Medical and Dietary Uses of N-Acetylcysteine.

Antioxidants (Basel). 2019 Apr 28;8(5):

Authors: Šalamon Š, Kramar B, Marolt TP, Poljšak B, Milisav I

Abstract
N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.

PMID: 31035402 [PubMed]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/04/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

HLA and immune-mediated adverse drug reactions: another hit with vancomycin.

J Allergy Clin Immunol. 2019 Apr 25;:

Authors: Pirmohamed M

PMID: 31029771 [PubMed - as supplied by publisher]

Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization-Gas Chromatography.

Drug Metab Dispos. 2019 Apr 26;:

Authors: Patrick KS, Rodriquez W

Abstract
A tenable hypothesis is presented which explains disparities between the older oral dl-MPH bioavailability data generated using chiral derivatization gas chromatography versus more recent findings using chiral liquid chromatography. These disparities continue to persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-(R,R)-MPH is 23% and that of l-(S,S)-MPH is 5% (i.e., 82% exists as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. The older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent will yield the (R,R,R)-MPH-prolyl diastereomer from d-MPH which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimating the percent l-MPH at the expense of underestimating d-MPH. Thus, unless compelling reasons exist to justify use of any chiral discriminators, then less complex and less costly achiral analyses of plasma dl-MPH fundamentally allows d-MPH quantitation since 99% exists as d-MPH. However, simultaneous monitoring of both d-MPH and l-MPH appear warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For examples: (a) using transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which especially elevates l-MPH concentrations; (d) in forensic studies of intravenous/intranasal dl-MPH abuse or (e) were dl-MPH to be formulated as a free base sublingual product for direct oral mucosal transport. SIGNIFICANCE STATEMENT: N/A.

PMID: 31028056 [PubMed - as supplied by publisher]

From the beginning to resistance: Study of plasma monitoring and resistance mechanisms in a cohort of patients treated with osimertinib for advanced T790M-positive NSCLC.

Lung Cancer. 2019 May;131:78-85

Authors: Bordi P, Del Re M, Minari R, Rofi E, Buti S, Restante G, Squadrilli A, Crucitta S, Casartelli C, Gnetti L, Azzoni C, Bottarelli L, Petrini I, Cosenza A, Ferri L, Rapacchi E, Danesi R, Tiseo M

Abstract
INTRODUCTION: Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance.
MATERIALS AND METHODS: Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed.
RESULTS: Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [< 2200 copies/mL or allele frequency (AF) < 6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation.
CONCLUSIONS: The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.

PMID: 31027702 [PubMed - in process]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/04/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Precision medicine: a call for increased pharmacogenomic education.

Per Med. 2019 Apr 26;:

Authors: Ta R, Cayabyab MA, Coloso R

Abstract
Precision medicine is an emerging model of care where providers consider patients' genetic profiles, lifestyles and environments to offer more precise therapy. The potential of precision medicine is boundless as interdisciplinary teams utilize genetic technologies to improve patient outcomes. The integration of precision medicine into healthcare faces many barriers, including a lack of standardization and reimbursement concerns. This article argues that increased pharmacogenetics education and system-wide implementation is necessary to overcome some of these challenges. Extensive expansion of pharmacogenomics education is a step toward producing knowledgeable clinicians who are poised to apply its methodology and champion for patient-centered care.

PMID: 31025601 [PubMed - as supplied by publisher]

Estimation of CYP3A4*1B single nucleotide polymorphism in patients with recurrent Major Depressive Disorder.

Mol Genet Genomic Med. 2019 Apr 25;:e669

Authors: Świechowski R, Jeleń A, Mirowski M, Talarowska M, Gałecki P, Pietrzak J, Wodziński D, Balcerczak E

Abstract
BACKGROUND: Major depression is the most common mental illness in the world. Failures in treatment may occur due to the presence of a subtype of depression called TRD (Treatment- Resistant Depression). CYP3A4 polymorphism (rs2740574) can increase the activity of Cytochrome P450 3A4, contributing to faster metabolism of xenobiotics and reduced response to treatment. The aim of the study was to assess the distribution of CYP3A4*1B in study and control group and to estimate the influence of particular genotypes on parameters such as: age at onset, severity of symptoms before treatment and on the effectiveness of therapy.
METHODS: Total of 192 patients were enrolled in this study (102 patients suffering from recurrent Major Depression Disorder, 90 healthy blood donors). PCR Restriction Fragment Length Polymorphism method with MboII enzyme was performed. The presence of CYP3A4*1B allele was evaluated on the basis of agarose gel electrophoresis.
RESULTS: There was a tendency in frequency of genotypes distribution in the study group in comparison with the control group (p = 0.050). There were no statistically significant differences in the distribution mutant allele among these two groups, but there was a tendency for mutant allele to occur more often in the study group (p = 0.050). No significant correlations were found between the specific genotype and the studied parameters: age at onset (p = 0.232), severity of the symptoms (p = 0.946), and efficacy of treatment (p = 0.882).
CONCLUSION: The study suggests that CYP3A4*1B polymorphism have no influence on the predisposition to depression, the severity of depressive symptoms and the efficiency of antidepressant therapy.

PMID: 31025537 [PubMed - as supplied by publisher]

Comparative pharmacokinetic study on three formulations of Astragali Radix by a LC-MS/MS method for determination of formononetin in human plasma.

Biomed Chromatogr. 2019 Apr 26;:e4563

Authors: Rao T, Gong YF, Peng JB, Wang YC, He K, Zhou HH, Zhi-Rong T, Lv LZ

Abstract
Astragali Radix (AR) is a widely used traditional Chinese medicine for healing the cardiovascular, liver and immune systems. Recently, superfine pulverizing technology has been applied to developing novel formulations to improve bioavailability of the active constituents in herbs, such as ultrafine granular powder of AR. In this study, a universal and sensitive quantitative method based on LC-MS/MS was employed for determining formononetin, a main flavonoid in AR, in human plasma for comparative pharmacokinetics of three oral formulations of AR. Formononetin and IS (quercetin) were extracted by ethyl acetate from human plasma and were separated on a C18 column with a mobile phase consisting of acetonitrile and 0.1% formic acid. Positive-ion electrospray- ionization mode was applied in mass spectrometric detection. The quantitative method was validated with regards to selectivity, linearity, accuracy and precision, matrix effect, extraction recovery and stability, and was applied to comparing the pharmacokinetics of ultrafine granular powder (UGP), ultrafine powder (UP) and traditional decoction pieces (TDP) of AR after oral administration. The Cmax , AUC0-48 and AUC0-∞ of formononetin in UGP and UP were significantly higher than those of TDP. UGP and UP could significantly improve the bioavailability of AR in human compared with TDP after oral administration.

PMID: 31025385 [PubMed - as supplied by publisher]

Significant association of DRD2 enhancer variant rs12364283 with heroin addiction in a Pakistani population.

Ann Hum Genet. 2019 Apr 26;:

Authors: Jabeen S, Pinsonneault JK, Sadee W, Lee SH, Zafar MM, Raja MS, Raja GK

Abstract
The dopamine D2 receptor encoded by DRD2 has been implicated in multiple psychiatric disorders, mediated at least in part by two intronic variants affecting mRNA splicing, rs1076560 and rs2283265, and a less frequent enhancer variant, rs12364283, which increases DRD2 mRNA expression. This study tests whether these functionally validated variants confer susceptibility toward heroin addiction in a Pakistani population. A total of 540 heroin addicts and 467 healthy controls were genotyped, basic allele and genotype tests were performed. Neither rs1076560 nor rs2283265 significantly associated with heroin addiction. The enhancer rs12364283 occurs more frequently in heroin-dependent cases than controls (MAF 13% vs. 7%, respectively), revealing significant association with heroin addiction (p = 3.0E-06, OR 2.1). This study identifies rs12364283 of DRD2 as a potential risk factor for heroin addiction in the Pakistani study population. This enhancer variant had been shown to increase DRD2 mRNA expression, a possible factor in increased vulnerability to heroin addiction. Further studies are needed to validate this association of rs12364283.

PMID: 31025317 [PubMed - as supplied by publisher]

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.

Cell Res. 2019 Apr 25;:

Authors: Mugoni V, Panella R, Cheloni G, Chen M, Pozdnyakova O, Stroopinsky D, Guarnerio J, Monteleone E, Lee JD, Mendez L, Menon AV, Aster JC, Lane AA, Stone RM, Galinsky I, Zamora JC, Lo-Coco F, Bhasin MK, Avigan D, Longo L, Clohessy JG, Pandolfi PP

Abstract
Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.

PMID: 31024166 [PubMed - as supplied by publisher]

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

Oncologist. 2019 Apr 25;:

Authors: Ciruelos E, Apellániz-Ruiz M, Cantos B, Martinez-Jáñez N, Bueno-Muiño C, Echarri MJ, Enrech S, Guerra JA, Manso L, Pascual T, Dominguez C, Gonzalo JF, Sanz JL, Rodriguez-Antona C, Sepúlveda JM

Abstract
BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity.
MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated.
RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy.
CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

PMID: 31023863 [PubMed - as supplied by publisher]

Journal of Translational Medicine advances in Translational Genomics and Genetics Era.

J Transl Med. 2019 Apr 25;17(1):134

Authors: Liu W

Abstract
We are delighted to announce the launch of a new section in the Journal of Translational Medicine, 'Translational Genomics and Genetics'. Central to translational medicine trend is the ability to sequence, annotate and interpret the genomic variants in a given patient to guide precision diagnosis and personalized treatment. This new section intends to promote the translation of emerging genomic technologies into clinical applications. The coverage extends to basic, translational and clinical studies related to human genomics and genetics. The manuscripts in following categories are welcome, but not limited to: Application of next generation sequencing in clinical diagnosis, including but not limited to rare genetic disease, complex inherited disease, prenatal/perinatal screening, oncology, organ transplantation and pathogen identification; Novel bioinformatics approaches in human genomics; Single cell sequencing, liquid biopsy and other emerging genomic assays in molecular genetics, pharmacogenomics, oncology and immuno-oncology; Integration of genomics with other "omics" technology in genetic medicine.

PMID: 31023327 [PubMed - in process]

Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy.

Nat Genet. 2018 10;50(10):1399-1411

Authors: Lee JK, Liu Z, Sa JK, Shin S, Wang J, Bordyuh M, Cho HJ, Elliott O, Chu T, Choi SW, Rosenbloom DIS, Lee IH, Shin YJ, Kang HJ, Kim D, Kim SY, Sim MH, Kim J, Lee T, Seo YJ, Shin H, Lee M, Kim SH, Kwon YJ, Oh JW, Song M, Kim M, Kong DS, Choi JW, Seol HJ, Lee JI, Kim ST, Park JO, Kim KM, Song SY, Lee JW, Kim HC, Lee JE, Choi MG, Seo SW, Shim YM, Zo JI, Jeong BC, Yoon Y, Ryu GH, Kim NKD, Bae JS, Park WY, Lee J, Verhaak RGW, Iavarone A, Lee J, Rabadan R, Nam DH

Abstract
Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.

PMID: 30262818 [PubMed - indexed for MEDLINE]

Pharmacogenomics of osteonecrosis of the jaw.

Bone. 2019 Apr 22;:

Authors: Yang G, Singh S, Chen Y, Hamadeh IS, Langaee T, McDonough CW, Holliday LS, Lamba J, Moreb JS, Katz J, Gong Y

Abstract
Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.

PMID: 31022475 [PubMed - as supplied by publisher]

Effects of the ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of afatinib in healthy Chinese volunteers.

Xenobiotica. 2019 Apr 25;:1-21

Authors: Tan YN, Cao KN, Ren GH, Qin ZY, Zhao D, Li N, Chen XJ, Xia YF, Lu Y

Abstract
1. Afatinib is an oral, selective tyrosine kinase inhibitor (TKI) primarily transported by P-glycoprotein (MDR1, gene code ABCB1) and breast cancer resistance protein (BCRP, gene code ABCG2). In the present study, the effects of ABCB1 and ABCG2 genetic polymorphisms on the pharmacokinetics of afatinib in healthy Chinese was investigated. 2. Blood samples from 24 healthy participants who received afatinib were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (34G > A, 421C > A) polymorphisms. Subsequently, the association between afatinib plasma concentrations and target single-nucleotide polymorphisms (SNPs) was analyzed. 3. Among the five polymorphisms, plasma concentrations of afatinib in healthy subjects with ABCB1 1236CC-3435CC were remarkably higher than in other genotype subjects. No significant differences of afatinib exposure were found between the ABCG2 wild type and heterozygous groups. 4. The ABCB1 genetic polymorphism influenced the plasma exposure of afatinib, and gene testing before drug administration may be useful for clinically individualized use of afatinib. Our data suggest the usefulness of afatinib pharmacogenetics in treatment optimization.

PMID: 31021303 [PubMed - as supplied by publisher]

Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Platelet Reactivity and Early Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention and Treated With Aspirin and Clopidogrel.

Circ Cardiovasc Interv. 2019 May;12(5):e007019

Authors: Xu K, Ye S, Zhang S, Yang M, Zhu T, Kong D, Chen J, Xu L, Li J, Zhu H, Wang F, Yang L, Zhang J, Fan Y, Ying L, Hu X, Zhang X, Chan NC, Li C

Abstract
BACKGROUND: The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents.
METHODS AND RESULTS: In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups.
CONCLUSIONS: About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1 rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.

PMID: 31018667 [PubMed - in process]

Safety, Pharmacokinetics, and Pharmacogenetics of Single-Dose Teriflunomide Sodium and Leflunomide in Healthy Chinese Subjects.

Clin Drug Investig. 2019 Apr 23;:

Authors: Yao X, Wu Y, Jiang J, Hu P, Liu D, Chen X

Abstract
BACKGROUND: Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus.
OBJECTIVE: The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development.
METHODS: A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10 mg or leflunomide 10 mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected.
RESULTS: All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341 mg/L and 0.718 ± 0.169 mg/L, and area under the concentration-time curve from time zero to infinity (AUC∞) was 423 ± 229 mg·h/L and 303 ± 159 mg·h/L, respectively. Overall, teriflunomide AUC∞ in ABCG2 34A/A mutants was 70.4% lower than in wild-type ABCG2 34G/G after administration of teriflunomide sodium. In addition, after administration of leflunomide, teriflunomide AUC∞ in ABCG2 34A/A mutants was 30.0% lower than in subjects carrying ABCG2 34G/G.
CONCLUSIONS: Teriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34G>A was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34G>A may be a significant influencing factor.
CLINICAL TRIAL REGISTRATION: This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).

PMID: 31016613 [PubMed - as supplied by publisher]

Role of epigenetic mechanisms in cisplatin-induced toxicity.

Crit Rev Oncol Hematol. 2019 May;137:131-142

Authors: Quintanilha JCF, Saavedra KF, Visacri MB, Moriel P, Salazar LA

Abstract
Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity.

PMID: 31014509 [PubMed - in process]

The dysregulation of tRNAs and tRNA derivatives in cancer.

J Exp Clin Cancer Res. 2018 May 09;37(1):101

Authors: Huang SQ, Sun B, Xiong ZP, Shu Y, Zhou HH, Zhang W, Xiong J, Li Q

Abstract
Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

PMID: 29743091 [PubMed - indexed for MEDLINE]