenomics. The field offers an elegant solution for minimizing the effects and occurrence of adverse drug reactions (ADRs). The Clinical Pharmacogenetics Implementation Consortium (CPIC) plays an important role in this context, and it aims at specifically guiding the translation of clinically relevant and evidence-based pharmacogenomics research. In this forward-looking analysis, we make particular reference to several of the CPIC guidelines and their role in guiding the treatment of highly relevant diseases, namely cardiovascular disease, major depressive disorder, cancer, and human immunodeficiency virus, with a view to predicting and managing ADRs. In addition, we provide a list of the top 10 crosscutting opportunities and challenges facing the fields of precision medicine and pharmacogenomics, which have broad applicability independent of the drug class involved. Many of these opportunities and challenges pertain to infrastructure, study design, policy, and science culture in the early 21st century. Ultimately, rational pharmacogenomics study design and the acquisition of comprehensive phenotypic data that proportionately match the genomics data should be an imperative as we move forward toward global precision medicine.http://www.liebertpub.com/overview/omics-a-journal-of-integrative-biology/43hb2016Immunolog

Spin-Orbit Splitting in Non-Relativistic and Relativistic Self-Consistent Models

The splitting of single-particle energies between spin-orbit partners in nuclei is examined in the framework of different self-consistent approachs, non-relativistic as well as relativistic. Analytical expressions of spin-orbit potentials are given for various cases. Proton spin-orbit splittings are calculated along some isotopic chains (O, Ca, Sn) and they are compared with existing data. It is found that the isotopic dependence of the relativistic mean field predictions is similar to that of some Skyrme forces while the relativistic Hartree-Fock approach leads to a very different dependence due to the strong non-locality.Comment: 12 pages, RevTeX, 4 new figs.in .zip format, unchanged conclusions, Phys. ReV.

Cardiovascular pharmacogenetics

Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (e.g. drug metabolizing enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimizing drug toxicity and optimizing drug efficacy in cardiovascular medicine.http://www.elsevier.com/locate/pharmther

Research Paper for Australian Human Rights Commission (National Children's Commissioner): Effective support and early intervention approaches to offending behaviour by children and innovative international responses to serious offending by children and young people

This literature review outlines the arguments for raising the age of criminal responsibility for children in Australia from 10 years to at least 14 years of age. It advocates for systems reform so that young offenders are diverted away from the criminal justice system. Ecological Systems Theory postulates that a child’s development involves a complex interrelated systems of social relations. Using this as a base, this review highlights how key structural drivers such as health, mental disability, family and societal factors underlie some offending behaviours

Risperidone-associated adverse drug reactions and CYP2D6 polymorphisms in a South African cohort

BACKGROUND : Contradictory information exists regarding the influence of CYP2D6 polymorphisms on adverse drug reactions (ADRs) (extrapyramidal symptoms (EPS) and weight gain) related to risperidone treatment. This prompted us to evaluate the influence of CYP2D6 genetic variation in a cohort of South African patients who presented with marked movement disorders and/or weight gain while on risperidone treatment. METHODS : Patients who were experiencing marked risperidone ADRs were recruited from Weskoppies Public Psychiatric Hospital. As poor or intermediate metabolism was expected, comprehensive CYP2D6 sequence variations were evaluated using XL-PCR + Sequencing. RESULTS : No statistically significant association was found between CYP2D6 poor metabolism and risperidone ADRs. An inverse relationship between EPS and weight gain was however identified. A novel CYP2D6 allele was identified which is unlikely to affect metabolism based on in silico evaluation. CONCLUSION : CYP2D6 variation appeared not to be a good pharmacogenetic marker for predicting risperidonerelated ADRs in this naturalistic South African cohort. Evaluation of a larger cohort would be needed to confirm these observations, including an examination of the role of potential intermediaries between the hypothesised genetic and clinical phenotypes.Departments of Pharmacology and Immunology, and the Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, the National Research Foundation of South Africa (grant numbers: TK2006051500005,FA2006032700005, FA2007050200007), the National Health Laboratory Services Research Trust (grant number: 94088), the South African Medical Research Council (Inflammation and Immunity Research Unit) and the Ampath Trusthttp://www.elsevier.com/locate/atghb201

Microscopics of meson degrees of freedom in nucleons and mesons in nuclei - what can be seen in the process of quasielastic knockout of mesons by high-energy electrons

Developed earlier concept of quasielastic knock out of pions from nucleons by high-energy electrons is propounded as a tool for checking microscopical model ($^3P_0$ - fluctuation) for decay of N to different channels $\pi+B$ and Preparata model of nucleus structure.Comment: 6 pages, 5 figures, Talk given at 16 Baldin Symposium in June 200

Impact of CYP2D6 genotype on amitriptyline efficacy for the treatment of diabetic peripheral neuropathy : a pilot study

AIM : Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. METHOD : To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. RESULTS : Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. CONCLUSION : Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.The South African Medical Research Council, the National Research Foundation of South Africa, the National Health Laboratory Services and the Institute for Cellular and Molecular Medicine, University of Pretoria. http://www.futuremedicine.com/loi/pgshj2018Consumer ScienceImmunologyInternal MedicinePharmacolog

Discovery of the Isotopes with 11 <= Z <= 19

A total of 194 isotopes with 11 $\le$ Z $\le$ 19 have been identified to date. The discovery of these isotopes which includes the observation of unbound nuclei, is discussed. For each isotope a brief summary of the first refereed publication, including the production and identification method, is presented.Comment: to be pubslihed in At. Data Nucl. Data Table

Evaluation of predictive CYP2C19 genotyping assays relative to measured phenotype in a South African cohort

AIM : To align predicted and measured CYP2C19 phenotype in a South African cohort. MATERIALS AND METHODS : Genotyping of CYP2C19*2, *3, *9, *15, *17, *27 and *28 was performed using PCR-RFLP, and an Activity Score (AS) system was used to predict phenotype.True phenotype was measured using plasma concentrations of omeprazole and its metabolite 5’-hydroxyomperazole. RESULTS : Partial genotype-phenotype discrepancies were reported, and an adapted AS system was developed, which showed a marked improvement in phenotype prediction. Results highlight the need for a more comprehensive CYP2C19 genotyping approach to improve prediction of omeprazole metabolism. CONCLUSION : Evidence for the utility of a CYP2C19 AS system is provided, for which the accuracy can be further improved by means of comprehensive genotyping and substrate specific modification.Departments of Pharmacology and Immunology, University of Pretoria; the National Research Foundation of South Africa (NRF) grant numbers FA2006032700005 and TK2006051500005; the National Health Laboratory Services of South Africa (NHLS); the South African Medical Research Council (SAMRC) Extramural Unit for Inflammation and Immunity, and Ampath Laboratories, South Africa.http://www.futuremedicine.com/loi/pgs2016-08-31hb201

Pharmacogenetics of CYP2D6 and CYP2C19 as a pre-prescription tool for drug efficacy and toxicity in a demographically-representative sample of theSouth African population

The Cytochrome P450 family of enzymes is responsible for the majority of Phase I metabolism, and has been identified as an important source of pharmacokinetic variation in therapeutic responses. CYP2C19 and CYP2D6, metabolising >35% of commonly prescribed medications, are two of the most important pharmacogenetic markers that have been studied with the aim of improving treatment response and reducing adverse drug reactions. The Food and Drug Administration (FDA) approved AmpliChip CYP450 Test (AmpliChip) was compared to a previously developed PCR-RFLP platform and a newly developed XLPCR+ Sequencing platform for the ability to identifying genotype and predicting phenotype for CYP2C19 and CYP2D6 respectively. The AmpliChip was found not to be genotypically comprehensive enough for evaluating CYP2C19 genotype, not robust enough for determining CYP2D6 genotype and inaccurate in predicting phenotype for both. The XLPCR+ Sequencing method identified three novel alleles and one sub-variant. Advances in online column-switching solid phase extraction generated a rapid and robust LCMS/ MS method for simultaneously quantifying the probe drugs omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate) and their metabolites. Antimodes were identified for phenotypic cut-offs which offered measured phenotype for comparison to predicted phenotype. Omeprazole metabolism by CYP2C19 correlated well with predicted phenotype in a demographically representative South African cohort. There are concerns regarding the use of omeprazole as a probe drug as participants predicted to be ultrarapid metabolisers for CYP2C19 had similar rates to extensive metabolisers. Regardless of this concern, decreased metabolism was assigned to the CYP2C19*15 for the first time. CYP2D6 predicted phenotype correlated very well with measured phenotype, validating the suitability of dextromethorphan use for measuring CYP2D6 metabolism. Substrate modified activity score using 0.5 to predict intermediate metabolisers fine-tuned the XLPCR+ Sequencing platform for phenotype prediction. This finding, along with observations in CYP2C19 metabolism of omeprazole, highlights the importance of substrate specific phenotype prediction strategies. Controversially, attempts to associate CYP2D6 phenotype prediction with risperidone-related adverse drug reactions has yielded conflicting results. The XL-PCR+Sequencing platform was able to discount this association by predicting a variety of metabolisers in a pilot cohort selected to be experiencing risperidone-related adverse drug reactions. The comprehensive capability of the XL-PCR+Sequencing allowed for the identification of an additional novel allele in this cohort. The data presented in thisthesis has provided insight into the relationship between predicted and measured phenotype for CYP2C19 and CYP2D6 in the South African population. The XL-PCR+Sequencing platform can be used for future research or can be applied to improve treatment outcome. The LC-MS/MS method developed could be used for future evaluations of predicted and measured phenotype with the ability to be adjusted for therapeutic drug monitoring. This thesis advances pharmacogenetics of CYP2C19 and CYP2D6 for use in the South African population.Thesis (PhD)--University of Pretoria, 2013.gm2014Pharmacologyunrestricte