Beta-blocker Dose Stratifies Mortality Risk in a Racially Diverse Heart Failure Population.

J Cardiovasc Pharmacol. 2019 Dec 31;:

Authors: Lteif C, Arwood MJ, Kansal M, Cavallari LH, Desai AA, Duarte JD

Abstract
Heart failure (HF) is highly prevalent and a major cause of death in the US. The effect of HF medications on survival has been predicted by validated models studied in populations predominantly of European descent. This study aimed to identify medications associated with survival in a racially diverse HF population. HF patients were recruited and followed from 2001 to 2015. Data were collected from electronic health records and the Social Security Death Index. The primary analysis tested the association between medication dose and all-cause mortality, with a secondary analysis assessing the composite outcome of death or cardiac-related hospitalization. Circulating concentration of the fibrotic marker procollagen type III N-terminal peptide (PIIINP) was also compared with medication doses in patients with concentrations available. The study population consisted of 337 patients, of which 23% died and 46% were hospitalized. Increased beta blocker (BB) dose was significantly associated with survival in the base model (HR=0.71, P=0.017), and marginally associated in the comprehensive model (HR=0.75, P= 0.068). BB dose was also associated with decreased risk of the composite endpoint in the base model (HR= 0.80, P=0.029) and to a lesser extent in the comprehensive model (HR=0.83, P=0.085). Further, increased BB dose was inversely associated with circulating PIIINP concentration (P=0.041). In conclusion, our study highlights the importance of BB dose escalation for survival and decreased hospitalization in patients with HF, regardless of race or HF type. It also suggests that benefits observed with high-dose BBs could be mediated, at least in part, by decreased cardiac fibrosis, however further research is needed.

PMID: 31895871 [PubMed - as supplied by publisher]

Simultaneous determination of eight arginine-related metabolites in cellular extracts using liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Dec 15;1137:121936

Authors: Amatya S, Shin Y, Ha JY, Lee SJ, Kang SW, Kwon B, Kim DH

Abstract
A simple, sensitive, and rapid liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method was developed for the simultaneous determination of arginine and its pathway-related metabolites (ornithine, proline, citrulline, glutamate, agmatine, spermidine, and spermine) in cellular extracts. Cells were lysed and cellular proteins precipitated by the addition of acetonitrile followed by ultra-sonication. Supernatants were analyzed using a Chromolith High Resolution RP-18 endcapped column (100 × 4.6 mm, 1.15 μm, 150 Å), with mobile phases of 0.1% formic acid solution and 0.1% formic acid in acetonitrile. Detection was carried out in multiple reaction monitoring (MRM) mode. Calibration curves showed linearity (r2 > 0.99) for all metabolites over the calibration ranges used. The intra- and inter-day precision was less than 13.5%, and the accuracy was between 91.3 and 114.7%. The method developed in this study was successfully applied to measure arginine and its pathway-related metabolites, which are related to nitric oxide synthase/arginase pathways in mouse bone marrow-derived dendritic cells (BMDCs). The ability to simultaneously measure arginine and its pathway-related metabolites is valuable for better understanding local and systemic inflammatory processes.

PMID: 31891857 [PubMed - as supplied by publisher]

Response to: Heterogeneous Treatment Response by Race Cannot Be Claimed in the Absence of Evidence.

Am J Hypertens. 2019 Dec 31;:

Authors: Mehanna M, Wang Z, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, Schwartz GL, Bailey KR, Johnson JA, Turner ST, Cooper-Dehoff RM

PMID: 31891170 [PubMed - as supplied by publisher]

Influence of UGT1A1 and SLCO1B1 Polymorphisms and Efavirenz on Bilirubin Disposition in Healthy Volunteers.

Drug Metab Dispos. 2019 Dec 30;:

Authors: Collins KS, Metzger IF, Gufford BT, Lu J, Medeiros EB, Pratt VM, Skaar TC, Desta Z

Abstract
Chronic administration of efavirenz is associated with decreased serum bilirubin levels, probably through induction of UGT1A1. We assessed the impact of efavirenz monotherapy and UGT1A1 phenotypes on total, conjugated, and unconjugated serum bilirubin levels in healthy volunteers. Healthy volunteers were enrolled into a clinical study designed to address efavirenz pharmacokinetics, drug interactions, and pharmacogenetics. Volunteers received multiple oral doses (600 mg/d for 17 days) of efavirenz. Serum bilirubin levels were obtained at study entry and 1 week after completion of the study. DNA genotyping was performed for UGT1A1 (*80 (C>T), *6 (G>A), *28 (TA7), *36 (TA5) and *37 (TA8)) and for SLCO1B1 (*5 (521T>C) and *1b (388A>G) variants. Diplotype predicted phenotypes were classified as normal, intermediate and slow metabolizers. Compared to bilirubin levels at screening, treatment with efavirenz significantly reduced total, conjugated, and unconjugated bilirubin. After stratification by UGT1A1 phenotypes, there was a significant decrease in total bilirubin among all phenotypes, conjugated bilirubin among intermediate metabolizer, and unconjugated bilirubin among normal and intermediate metabolizers. The data also show that UGT1A1 genotype predicts serum bilirubin levels at baseline, but this relationship is lost after efavirenz treatment. SLCO1B1 genotypes did not predict bilirubin levels at baseline or after efavirenz treatment. Our data suggest that efavirenz may alter bilirubin disposition mainly through induction of UGT1A1 metabolism and efflux through MRP2. SIGNIFICANCE STATEMENT: Efavirenz likely alters the pharmacokinetics of coadministered drugs, potentially causing lack of efficacy or increased adverse effects, as well as the disposition of endogenous compounds relevant in homeostasis through upregulation of UGT1A1 and MRP2. Measurement of unconjugated and conjugated bilirubin during new drug development may provide mechanistic understanding regarding enzyme and transporters modulated by the new drug. .

PMID: 31888882 [PubMed - as supplied by publisher]

Carboxymethyl cellulose/diclofenac bioactive coatings on AISI 316LVM for controlled drug delivery, and improved osteogenic potential.

Carbohydr Polym. 2020 Feb 15;230:115612

Authors: Maver U, Xhanari K, Žižek M, Gradišnik L, Repnik K, Potočnik U, Finšgar M

Abstract
This work reports on the preparation and systematic testing of a novel multi-layered coating, comprised of the non-steroid anti-inflammatory drug diclofenac and biopolymer carboxymethyl cellulose. Drug release testing was performed on an Automated Transdermal Diffusion Cells Sampling System in combination with UV-VIS spectroscopy as the released drug concentration determination method. The results showed that most of the drug is released in the first six hours, whereas the overall released amount could be tailored through changes in the multi-layered coating composition. Biocompatibility tests performed on human osteoblast cells, showed cell viability improvement between 7% and 17% compared to the control sample. The expression of proteins playing important roles in extracellular matrix production and functioning was performed in order to obtain additional proof of the prepared materials' osteointegration boosting capacity. Finally, electrochemical measurements confirmed that the coatings do not influence the corrosion susceptibility of AISI 316LVM stainless steel.

PMID: 31887952 [PubMed - in process]

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Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.

BMC Psychiatry. 2019 Dec 27;19(1):420

Authors: Dunlop BW, Parikh SV, Rothschild AJ, Thase ME, DeBattista C, Conway CR, Forester BP, Mondimore FM, Shelton RC, Macaluso M, Logan J, Traxler P, Li J, Johnson H, Greden JF

Abstract
BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.
METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6.
RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms.
CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms.
TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

PMID: 31881956 [PubMed - in process]

Pharmacogenomic Characterization in Bipolar Spectrum Disorders.

Pharmaceutics. 2019 Dec 21;12(1):

Authors: Fortinguerra S, Sorrenti V, Giusti P, Zusso M, Buriani A

Abstract
The holistic approach of personalized medicine, merging clinical and molecular characteristics to tailor the diagnostic and therapeutic path to each individual, is steadily spreading in clinical practice. Psychiatric disorders represent one of the most difficult diagnostic challenges, given their frequent mixed nature and intrinsic variability, as in bipolar disorders and depression. Patients misdiagnosed as depressed are often initially prescribed serotonergic antidepressants, a treatment that can exacerbate a previously unrecognized bipolar condition. Thanks to the use of the patient's genomic profile, it is possible to recognize such risk and at the same time characterize specific genetic assets specifically associated with bipolar spectrum disorder, as well as with the individual response to the various therapeutic options. This provides the basis for molecular diagnosis and the definition of pharmacogenomic profiles, thus guiding therapeutic choices and allowing a safer and more effective use of psychotropic drugs. Here, we report the pharmacogenomics state of the art in bipolar disorders and suggest an algorithm for therapeutic regimen choice.

PMID: 31877761 [PubMed]

Pharmacogenomics and Endocrine Therapy in Breast Cancer.

J Clin Oncol. 2019 Dec 27;:JCO1903119

Authors: Hayes DF, Rae JM

PMID: 31880969 [PubMed - as supplied by publisher]

Profiling of Drug-Metabolizing Enzymes and Transporters in Human Tissue Biopsy Samples; A Review of the Literature.

J Pharmacol Exp Ther. 2019 Dec 26;:

Authors: Rodrigues AD, Rowland A

Abstract
Within the drug pharmacokinetics-absorption, distribution, metabolism and excretion (PK-ADME) research community, investigators regularly generate in vitro data sets using appropriately vendor-sourced and processed human tissue. Such data enable drug screening, the generation of kinetic parameters, extrapolation of in vitro to in vivo, as well as the modeling and simulation of drug pharmacokinetics (PK). Although there are large numbers of manuscripts describing studies with deceased organ donor tissue, relatively few investigators have published studies utilizing living donor tissue biopsy samples. After a review of the available literature, it was possible to find publications describing the use of tissue biopsy samples to determine enzyme inhibition ex vivo, the study of genotype-phenotype associations, the evaluation of tissue expression profiling following an inducer, and assessment of correlations between tissue expression profiles and in vivo-derived trait measures (e.g., biomarker plasma levels and probe drug PK). Some reports described multiple single tissue biopsies, while others described single multiple organ biopsies. It is concluded that biopsy-derived data can support modeling exercises (as input data and when validating models) and enable the assessment of organ-specific changes in enzyme and transporter profiles resulting from drug interactions, disease (e.g., metabolic disease, fibrosis, inflammation, cancer, infection), age, pregnancy, organ impairment, and genotype. With the emergence of multi-organ axes (e.g., microbiome-gut-liver-kidney) and interest in remote sensing (inter-organ communication), it is envisioned that there will be increased demand for single and multi-organ tissue biopsy data to support hypothesis testing and PK-ADME model building. SIGNIFICANCE STATEMENT: With the advent of physiologically-based PK (PBPK) modeling, researchers now have a greater appreciation for the various ADME-related processes, involving multiple organs, and their net impact on a drugs PK profile. Therefore, it is not surprising that such modeling has galvanized the development of companion tools like extensively humanized rodents and multi-organ microphysiological systems. With the reported utility of conventional tissue biopsy as precedent, it is envisioned that attention will also turn to less invasive liquid biopsy methods in support of ADME-related studies (e.g., the profiling of immunocaptured cargo-laden tissue-specific nanovesicles present in human blood). Generation of such multi-organ liquid biopsy data, in larger numbers of subjects and at multiple study time points, will provide a rich dataset for modeling purposes.

PMID: 31879375 [PubMed - as supplied by publisher]

Psychotropic drug-induced genetic-epigenetic modulation of CRTC1 gene is associated with early weight gain in a prospective study of psychiatric patients.

Clin Epigenetics. 2019 Dec 26;11(1):198

Authors: Delacrétaz A, Glatard A, Dubath C, Gholam-Rezaee M, Sanchez-Mut JV, Gräff J, von Gunten A, Conus P, Eap CB

Abstract
BACKGROUND: Metabolic side effects induced by psychotropic drugs represent a major health issue in psychiatry. CREB-regulated transcription coactivator 1 (CRTC1) gene plays a major role in the regulation of energy homeostasis and epigenetic mechanisms may explain its association with obesity features previously described in psychiatric patients. This prospective study included 78 patients receiving psychotropic drugs that induce metabolic disturbances, with weight and other metabolic parameters monitored regularly. Methylation levels in 76 CRTC1 probes were assessed before and after 1 month of psychotropic treatment in blood samples.
RESULTS: Significant methylation changes were observed in three CRTC1 CpG sites (i.e., cg07015183, cg12034943, and cg 17006757) in patients with early and important weight gain (i.e., equal or higher than 5% after 1 month; FDR p value = 0.02). Multivariable models showed that methylation decrease in cg12034943 was more important in patients with early weight gain (≥ 5%) than in those who did not gain weight (p = 0.01). Further analyses combining genetic and methylation data showed that cg12034943 was significantly associated with early weight gain in patients carrying the G allele of rs4808844A>G (p = 0.03), a SNP associated with this methylation site (p = 0.03).
CONCLUSIONS: These findings give new insights on psychotropic-induced weight gain and underline the need of future larger prospective epigenetic studies to better understand the complex pathways involved in psychotropic-induced metabolic side effects.

PMID: 31878957 [PubMed - in process]

Caffeine Consumption in Switzerland: Results from the First National Nutrition Survey MenuCH.

Nutrients. 2019 Dec 20;12(1):

Authors: Rochat C, Eap CB, Bochud M, Chatelan A

Abstract
Caffeine is a natural psychostimulant with a potentially positive impact on health when consumed in moderation and a negative impact at high dose (> 400 mg/day). So far, no study has examined self-reported caffeine consumption in Switzerland. Our objectives were to determine 1) the caffeine consumption per adult, 2) the main sources of caffeine intake in the Swiss diet, and 3) the timing of caffeine consumption during the day. We used data from the 2014-2015 national nutrition survey menuCH (adults aged 18 to 75 years old, n = 2057, weighted n = 4,627,878), consisting of two 24-hour dietary recalls. Caffeine content in consumed foods was systematically assessed using laboratory analyses in samples of Swiss caffeinated beverages, information from food composition databases, and estimations from standard recipes. Mean (± SD) daily caffeine consumption per person and percentile 95 were 191 mg/day (± 129) and 426 mg/day, respectively. We observed differences in mean caffeine consumption across age groups (18-34 y: 140 mg/day; 50-64 y: 228 mg/day), linguistic regions (German-speaking: 204 mg/day; French-speaking: 170 mg/day, Italian-speaking: 136 mg/day), and smoking status (never smokers: 171 mg/day; current smokers: 228 mg/day). The three main sources of caffeine intake were 1) coffee (83% of total caffeine intake), 2) tea (9%) and 3) soft drinks (4%). Caffeine consumption was highest between 06:00 and 09:00 (29%) and the circadian rhythm slightly differed across linguistic regions and age groups. The mean caffeine consumption in the Swiss adult population was similar to that reported in neighbouring countries.

PMID: 31877632 [PubMed - in process]

Pharmacodynamics, clinical findings and approval status of current and emerging tyrosine-kinase inhibitors for pancreatic neuroendocrine tumors.

Expert Opin Drug Metab Toxicol. 2019 Dec;15(12):993-1004

Authors: Fazio N, Cella CA, Del Re M, Laffi A, Rubino M, Zagami P, Spada F

Abstract
Introduction: Pancreatic neuroendocrine tumors (panNETs) represent a rare group of malignancies. For decades, chemotherapy, somatostatin analogs and interferon represented the only systemic therapies; however, over the latest years, new options were registered, including Everolimus, Sunitinib (SUN), and Peptide Receptor Radionuclide Therapy.Areas covered: This review discusses the role of tyrosine kinase inhibitors (TKIs) in advanced panNETs.Expert opinion: TKIs showed an antiangiogenic and antiproliferative impact on advanced panNETs. Sunitinib is the only TKI currently available in clinical practice, having been approved on the basis of relevant results of a specific panNET phase III trial. New TKIs, such as Cabozantinib, Lenvatinib, Pazopanib, Surufatinib are still on investigation in panNETs. Although some phase II studies with the new TKIs yielded better PFS and RR compared with SUN, different study designs and tumor populations may have induced selection biases. However, it was reported that panNETs resistant to SUN could respond to a new TKI, indicating a possible further therapeutic line in this context. The global investigation plan of TKIs in panNETs is not homogeneous and it is difficult to understand what kind of development this can have in the near future for clinical practice.

PMID: 31794273 [PubMed - indexed for MEDLINE]

Loss of ELK1 has differential effects on age-dependent organ fibrosis.

Int J Biochem Cell Biol. 2019 Dec 23;:105668

Authors: Cairns JT, Habgood A, Edwards-Pritchard RC, Joseph C, John AE, Wilkinson C, Stewart ID, Leslie J, Blaxall BC, Sustak K, Alberti S, Nordheim A, Oakley F, Jenkins G, Tatler AL

Abstract
ETS domain-containing protein-1 (ELK1) is a transcriptional repressor important in regulating αvβ6 integrin expression. αvβ6 integrins activate the profibrotic cytokine Transforming Growth Factor β1 (TGFβ1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where αvβ6 mediated TGFβ activation has been implicated. Here we identify that Elk1-knockout (Elk1-/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1-/0 aged mice demonstrated increased collagen deposition, in particular collagen 3α1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1-/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 genes expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1in human disease Finally we exposed human cells and murine lung slices to cigarette smoke extract which lead to reduced ELK1 expression which may explain the loss of ELK1 in human disease. These data support a fundament role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.

PMID: 31877385 [PubMed - as supplied by publisher]

Impact of CYP2D6 polymorphisms on tamoxifen treatment in patients with retroperitoneal fibrosis: A first step towards tailored therapy?

Urology. 2019 Dec 23;:

Authors: Dreger NM, Degener S, Roth S, Ahmad-Nejad P, Kamper L, Müller E, von Rundstedt FC, Brandt AS

Abstract
OBJECTIVE: To investigate the influence of CYP2D6 polymorphisms on outcomes and health-related quality of life (HRQoL) of patients with retroperitoneal fibrosis (RPF) receiving tamoxifen (TMX). TMX is an effective alternative to corticosteroids for patients with RPF. Conversion of tamoxifen to more potent endoxifen is dependent on enzyme activity of CYP2D6.
MATERIALS AND METHODS: CYP2D6 genotyping and phenotype prediction of all patients treated with tamoxifen between 02/2007-01/2018 was assessed using multiplex PCR. Groups were classified by phenotype: extensive (EM) vs. poor & intermediate (PM+IM) vs. ultrarapid metabolizer (UM). Retrospective evaluation of outcome (including MRI and PET-CT) and HRQoL using the SF-36 was performed.
RESULTS: A total of 63/194 patients received tamoxifen, 40/63 with complete follow-up were sequenced: Twenty-nine patients with EM phenotype, eight PM+IM and three UM. The median therapy duration was 364,5 days with a mean follow-up of 62.9 months. Seven therapy terminations occurred due to lack of response (17,5%), including all UM patients (p<.001). MRIs showed a regression of fibrosis for EM and PM+IM in 69% and 62.5% of cases and a progression for UM in 100% (p=.004). In PET-CT, glucose utilization of RPF decreased significantly for EM and PM+IM. The physical sum-score of SF-36 improved for EM and PM+IM and decreased for UM (p<.05). The removal of DJ-stents was successful for EM, PM+IM and UM in 48.3%, 75% and 0% of cases (p=.0581).
CONCLUSION: Contrary to expectations, UM showed the lowest success rate, which concludes that genotyping of RPF-patients may be useful in the sense of a tailored-therapy.

PMID: 31877313 [PubMed - as supplied by publisher]

Methodological quality of clinical practice guidelines for genetic testing in children: A systematic assessment using the appraisal of guidelines for research and evaluation II instrument.

Medicine (Baltimore). 2019 Dec;98(52):e18521

Authors: Jiao XF, Li HL, Cheng L, Zhang C, Yang CS, Han J, Yi QS, Chen Z, Zeng LN, Zhang LL

Abstract
Genetic testing of children is faced with numerous problems. High-quality clinical practice guidelines (CPGs) are needed to ensure its safe, and appropriate use. This study aimed to systematically identify the current CPGs for genetic testing in children, and to assess the methodological quality of these CPGs.We searched 6 databases, 3 guideline clearinghouses, and 9 web sites of relevant academic agencies from inception to February 2019. CPGs focused on genetic testing in children were included. Four reviewers independently appraised the quality of the eligible CPGs using the appraisal of guidelines for research, and evaluation (AGREE) II instrument.Seventeen CPGs meeting our inclusion criteria were included. Among them, 16 CPGs were focused on the genetic diagnosis/evaluation of diseases, while only 1 CPG was focused on pharmacogenetics. The median domain scores from highest to lowest were: scope and purpose 80.56% (range: 56.95%-87.50%), clarity of presentation 72.22% (range: 45.83%-88.89%), stakeholder involvement 45.83% (range: 27.78%-55.56%), applicability 31.25% (range: 19.79%-54.17%), rigor of development 21.88%, (range: 13.02%-71.88%), and editorial independence 18.75% (range: 0%-83.33%). According to the overall quality, 6 (35%) CPGs were "not recommended," 8 (47%) CPGs were "recommended with modifications," and only 3 (18%) CPGs were "recommended." The clinical topics of the "recommended" CPGs were warfarin, familial Mediterranean fever, and pediatric pulmonary arterial hypertension.The quality of CPGs for genetic testing in children was generally low, and variable across different CPGs and different AGREE II domains. In future guideline development, more attention should be paid to the aspects of stakeholder involvement, rigor of development, applicability, and editorial independence. Not only will guideline users benefit from our results when determining whether to adopt related CPGs to guide genetic testing in children, but guideline developers could also take into account our results to improve the quality of future CPGs.

PMID: 31876744 [PubMed - in process]

Letter to the Editor in Response to "Effect of Polymorphisms in CYP2C9 and CYP2C19 on the Disposition, Safety and Metabolism of Progesterone Administrated Orally or Vaginally".

Adv Ther. 2019 Dec 24;:

Authors: Lazorwitz A, Aquilante CL, Sheeder J, Teal S

PMID: 31875298 [PubMed - as supplied by publisher]

Author's Response to: 'Letter to the Editor in Response to: "Effect of Polymorphisms in CYP2C9 and CYP2C19 on the Disposition, Safety and Metabolism of Progesterone Administrated Orally or Vaginally"'.

Adv Ther. 2019 Dec 24;:

Authors: Zubiaur P, Saiz-Rodríguez M, Abad-Santos F

PMID: 31875297 [PubMed - as supplied by publisher]

Intermittent Versus Continuous Dosing of MAPK Inhibitors in the Treatment of BRAF-Mutated Melanoma.

Transl Oncol. 2019 Dec 21;13(2):275-286

Authors: Reger de Moura C, Vercellino L, Jouenne F, Baroudjian B, Sadoux A, Louveau B, Delyon J, Serror K, Goldwirt L, Merlet P, Bouquet F, Battistella M, Lebbé C, Mourah S

Abstract
The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.

PMID: 31874374 [PubMed - as supplied by publisher]

Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle.

Sci Rep. 2019 Dec 23;9(1):19672

Authors: Giantin M, Rahnasto-Rilla M, Tolosi R, Lucatello L, Pauletto M, Guerra G, Pezzato F, Lopparelli RM, Merlanti R, Carnier P, Capolongo F, Honkakoski P, Dacasto M

Abstract
Cytochrome P450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism. However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (SNVs) and evaluated their functional effects. CYP3A28, CYP3A38 and CYP3A48 missense SNVs were identified in 300 bulls of Piedmontese breed through targeted sequencing. Wild-type and mutant bCYP3A cDNAs were cloned and expressed in V79 cells. CYP3A-dependent oxidative metabolism of testosterone (TST) and nifedipine (NIF) was assessed by LC-MS/MS. Finally, SNVs functional impact on TST hydroxylation was measured ex vivo in liver microsomes from individually genotyped animals. Thirteen missense SNVs were identified and validated. Five variants showed differences in CYP3A catalytic activity: three CYP3A28 SNVs reduced TST 6β-hydroxylation; one CYP3A38 variant increased TST 16β-hydroxylation, while a CYP3A48 SNV showed enhanced NIF oxidation. Individuals homozygous for rs384467435 SNV showed a reduced TST 6β-hydroxylation. Molecular modelling showed that most of SNVs were distal to CYP3A active site, suggesting indirect effects on the catalytic activity. Collectively, these findings demonstrate the importance of pharmacogenetics studies in veterinary species and suggest bCYP3A genotype variation might affect the fate of xenobiotics in food-producing species such as cattle.

PMID: 31873175 [PubMed - in process]