NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine.

Prog Nucl Magn Reson Spectrosc. 2017 Nov;102-103:1-14

Authors: Everett JR

Abstract
Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systems-based approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in pre-dose metabolite profiles between groups of subjects are used to predict post-dose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21st century healthcare.

PMID: 29157489 [PubMed - in process]

Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease progression: implications for personalised treatment.

Oncotarget. 2017 Oct 17;8(49):86056-86065

Authors: Del Re M, Bordi P, Petrini I, Rofi E, Mazzoni F, Belluomini L, Vasile E, Restante G, Di Costanzo F, Falcone A, Frassoldati A, van Schaik RHN, Steendam CMJ, Chella A, Tiseo M, Morganti R, Danesi R

Abstract
Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking.
Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib. Cell-free circulating tumor DNA (cftDNA) was extracted from plasma and the quantitative analysis of EGFR ex19del, p.L858R and p.T790M was performed by digital droplet PCR.
Results: The mean amount of mutated alleles at progression to first-line EGFR-TKIs was 108,492 copies/ml for ex19del, 97,336 copies/ml for p.L858R, but only 8,754 copies/ml for p.T790M. There was no significant correlation between progression-free survival and the ratio of p.T790M over EGFR activating mutations. The analysis of cftDNA in 5 patients treated with osimertinib revealed a marked decrease of all EGFR mutant alleles.
Conclusions: The amount of p.T790M in plasma can be much lower than activating EGFR mutations. Despite this finding, osimertinib is effective in p.T790M-positive patients. These results indicate that clones driving resistance to EGFR-TKIs represent a minority among cells bearing activating EGFR-mutations. In addition, the identification of a threshold level of p.T790M is not a strict requirement for the selection of patients to be treated with osimertinib, since treatment showed a decrease in all EGFR mutated cells.

PMID: 29156777 [PubMed]

Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2 and CYP3A4-selective Inhibitors.

Basic Clin Pharmacol Toxicol. 2017 Nov 20;:

Authors: Murray M, Zhang WV, Edwards RJ

Abstract
The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to conventional antipsychotic drugs. Cytochromes P450 (CYPs) 1A2 and 3A4 oxidise CLZ to norCLZ and CLZ N-oxide in human liver. Concurrent treatment with inducers and inhibitors of CYP1A2 modulates CLZ elimination that disrupts therapy. Drug-drug interactions involving CYP3A4 are also significant but less predictable. To further characterise the factors underlying these interactions, we used samples from a cohort of human livers to assess variation in CLZ oxidation pathways in relation to intrinsic CYP3A4 and CYP1A2 activities and the effects of the corresponding selective inhibitors ketoconazole (0.2 and 2 μM) and fluvoxamine (1 and 10 μM). The CYP3A4-selective inhibitor ketoconazole (2 μM) impaired CLZ N-oxide formation in all 14 of the livers used in inhibition studies (≥50% inhibition) while the CYP1A2-selective inhibitor fluvoxamine (10 μM) decreased norCLZ formation in nine. Ketoconazole effectively inhibited CLZ metabolism in 5 of 7 livers that catalysed CYP3A4-dependent testosterone 6β-hydroxylation at or above the median rate and in four other livers with lower intrinsic CYP3A4 activity. Similarly, fluvoxamine (10 μM) readily inhibited CLZ oxidation in seven livers with high CYP1A2-mediated 7-ethoxyresorufin O-deethylation activity (at or above the median) and three livers with lower intrinsic CYP1A2 activity. In three livers CLZ biotransformation was impaired by both ketoconazole and fluvoxamine, consistent with a major role for both CYPs. These findings suggest that the intrinsic activities of CYPs 1A2 and 3A4 are unrelated to the response to CYP-selective inhibitors and that assessment of the activities in vivo may not assist the prediction of drug-drug interactions. This article is protected by copyright. All rights reserved.

PMID: 29155491 [PubMed - as supplied by publisher]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update.

Clin Pharmacol Ther. 2017 Nov 20;:

Authors: Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M

Abstract
The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC(®) ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).

PMID: 29152729 [PubMed - as supplied by publisher]

The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia.

Oncotarget. 2017 Oct 20;8(50):88021-88033

Authors: Galimberti S, Bucelli C, Arrigoni E, Baratè C, Grassi S, Ricci F, Guerrini F, Ciabatti E, Fava C, D'Avolio A, Fontanelli G, Cambrin GR, Isidori A, Loscocco F, Caocci G, Greco M, Bocchia M, Aprile L, Gozzini A, Scappini B, Cattaneo D, Scortechini AR, La Nasa G, Bosi A, Leoni P, Danesi R, Saglio G, Visani G, Cortelezzi A, Petrini M, Iurlo A, Di Paolo A

Abstract
First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.

PMID: 29152138 [PubMed]

Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.

Acta Neuropathol. 2017 Nov 17;:

Authors: Bogeas A, Morvan-Dubois G, El-Habr EA, Lejeune FX, Defrance M, Narayanan A, Kuranda K, Burel-Vandenbos F, Sayd S, Delaunay V, Dubois LG, Parrinello H, Rialle S, Fabrega S, Idbaih A, Haiech J, Bièche I, Virolle T, Goodhardt M, Chneiweiss H, Junier MP

Abstract
Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients' glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients' tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.

PMID: 29149419 [PubMed - as supplied by publisher]

Philosophical Issues and Psychological Variables that Influence the Determination of Opioid Effectiveness: A Narrative Review.

Pain Physician. 2017 Nov;20(7):E1091-E1105

Authors: Doleys DM

Abstract
BACKGROUND: The prescribing of opioids in the chronic pain setting is often based on the pharmacodynamics, pharmacokinetics, and pharmacogenetics of the drug obtained during development and clinical trials. However, the effectiveness of opioids varies widely and often appears to bear no relationship to the aforementioned variables. The impact of philosophical issues and psychological factors on determining how clinically effective opioid therapy is has often been over looked.
OBJECTIVES: This manuscript provides a selective review and narrative summary of the philosophical issues and psychological factors which can influence opioid effectiveness.
STUDY DESIGN: A selective review and narrative analysis of the literature.
METHODS: Experimental and clinical-based studies examining the impact of psychological factors on the effectiveness of opioids were extracted from the literature. Studies in which psychological factors were used as an independent variable were given preference.
RESULTS: The philosophical issues reviewed include: (a) one's understanding of the nature of chronic pain, (b) the meaning of the score on the pain numerical rating scale (NRS), and (c) the selection of outcome measures. The psychological factors found to influence the effectiveness of opioids include: (a) role conditioning and learning, especially as they relate to conditioned analgesia, non-associative tolerance, and the nocebo effect, (b) dosing pattern, (c) patient specific factors, e.g., mood, overall psychological and neurocognitive status, (d) social variables, e.g., personal environment and the media, and (e) the dysfunctional endogenous opioid system and its relationship to various psychological disorders.
LIMITATIONS: This is a selective review of the literature. Some of the hypotheses presented have not been experimentally validated. The review includes animal, human, experimental, and clinical studies.
CONCLUSIONS: In general, the effectiveness of opioids may be influenced as much by the overall context in which they are used, including the physician-patient relationship as well as their pharmacological properties. Data obtained from short-term and well-controlled trials may not generalize to the clinical setting, which is often more complex and dynamic. Appreciating the impact of psychological factors may assist the clinician in proper patient selection, monitoring, and improved outcomes.
KEY WORDS: Psychological factors, philosophical issues, chronic pain, opioid therapy, effectiveness, conditioning, placebo, cognitive dysfunction.

PMID: 29149154 [PubMed - in process]

Pharmacogenomics: Principles and Relevance to Oncology Nursing
.

Clin J Oncol Nurs. 2017 Dec 01;21(6):739-745

Authors: Dodson CH

Abstract
BACKGROUND: Pharmacogenomics is the fastest growing field in precision medicine. Based on current use, oncology encompasses the largest share of the precision medicine market, necessitating that oncology nurses understand the principles of pharmacogenomics and how it affects clinical practice.
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OBJECTIVES: This article will define precision medicine and pharmacogenomics and will provide examples of pharmacogenomic tests, including those associated with tumor markers, and nursing implications.
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METHODS: Educational and clinical resources are supplied for oncology nurses to expand their pharmacogenomics expertise.
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FINDINGS: The knowledge surrounding precision medicine and pharmacogenomics will position oncology nurses to engage in current research, improve practice, and educate patients. As the focus of health care remains on reducing costs and improving morbidity and mortality, the reduction in adverse drug reactions will continue to be highlighted. Tailoring medications based on individual responses will not only help improve patient outcomes but also potentially affect the cost of health care as these genetic tests become a standard of care.

PMID: 29149126 [PubMed - in process]

Role of Transforming Growth Factor β in Uterine Fibroid Biology.

Int J Mol Sci. 2017 Nov 17;18(11):

Authors: Ciebiera M, Włodarczyk M, Wrzosek M, Męczekalski B, Nowicka G, Łukaszuk K, Ciebiera M, Słabuszewska-Jóźwiak A, Jakiel G

Abstract
Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor β (TGF-βs) is a polypeptide that consists of three isoforms: TGF-β1, TGF-β2, and TGF-β3. At present, TGF-β is considered to be one of the key factors in the pathophysiology of UFs. It plays a major role in cellular migration within the tumor, stimulates tumor growth, and enhances tumor metabolism. As a consequence of various dependencies, the synthesis and release of TGF-β in a UF tumor is increased, which results in excessive extracellular matrix production and storage. High concentrations or overexpression of TGF-β mediators may be responsible for clinically symptomatic UFs. The aim of this review was to check the available evidence for the influence of the TGF-β family on UF biology. We conducted their search in PubMed of the National Library of Medicine with the use of the following selected keywords: "uterine fibroid", "leiomyoma", and "transforming growth factor β". After reviewing the titles and abstracts, more than 115 full articles were evaluated. We focused on the TGF-β-related molecular aspects and their influence on the most common symptoms that are associated with UFs. Also, we described how the available data might implicate the current medical management of UFs.

PMID: 29149020 [PubMed - in process]

Biological evaluation and energetic analyses of novel GSK-3β inhibitors.

J Cell Biochem. 2017 Nov 16;:

Authors: Zhang D, Liu L, Pang L, Jin Q, Ke K, Hu M, Yang J, Ma W, Xie H, Chen X

Abstract
Glycogen synthase kinase-3 beta (GSK-3β) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3β activity have been implicated in diabetes, heart disease, Parkinson disease and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3β were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Twenty selected compounds were tested, which led to the discovery of two hits. Compound 14 (IC5 0 = 8.48 μM) and compound 19 (IC50 = 2.19 μM) were identified with high affinity. Molecular dynamics (MD) simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the binding modes and energetics of GSK-3β inhibitors. The detailed analysis of molecular dynamics results shows that Ile62, Val70, Tyr134 and Leu188 in GSK-3β are key residues responsible to the binding of compound 14 and compound 19. Importantly, our results also validated this combined virtual screening and biophysical technique approach to discovery kinase inhibitors, which may be applied for future inhibitor discovery work for GSK-3β. This article is protected by copyright. All rights reserved.

PMID: 29144001 [PubMed - as supplied by publisher]

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484.

Open Biol. 2017 Nov;7(11):

Authors: Bradshaw NJ, Ukkola-Vuoti L, Pankakoski M, Zheutlin AB, Ortega-Alonso A, Torniainen-Holm M, Sinha V, Therman S, Paunio T, Suvisaari J, Lönnqvist J, Cannon TD, Haukka J, Hennah W

Abstract
Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the 'DISC1 network'. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10(-8)), located on a non-coding exon of NDE1 Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

PMID: 29142105 [PubMed - in process]

A safety review of medications used for labour induction.

Expert Opin Drug Saf. 2017 Nov 15;:1-7

Authors: Sheibani L, Wing DA

Abstract
INTRODUCTION: Induction of labour is a commonly performed procedure around the world. There are various medications used for induction including those commonly used for cervical ripening (prostaglandins) and oxytocin. The ideal agent is one that decreases the time to achieving delivery without compromising maternal or neonatal safety. The 'optimal safe agent' remains undetermined. Areas covered: This article reviews the safety of currently used induction agents. Prostaglandins and oxytocin have proven to be effective in labour induction, and their profiles will be reviewed in this article. We discuss the data that supports combining some of the agents. We also cover the safety of medications used for labour induction in setting of a scarred uterus. Expert Opinion: There is continuous debate about the ideal induction agent: one that balances safety with efficacy. We recommend the practice that there is not one perfect agent for all, and that the clinical scenario and previous obstetric history should be considered before choosing an agent. In the future, pharmacogenomics may show that genetics may affect the individual response and adverse reactions to the various agents.

PMID: 29141462 [PubMed - as supplied by publisher]

Matrix Metalloproteinases Polymorphisms as Prognostic Biomarkers in Malignant Pleural Mesothelioma.

Dis Markers. 2017;2017:8069529

Authors: Štrbac D, Goričar K, Dolžan V, Kovač V

Abstract
Background: Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could also serve as a prognostic biomarker in MPM.
Methods: We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9; and rs1042703, rs1042704, and rs743257 in MMP14. We determined the influence on survival using Cox regression.
Results: Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45-4.14, p = 0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37-4.18, p = 0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38-0.86 p = 0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37-0.85, p = 0.007). MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06-4.12, p = 0.032).
Conclusions: Selected MMP SNPs were associated with survival and could be used as potential genetic biomarkers in MPM.

PMID: 29138529 [PubMed - in process]

Excessive fuel availability amplifies the FTO-mediated obesity risk: results from the TUEF and Whitehall II studies.

Sci Rep. 2017 Nov 14;7(1):15486

Authors: Wagner R, Tabák ÁG, Fehlert E, Fritsche L, Jaghutriz BA, Bánhegyi RJ, Schmid SM, Staiger H, Machicao F, Peter A, Häring HU, Fritsche A, Heni M

Abstract
Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 × 10(-7), respectively). The effect size of one risk allele was 1.4 ± 0.3 vs. 2.2 ± 0.44 kg/m² in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 ± 0.3 to 1.7 ± 0.4 kg/m(2). In the Whitehall II study, body weight increased by 2.96 ± 6.5 kg during a follow-up of 13.5 ± 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes.

PMID: 29138452 [PubMed - in process]

Clopidogrel carboxylic acid glucuronidation is mediated mainly by UGT2B7, UGT2B4 and UGT2B17: Implications for pharmacogenetics and drug-drug interactions.

Drug Metab Dispos. 2017 Nov 14;:

Authors: Kahma H, Filppula AM, Neuvonen M, Tarkiainen EK, Tornio A, Holmberg MT, Itkonen MK, Finel M, Neuvonen PJ, Niemi M, Backman JT

Abstract
The antiplatelet drug clopidogrel is metabolized to an acyl-β-D-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl-β-D-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLM and HIM, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers. UGT2B7 and UGT2B17 exhibited the highest clopidogrel carboxylic acid glucuronidation activities, with a CLint,u of 2.42 and 2.82 µL∙min(-1)·mg(-1), respectively. Of other enzymes displaying activity (UGT1A3, UGT1A9, UGT1A10-H and UGT2B4), UGT2B4 (CLint,u 0.51 µL∙min(-1)·mg(-1)) was estimated to contribute significantly to the hepatic clearance. Nonselective UGT2B inhibitors strongly inhibited clopidogrel acyl-β-D-glucuronide formation in HLM and HIM. The UGT2B17 inhibitor imatinib and the UGT2B7 and UGT1A9 inhibitor mefenamic acid inhibited clopidogrel carboxylic acid glucuronidation in HIM and HLM, respectively. Incubation of clopidogrel carboxylic acid in HLM with UDPGA and NADPH resulted in strong inhibition of CYP2C8 activity. In healthy volunteers, UGT2B17*2 deletion allele was associated with a 10% decrease per copy in the plasma clopidogrel acyl-β-D-glucuronide to clopidogrel carboxylic acid AUC0-4 ratio (P<0.05). To conclude, clopidogrel carboxylic acid is mainly metabolized by UGT2B7 and UGT2B4 in the liver, and by UGT2B17 in the small intestinal wall. The formation of clopidogrel acyl-β-D-glucuronide is impaired in carriers of the UGT2B17 deletion. The findings may have implications regarding intracellular mechanisms leading to CYP2C8 inactivation by clopidogrel.

PMID: 29138287 [PubMed - as supplied by publisher]

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Cancer Cell. 2017 Nov 13;32(5):654-668.e5

Authors: Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, Hashimoto A, Vonteddu P, Behera R, Goins MA, Mulligan C, Nam B, Hockstein N, Denstman F, Shakamuri S, Speicher DW, Weeraratna AT, Chao T, Vonderheide RH, Languino LR, Ordentlich P, Liu Q, Xu X, Lo A, Puré E, Zhang C, Loboda A, Sepulveda MA, Snyder LA, Gabrilovich DI

Abstract
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

PMID: 29136508 [PubMed - in process]

Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers.

Basic Clin Pharmacol Toxicol. 2017 Nov 14;:

Authors: Saiz-Rodríguez M, Belmonte C, Román M, Ochoa D, Koller D, Talegón M, Ovejero-Benito MC, López-Rodríguez R, Cabaleiro T, Abad-Santos F

Abstract
Sertraline is a selective serotonin reuptake inhibitor (SSRI) widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of the present study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP binding cassette subfamily B member 1 (ABCB1), Solute carrier family 6 member 4 (SLC6A4), 5-Hydroxytryptamine receptor 2A (HTR2A) and 5-Hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Subjects carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and subjects with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T subjects. This article is protected by copyright. All rights reserved.

PMID: 29136336 [PubMed - as supplied by publisher]

A critical appraisal of pharmacogenetic inference.

Clin Genet. 2017 Nov 14;:

Authors: Smit RAJ, Noordam R, le Cessie S, Trompet S, Jukema JW

Abstract
In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up with this goal in mind. It is therefore of great importance that researchers clearly communicate which assumptions they have had to make, and which inherent limitations apply to the interpretation of their results. This review discusses considerations of, and the underlying assumptions for, utilizing different response phenotypes and study designs popular in pharmacogenetic research to infer gene-treatment interaction effects, with a special focus on those dealing with of clinical effects of drug treatment.

PMID: 29136278 [PubMed - as supplied by publisher]

The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database.

Clin Pharmacol Ther. 2017 Nov 14;:

Authors: Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE, PharmVar Steering Committee

Abstract
The Human Cytochrome P450 (CYP) Allele Nomenclature Database, a critical resource for the pharmacogenetics and genomics communities, has transitioned to the Pharmacogene Variation (PharmVar) Consortium. In this report we provide a summary of the current database, provide an overview of the PharmVar consortium, and highlight the PharmVar database which will serve as the new home for pharmacogene nomenclature.

PMID: 29134625 [PubMed - as supplied by publisher]

Psychotropic Drug Prescription in Adolescents: A Retrospective Study in a Swiss Psychiatric University Hospital.

J Child Adolesc Psychopharmacol. 2017 Nov 13;:

Authors: Ansermot N, Jordanov V, Smogur M, Holzer L, Eap CB

Abstract
OBJECTIVES: This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland.
METHODS: Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations.
RESULTS: A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively.
CONCLUSION: The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

PMID: 29131655 [PubMed - as supplied by publisher]