您现在的位置:首页>美国卫生研究院文献>Clinical and Translational Science

期刊信息

  • 期刊名称:

    -

  • 刊频: Bimonthly, 2009-
  • NLM标题:
  • iso缩写: -
  • ISSN: -

年度选择

更多>>

  • 排序:
  • 显示:
  • 每页:
全选(0
<5/20>
1170条结果
  • 机译 2018年美国食品药品监督管理局批准的药物的转运体抑制数据的体外至体外推断
    摘要:A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (  = 42) was performed. ‐to‐ predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P‐gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti‐infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated , 56% showed positive clinical interactions (area under the concentration‐time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically‐based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters (AUCRs of 0.94–1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs
  • 机译 将医疗技术快速引入日本国民健康保险体系的高级医疗计划
    摘要:Japan’s Advanced Medical Care Program (AMCP) seeks to facilitate patient access to promising healthcare technologies through National Health Insurance (NHI) coverage. This study aimed to examine AMCP’s contribution to the accelerated introduction of new technologies through NHI coverage. AMCP‐type B technologies registered May 2006–March 2019 were examined. To investigate the use of AMCP for NHI coverage, data from the AMCP website and from regulatory authority documents were used. Of 127 AMCP‐type B technologies, 38 underwent final review. Fifteen technologies were successfully introduced into NHI coverage. Eight technologies introduced directly through the Advanced Medical Care Conference were related to medical devices. Other technologies, including drugs, required additional accelerated frameworks for market approval. A strategic approach with the careful selection of target therapeutic technologies and accelerated frameworks is key for the rapid introduction of medical technologies through AMCP.
  • 机译 一种新颖的LC-MS / MS测定脱羧凝血酶原的定量和华法林诱导变化的表征
    摘要:Warfarin is a narrow therapeutic index anticoagulant drug and its use is associated with infrequent but significant adverse bleeding events. The international normalized ratio (INR) is the most commonly used biomarker to monitor and titrate warfarin therapy. However, INR is derived from a functional assay, which determines clotting efficiency at the time of measurement and is susceptible to technical variability. Protein induced by vitamin K antagonist‐II (PIVKA‐II) has been suggested as a biomarker of long‐term vitamin K status, providing mechanistic insights about variation in the functional assay. However, the currently available antibody‐based PIVKA‐II assay does not inform on the position and number of des‐carboxylation sites in prothrombin. The assay presented in this paper provides simultaneous quantification of carboxy and des‐carboxy prothrombin that are essential for monitoring early changes in INR and, thus, serves as the superior tool for managing warfarin therapy. Additionally, this assay permits the quantification of total prothrombin level, which is affected by warfarin treatment. Prothrombin recovery from plasma was 95% and the liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay was linear (  = 0.98) with a dynamic range of 1–100 µg/mL. The assay interday precision was within 20%. A des‐carboxy peptide of prothrombin (GNLER) was negatively correlated with active prothrombin (Pearson  = 0.99,  r = 0.75,
  • 机译 CYP2C9和CYP2C19:基因突变的深层突变扫描和功能表征
    摘要:Single nucleotide variants in the open reading frames (ORFs) of pharmacogenes are important causes of interindividual variability in drug response. The functional characterization of variants of unknown significance within ORFs remains a major challenge for pharmacogenomics. Deep mutational scanning (DMS) is a high‐throughput technique that makes it possible to analyze the functional effect of hundreds of variants in a parallel and scalable fashion. We adapted a “landing pad” DMS system to study the function of missense variants in the ORFs of cytochrome P450 family 2 subfamily C member 9 ( ) and cytochrome P450 family 2 subfamily C member 19 ( ). We studied 230 observed missense variants in the and ORFs and found that 19 of 109 and 36 of 121 variants displayed less than ~ 25% of the wild‐type protein expression, a level that may have clinical relevance. Our results support DMS as an efficient method for the identification of damaging ORF variants that might have potential clinical pharmacogenomic application.
  • 机译 类风湿关节炎患者西妥索单抗的暴露-反应关系与低疾病活动性和缓解的达成
    摘要:Anti‐tumor necrosis factor (anti‐TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune‐mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti‐TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C‐reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure‒response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (
  • 机译 万古霉素诱导的肠道菌群变化对辛伐他汀药代动力学的影响
    摘要:The pharmacokinetic (PK) properties of drugs are affected in several ways by interactions with microbiota. The aim of this study was to investigate the effects of oral vancomycin on the gut microbiota and, consequently, on the PKs of simvastatin. An open‐label, single arm, sequential crossover study was conducted in six healthy Korean male subjects. After 6 days on a control diet, simvastatin 40 mg was orally administered to the subjects before and after 1 week of oral vancomycin treatment. Blood samples for PK analysis and fecal samples for metagenomic and metabolomic analyses were collected. After vancomycin treatment, the richness of microbiota considerably decreased, and the composition was altered. In particular, the relative abundance of Bacteroidetes decreased, whereas that of proteobacteria increased. In addition, changes in fecal metabolites, including D‐glucuronic acid, were observed. However, systemic exposure of simvastatin was not changed whereas that of hydroxysimvastatin showed a tendency to increase. The relationship between the change of PKs of simvastatin and the change of gut microbiota and fecal metabolites were not clearly observed.
  • 机译 一种简单快速的UPLC-UV检测癌症患者DPD缺乏症的方法
    摘要:Detecting patients with dihydropyrimidine dehydrogenase (DPD) deficiency is becoming a major concern in clinical oncology. Monitoring physiologic plasma uracil and/or plasma uracil‐to‐dihydrouracil metabolic ratio is a common surrogate frequently used to determine DPD phenotype without direct measurement of the enzymatic activity. With respect to the increasing number of patients rquiring analysis, it is critical to develop simple, rapid, and affordable methods suitable for routine screening. We have developed and validated a simple and robust ultraperformance liquid chromatography‒ultraviolet (UPLC‐UV) method with shortened (i.e., 12 minutes) analytical run‐times, compatible with the requirements of large‐scale upfront screening. The method enables detection of uracil (U) over a range of 5–500 ng/ml (265 nm) and of dihydrouracil (UH2) over a range of 40–500 ng/ml (210 nm) in plasma with no chromatographic interference. When used as part of routine screening for DPD deficiency, this method was fully able to discriminate nondeficient patients (i.e., with U levels < 16 ng/ml) from deficient patients at risk of severe toxicity (i.e., U > 16 ng/ml). Results from 1 month of routine testing are presented and, although no complete deficits were detected, 10.7% of the screened patients presented DPD deficiency and would thus require s decresed dose. Overall, this new method, using a simple preanalytical solid‐phase extraction procedure, and based on use of a standard UPLC apparatus, is both cost‐ and time‐effective and can be easily implemented in any laboratory aiming to begin routine DPD testing.
  • 机译 Temsavir(抗逆转录病毒药物Fostemsavir的活性部分)对QT间隔的影响:I期研究结果和暴露-反应分析
    摘要:Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV‐1) infection in heavily treatment‐experienced adults with multidrug‐resistant HIV‐1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure–response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline‐adjusted Fridericia‐corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two‐sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2‐fold higher than the geometric mean TMR peak plasma concentration (C ) of 1,770 ng/mL in heavily treatment‐experienced HIV‐1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study ( ).
  • 机译 真实世界房颤患者的利伐沙班精确剂量策略
    摘要:Rivaroxaban is a direct‐acting oral anticoagulant approved to prevent strokes in patients with atrial fibrillation. Dosage recommendations are approved for all adult patients to receive either 15 mg or 20 mg once daily depending upon renal function. There are a number of reasons to believe rivaroxaban dosing could be more effective and/or safer for more patients if increased dosing precision is available. Because real‐world patients are more diverse than those studied in phase III clinical trials, we evaluated the extremes of creatinine clearance (CrCl) on rivaroxaban clearance using a published population pharmacokinetic model and applying exposure variation limits (±20%) based on published literature. The proposed dosing recommendations are 10 mg once daily (CrCl 15–29 ml/min), 15 mg once daily (CrCl 30–69 ml/min), 10 mg twice daily (CrCl 70–159 ml/min), and 15 mg twice daily (CrCl 160–250 ml/min). These new dosing recommendations should be prospectively tested for predictive accuracy and to assess the impact on AF patient efficacy and safety.
  • 机译 马鞭草(Chumeria majdae)的精油在小鼠中的抗惊厥作用:GABAA神经传递和一氧化氮途径的作用
    摘要:The essential oil from the leaves of Rech. (ZMEO) has been shown to have several beneficial effects in the clinic. In this work we examined the anticonvulsant activities of ZMEO in an experimental mouse model of seizure and aimed to identify any possible underlying mechanisms. ZMEO (5, 10, 20, and 40 mg/kg intraperitoneally (i.p.)) or diazepam, as the reference anticonvulsant drug (25, 50 and 100 µg/kg i.p.), were administered 60 minutes prior to pentylenetetrazol (PTZ) injection (intravenously (i.v.) or i.p.) and changes in threshold, latency, and frequency of clonic seizure were examined. The PTZ i.p.‐induced model of seizure was also applied for examining the protective effects of ZMEO pretreatment against PTZ‐induced mortality. In some studies, the anticonvulsant effect of the combination of diazepam and ZMEO was also studied. The protective effects of ZMEO against hindlimb tonic extensions (HLTEs) were also examined by maximal electroshock (MES) seizure testing. The γ‐aminobutyric acid (GABA)ergic mechanism and nitric oxide (NO) pathway involvement in anticonvulsant activity of ZMEO were assessed by pretreating animals with flumazenil, ‐nitro‐L‐arginine methyl ester (L‐NAME), aminoguanidine, and L‐arginine in a PTZ‐induced model of seizure. Administration of 20 mg/kg ZMEO significantly increased chronic seizure threshold and latency while reducing frequency of convulsions and mortality in the PTZ‐induced model. In the doses studied, ZMEO could not protect mice from HLTE and mortality induced by MES. Pretreatment with L‐arginine and diazepam potentiated the anticonvulsant effects of ZMEO, whereas pretreatment with L‐NAME, aminoguanidine, and flumazenil reversed anticonvulsant activity. The anticonvulsant activity of ZMEO may be mediated in part through a GABAergic mechanism and the NO signaling pathway.
  • 机译 丹麦人群中的初级保健处方药使用和相关的可操作药物基因相互作用
    摘要:Pharmacogenetics (PGx) aims to improve drug therapy using the individual patients’ genetic make‐up. Little is known about the potential impact of PGx on the population level, possibly hindering implementation of PGx in clinical care. Therefore, we investigated how many patients use actionable PGx drugs, have actionable genotypes or phenotypes and which patients could benefit the most of PGx testing. We included PGx recommendations from two international PGx consortia (Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG)). Using data from publically accessible sales information drawn from the Danish Register of Medicinal Product Statistics (MEDSTAT), we identified the number of users of actionable prescription PGx drugs among the total Danish population in 2017. We estimated actionable genotypes or phenotypes based on reported frequencies from literature. We identified 49 drug‐gene interactions related to 41 unique prescription drugs. The estimated median frequency of actionable genotypes or phenotypes among prescription drug users was 25% (interquartile range 7–26%). Six of 41 drugs were used more than twice as much in women. Actionable PGx drugs were most frequently used by 45–79 year old patients (62%), followed by 25–44 year old patients (18%). Almost half of the actionable PGx drugs (19/41) were psychotropics (i.e., antidepressants, antipsychotics, or psychostimulants). PGx testing can have a substantial impact on the population, as one in four prescription drug users has an actionable genotype or phenotype and could thus benefit from PGx testing. We advocate for prospective panel‐based PGx testing at the time of the first PGx drug prescription (“as needed”), with PGx results ready prior to start of the first, and all future, therapies.
  • 机译 评估NIH CTSA计划对在ClinicalTrials.gov注册的临床试验的影响
    • 作者:Arthur Berg
    • 刊名:Clinical and Translational Science
    • 2020年第4期
    摘要:Since 2006, the US Congress has appropriated ~ 7 billion dollars in total toward the (CTSA) program of the National Institutes of Health (NIH), representing ~ 1.5% of the NIH total budget. There is no doubt this investment has led to substantial improvements in clinical and translational research, but the impact of these large NIH‐sponsored awards to academic medical centers have largely been documented by anecdotal accomplishments. This paper provides a purely quantitative assessment of the impact of these awards on clinical trials registered on . In particular, we find a dramatic increase in the number of registered clinical trials and clinical trial enrollment associated with the CTSA grant award. Additionally, the impact is shown to be magnified with the number of years of receiving CTSA funding.
  • 机译 发行信息
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第4期
    摘要:
  • 机译 发行信息
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第2期
    摘要:
  • 机译 发行信息
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第3期
    摘要:
  • 机译 发行信息
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第1期
    摘要:
  • 机译 2018年审稿人致谢
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第1期
    摘要:
  • 机译 对儿童实施精确治疗的注意事项
    • 作者:
    • 刊名:Clinical and Translational Science
    • 2019年第5期
    摘要:

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号