The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes ...the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on ...pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy based on pharmacogenetic test results. The current guideline describes the gene-drug interaction between CYP2D6 and venlafaxine, mirtazapine and duloxetine. In addition, the interaction between CYP2C19 and mirtazapine and moclobemide is presented. The DPWG identified a gene-drug interaction that requires therapy adjustment for CYP2D6 and venlafaxine. However, as the side effects do not appear to be related to plasma concentrations, it is not possible to offer a substantiated advice for dose reduction. Therefore, the DPWG recommends avoiding venlafaxine for CYP2D6 poor and intermediate metabolisers. Instead, an alternative antidepressant, which is not, or to a lesser extent, metabolized by CYP2D6 is recommended. When it is not possible to avoid venlafaxine and side effects occur, it is recommended to reduce the dose and monitor the effect and side effects or plasma concentrations. No action is required for ultra-rapid metabolisers as kinetic effects are minimal and no clinical effect has been demonstrated. In addition, a gene-drug interaction was identified for CYP2D6 and mirtazapine and CYP2C19 and moclobemide, but no therapy adjustment is required as no effect regarding effectiveness or side effects has been demonstrated for these gene-drug interactions. Finally, no gene-drug interaction and need for therapy adjustment between CYP2C19 and mirtazapine and CYP2D6 and duloxetine were identified. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for venlafaxine, indicating that genotyping prior to treatment can be considered on an individual patient basis.
Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the ...Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being "potentially beneficial" for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.
High sodium intake increases cardiovascular risk by increasing blood pressure. The intake of coffee elevates blood pressure acutely. Preclinical evidence shows that this action of caffeine is ...enhanced by high salt intake. We hypothesised that high sodium intake augments the acute blood pressure response to coffee in humans. A randomised cross-over study (n = 15) was performed comparing the effect of lower (6 g/d; LS) with higher (12 g/d; HS) sodium chloride diet on blood pressure before and 2 h after regular coffee intake. Baseline blood pressure was 115 ± 4/84 ± 2/68 ± 1 during LS and 121 ± 4/89 ± 2/69 ± 1 mmHg during HS (SBP/Mean Arterial Pressure (MAP)/DBP; mean ± SE, p < 0.05 for SBP). During LS, blood pressure increased to 121 ± 4/91 ± 2/73 ± 1 (p < 0.05 for SBP, MAP, DBP versus baseline). HS did not significantly affect the impact of coffee on blood pressure (p > 0.3 for SBP, DBP; p > 0.05 for MAP). Sodium intake does not relevantly modulate the impact of regular coffee consumption on blood pressure.
Using an emittance technique with a fast CO2 laser heating of glass samples, the high‐temperature absorption spectra in the near‐infrared region of ultrapure and colored (Co‐, Cu‐, Mn‐, and Ni‐doped) ...glasses are measured. The effects of higher glass temperatures on these absorption spectra are explained in the framework of the ligand field theory. Thus, the temperature‐dependent absorption bands of the previous transition metal ions are assigned to electronic transitions among the ligand field energy levels of these ions. In particular, spectral shifts, spectral broadening, and changes in absorption strength are ascribed to changes in the structural symmetry of the ionic sites in the glass matrix and to changes of the ligand field strength at increasing temperatures.
Besides, the temperature‐dependent Rosseland mean absorptions of the sulfate fined soda lime silicate glass melts, colored with the previous transition metal ions, are derived from the absorption spectra. Combining all the data, semiempirical correlations are derived, which predict the Rosseland thermal radiation properties as a function of glass temperature and of glass redox chemistry. The latter property involves the temperature‐dependent concentration of the specific valency of the coloring ions, determined independently, e.g. by a Gibbs minimization redox calculation tool.
Two innovative experimental techniques for measuring the high temperature near infrared optical spectra of glass melts are compared. The critical experimental features of both techniques, one based ...on transmission and the other based on emittance measurements, are reviewed. Typical results of both techniques, including high temperature spectra and values for the Rosseland mean absorption coefficient and thermal radiation conductivity versus temperature for similar glass melts, are compared. The study is focused on sulfate fined soda lime silicate glass melts colored with iron oxide and chromium oxide and on the effect of the glass redox state on the thermal radiation conductivity. It is shown that essentially different measuring principles provide consistent results for similar glass melt types, that is, colors. Using the high temperature spectra of a large variety of (colored) glasses, a new semi‐empirical model is developed for predicting the Rosseland radiation conductivity of arbitrary sulfate fined soda lime silicate glass melts, colored with iron oxide and chromium oxide. By separating the effects of (a) the temperature‐dependent redox state, (b) the high temperature changes in ligand field strengths and (c) the glass matrix, the model reliably predicts the Rosseland radiation conductivity, with a chemical analysis of the glass as input only.
Enterovirus infections have been implicated in the development of type I diabetes mellitus. They may cause β cell destruction either by cytolytic infection in the pancreas or indirectly by ...contributing to autoimmune reactivity. We sought evidence for these 2 mechanisms in a case of acute-onset diabetes mellitus that occurred during severe echovirus 9 infection. The virus was isolated and administered to cultured human β cells. No viral proliferation was observed, and no β cell death was induced, while parallel exposure to Coxsackie B virus serotype 3 resulted in viral proliferation and massive β cell death. Although the viral protein 2C exhibited a sequence similar to that of the β cell autoantigen glutamic acid decarboxylase (GAD65), no cross-reactive T cell responses were detected. The patient did not develop antibodies to GAD65 either. Absence of evidence for direct cytolytic action or an indirect effect through molecular mimicry with GAD65 in the present case raises the possibility of another indirect pathway through which enteroviruses can cause diabetes mellitus.
Primary central nervous system lymphomas (PCNSL) are derived from germinal center B cells. Recent molecular studies indicate that the tumor cells or their precursors have experienced antigenic ...stimulation. Attractive candidates for such antigens are pathogens with the capacity to reside in the brain. The aim of the present study was to evaluate whether human herpes virus (HHV)-8 is involved in the pathogenesis of PCNSL. A series of 46 PCNSL, 31 from HIV-negative and 15 from HIV-positive patients, were analyzed using various molecular biological and immunological approaches. Nested PCR with two different protocols unequivocally demonstrated that PCNSL from HIV-negative patients did not harbor HHV-8 DNA. Among AIDS-associated PCNSL, HHV-8 DNA was found in only 1 tumor. In situ hybridization studies revealed that the lymphoma cells were HHV-8 negative in all cases. Single small mononuclear cells, most likely corresponding to bystander lymphocytes, were identified as the cellular source of HHV-8 in the HIV-positive patient with an HHV-8 PCR signal. These studies largely rule out a role for HHV-8 in the pathogenesis of PCNSL in both HIV-negative as well as HIV-positive patients.
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