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共1170条结果
  • 1.

    【2hr】Metabolomic Differentials in Women With and Without Fibromyalgia

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    机译 有和没有纤维肌痛的女性的代谢组学差异
    摘要：A nontargeted plasma metabolomic analysis was conducted to compare differentially expressed metabolites in women with and without fibromyalgia ( ) using data and samples collected from two parent studies in women with FM ( = 20) and comparative data collected from newly recruited age‐matched women ( = 20). Blood plasma samples were analyzed for metabolite content using liquid chromatography mass spectrometry. Consolidation of positive and negative ion mode metabolomics data with fold change (>2 or <0.5) and variable importance of projection scores ≥1 revealed statistically significant metabolites comparing samples from women with and without . Metabolite profiles in patients with differed from the comparison group in energy, lipid and amino acid metabolites reflecting heightened oxidative stress, inflammation, and tryptophan degradation in patients with . Study results may contribute to further identification of unique metabolomic profiles enhancing understanding of the pathophysiology of and for the development of effective therapeutic options.
  • 2.

    【2hr】Assessment of Patient Knowledge and Perceptions of Pharmacogenomics Before and After Using a Mock Results Patient Web Portal

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    机译 在使用模拟结果前后评估患者的知识和药物基因组学知识
    摘要：Our objective was to build a mock pharmacogenomic ( x) patient portal and assess its ability to disseminate test results and information to patients. The Your x Portal delivered four sample x results (omeprazole, simvastatin, clopidogrel, and codeine). We hosted two study groups to assess patient knowledge and perceptions of x before and after accessing the portal. Ten x‐tested and 10 traditional care participants were included (average 61 years, 60% women, 50% African American, and 55% had a bachelor's/advanced degree). Participants scored significantly higher on the post‐test compared with the pre‐test, with no significant differences between baseline scores or score change between the groups. Patient perceptions also improved after accessing the portal—more patients wanted their providers to have access to test results, and more patients would encourage family/friends to get x testing. Patients would share their test results with their healthcare providers, spouse/partner, and family; none would share results with their friends or social media. Almost all patients (95%) said the portal was easy to use and 65% said it was easy to understand. In this pilot study, patients’ knowledge and perceptions of x improved after accessing the Your x Portal.
  • 3.

    【2hr】An Innovative Disease‐Drug‐Trial Framework to Guide Binge Eating Disorder Drug Development: A Case Study for Topiramate

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    机译 指导暴食症药物开发的创新疾病药物试验框架：托吡酯的案例研究
    摘要：As with other psychiatric disorders, development of drugs to treat binge‐eating disorder ( ) has been hampered by high placebo response and dropout rates in randomized controlled trials ( s). Although not approved for use in , several s have suggested that topiramate is efficacious for in obese individuals. Using data from a positive investigator‐initiated of topiramate in 61 obese individuals with , the objective of the present study is (i) to develop a quantitative disease‐drug‐trial framework to inform future clinical trial designs, and (ii) to determine the optimal topiramate dose to achieve therapeutic efficacy. Disease‐drug‐trial models were developed separately for the two efficacy measures, namely, longitudinal normalized weekly binge‐eating episode frequency ( ) and binge day frequency ( ). Model building consisted of (i) developing a placebo effect model that describes response from the placebo group, (ii) adding a drug effect to the placebo model to describe dose‐response relationships, and (iii) developing a parametric time to event model to characterize patient dropout patterns. The placebo effect on normalized and over time demonstrated a maximum decrease of ~ 57% by 5 weeks. Participants had a higher dropout probability if no weight loss occurred during the trial period. The identified dose‐response relationship demonstrated a daily dose of 125 mg was needed to exhibit a marked reduction in weekly . The developed comprehensive disease‐drug‐trial model will be utilized to simulate different clinical trial designs to increase the success for future drug development programs.
  • 4.

    【2hr】Development of an Integrated Platform Using Multidisciplinary Real‐World Data to Facilitate Biomarker Discovery for Medical Products

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    机译 利用多学科真实世界数据开发集成平台，以促进医疗产品生物标志物的发现
    摘要：Translational multidisciplinary research is important for the Center for Devices and Radiological Health's efforts for utilizing real‐world data ( ) to enhance predictive evaluation of medical device performance in patient subpopulations. As part of our efforts for developing new ‐based evidentiary approaches, including discovery of device‐related risk predictors and biomarkers, this study aims to characterize the sex/race‐related trends in hip replacement outcomes and identify corresponding candidate single nucleotide polymorphisms (SNPs). Adverse outcomes were assessed by deriving from a retrospective analysis of hip replacement hospital discharge data from the National Inpatient Sample ( ). Candidate s were explored using pre‐existing data from the Personalized Medicine Research Project ( ). High‐Performance Integrated Virtual Environment was used for analyzing and visualizing putative associations between s and adverse outcomes. Ingenuity Pathway Analysis ( ) was used for exploring plausibility of the sex‐related candidate s and characterizing gene networks associated with the variants of interest. The ‐based epidemiologic evidence showed that periprosthetic osteolysis ( ) was most prevalent among white men. The ‐based genetic evidence associated the ‐related male predominance with rs7121 (odds ratio = 4.89; 95% confidence interval = 1.41−17.05) and other candidate s. ‐based analysis of the expected gene expression alterations and corresponding signaling pathways suggested possible role of sex‐related metabolic factors in development of , which was substantiated by epidemiologic analysis identifying the sex‐related differences in metabolic comorbidities in men vs. women with hip replacement‐related . Thus, our study illustrates ‐based evidentiary approaches that may facilitate cost/time‐efficient discovery of biomarkers for informing use of medical products.
  • 5.

    【2hr】Relationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration

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    机译 别嘌呤醇剂量，氧嘌呤醇浓度与降低尿酸盐反应之间的关系-寻找最小有效氧嘌呤醇浓度
    摘要：The aims of this study were to determine factors that predict serum urate ( ) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24‐month open, randomized, controlled, parallel‐group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic ( ) curves were used to identify a minimum oxypurinol concentration predictive of P = 0.023), creatinine clearance (Cr ;  = 0.037), Q141K (  = 0.019), and (  = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 μmol/L, but predictive accuracy was poor ( curve area under the curve ( ) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on Cr and cannot reliably predict SU target. Other variables, including 2 Q141K genotype, impact on sensitivity to allopurinol ( 12611000845932).
  • 6.

    【2hr】Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

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    机译 将CYP2D6基因型标准化为表型翻译：临床药物遗传学实施联合会和荷兰药物遗传学工作组的共识性建议
    摘要：Translating genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium ( ) and the Dutch Pharmacogenetics Working Group ( ). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified‐Delphi method was used to obtain consensus for a uniform system for translating genotype to phenotype among a panel of international 2D6 experts. Experts with diverse involvement in 2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers;  = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the 2D6 experts agreeing to the final genotype to phenotype translation method. Broad adoption of the proposed genotype to phenotype translation method by guideline developers, such as and , and clinical laboratories as well as researchers will result in more consistent interpretation of genotype.
  • 7.

    【2hr】Comparing Model Performance in Characterizing the PK/PD of the Anti‐Myostatin Antibody Domagrozumab

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    机译 比较模型性能表征抗Myostatin抗体Domagrozumab的PK / PD
    摘要：
  • 8.

    【2hr】Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

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    机译 代谢组学分析，以鉴定细胞对甲氨蝶呤的体外反应的分子生物标志物
    摘要：Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.
  • 9.

    【2hr】Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

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    机译 CYP2D6结构变异等位基因的询问改善了CYP2D6基因型与CYP2D6介导的代谢活性之间的相关性
    摘要：
  • 10.

    【2hr】Population Pharmacokinetic/Pharmacodynamic Analysis of Intravenous Zanamivir in Healthy Adults and Hospitalized Adult and Pediatric Subjects With Influenza

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    机译 扎那米韦在健康成年人以及住院的成人和小儿流感患者中的人群药代动力学/药效学分析
    摘要：Zanamivir is a potent and highly selective inhibitor of influenza neuraminidase in which the inhibition of this enzyme prevents the virus from infecting other cells and specifically prevents release of the new virion from the host cell membrane. It is available as an oral powder for inhalation and intravenous formulations. The current population pharmacokinetic model based on data from eight studies of subjects treated with the intravenous formulation (125 healthy adults and 533 hospitalized adult and pediatric subjects with suspected or confirmed influenza) suggested a decreased zanamivir clearance in pediatric and renal impairment adult subjects. It also indicates that b.i.d. dosing is necessary to keep the exposure in influenza infected subjects above the 90% inhibitory concentration values of recently circulating viruses over the dosing interval. In the exposure‐response analysis (phases and studies), no apparent relationship was found between zanamivir exposure and clinically relevant pharmacodynamic end points.
  • 11.

    【2hr】Identification of Susceptibility Genes to Allergic Rhinitis by Gene Expression Data Sets

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    机译 通过基因表达数据集鉴定过敏性鼻炎的易感基因
    摘要：As an extremely prevalent disease worldwide, allergic rhinitis ( ) is a condition characterized by chronic inflammation of the nasal mucosa. To identify the finer molecular mechanisms associated with the susceptibility genes, differentially expressed genes ( s) in were investigated. The expression and clinical data of the 19187 data set were used for weighted gene co‐expression network analysis ( ). After the modules related to had been screened, the genes in the module were extracted for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes ( ) pathway enrichment analysis, whereby the genes enriched in the pathway were regarded as the pathway‐genes. The s in patients with were subsequently screened out from 19187, and the sensitive genes were identified in 18574 in connection with the allergen challenge. Two kinds of genes were compared with the pathway‐genes in order to screen the susceptibility genes. Receiver operating characteristic ( ) curve was plotted to evaluate the capability of the susceptibility genes to distinguish the state. Based on the in the 19187 data set, 10 co‐expression network modules were identified. The correlation analyses revealed that the yellow module was positively correlated with the disease state of . A total of 89 genes were found to be involved in the enrichment of the yellow module pathway. Four genes ( , , , and ) were upregulated in and sensitive to allergen challenge, whose potentials were further confirmed by curve. Taken together, , , , and are susceptibility genes to .
  • 12.

    【2hr】Prognostic Significance of Preoperative Systemic Cellular Inflammatory Markers in Gliomas: A Systematic Review and Meta‐Analysis

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    机译 胶质瘤术前系统性细胞炎性标志物的预后意义：系统评价和荟萃分析
    摘要：
  • 13.

    【2hr】Real‐Time and Wireless Assessment of Adherence to Antiretroviral Therapy With Co‐Encapsulated Ingestion Sensor in HIV‐Infected Patients: A Pilot Study

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    机译 艾滋病毒感染患者实时和无线评估抗逆转录病毒疗法的依从性与联合封装摄入传感器的一致性
    摘要：Adherence with antiretroviral therapy is important for preventing disease progression and transmission. The co‐encapsulated pill sensor system sends a signal through a cutaneous patch and allows real‐time monitoring of pill ingestion. A 16‐week pilot study used a sensor system in 15 ‐infected individuals with real‐time monitoring of pill‐taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow‐up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co‐encapsulated pills were “unable to take” or “poorly tolerated.” At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10–15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures.
  • 14.

    【2hr】Effect of Genetic and Nongenetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure

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    机译 遗传和非遗传因素对埃及心力衰竭患者盐皮质激素受体拮抗剂治疗临床反应的影响
    摘要：This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction ( ). Genotype frequencies for rs699 were:  = 16%,  = 48%, and  = 36%. Frequencies for rs1799998 were:  = 33%,  = 50%, and  = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction ( ) differed by rs699 ( , 14.6%; , 7.9%; , 2.7%;  = 2.1E‐26), and rs1799998 ( , 9.1%; , 8.7%; , 1.4%;  = 0.0006) genotypes. Multivariate linear regression showed that the rs699 and rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in improvement (  = 0.001), 63% of variability in serum potassium increase (  = 2.25E‐08), and 39% of the variability in improvement in quality of life (  = 2.3E‐04) with spironolactone therapy. These data suggest that and genotypes as well as baseline serum K are predictors of spironolactone response in .
  • 15.

    【2hr】Target‐Mediated Drug Disposition Pharmacokinetic/Pharmacodynamic Model‐Informed Dose Selection for the First‐in‐Human Study of AVB‐S6‐500

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    机译 针对AVB-S6-500的首次人体研究的靶点介导的药物处置药代动力学/药效学模型告知的剂量选择
    摘要：AVB‐S6‐500 neutralized growth arrest‐specific 6 (GAS6) protein and effectively inhibited AXL signaling in preclinical cancer models. A target‐mediated drug disposition (TMDD) pharmacokinetic/pharmacodynamic (PK/PD) model was used to select first‐in‐human (FIH) doses for AVB‐S6‐500 based on predicted target (GAS6) suppression in the clinic. The effect of TMDD on AVB‐S6‐500 clearance was incorporated into a standard two‐compartment model, providing parallel linear and nonlinear clearance. Observed AVB‐S6‐500 and GAS6 concentration data in cynomolgus monkeys and relevant interspecies differences were used to predict the PK (serum concentration)/PD (GAS6 suppression) relationship in humans. Human exposure and GAS6 suppression were simulated for the proposed FIH doses of 1, 2.5, 5, and 10 mg/kg. A dose of 1 mg/kg was selected to target GAS6 suppression for 2 weeks in the initial healthy volunteer study. The cynomolgus monkey:human ratios for the highest proposed FIH dose were anticipated to yield more than a 10‐fold margin to the nonclinical no observed adverse event level while maintaining > 90% GAS6 suppression. In human subjects, the first dose (1 mg/kg) model‐projected and clinically observed maximal concentration (C ) was within 10% of predicted; repeat dosing at 5 mg/kg was within 1% (C ) and 45% (area under the serum concentration‐time curve from time 0 to end of dosing interval) of predicted. Predicted GAS6 suppression duration of 14 days was accurate for the 1 mg/kg dose. A PK/PD model expedited clinical development of AVB‐S6‐500, minimized exposure of patients with cancer to subtherapeutic doses, and rationally guided the optimal dosing in patients.
  • 16.

    【2hr】Medicine and Media: The Ranitidine Debate

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    机译 医学与媒体：雷尼替丁辩论
    摘要：Ranitidine has been the topic of recent media reports. Current findings, confirmed by the US Food and Drug Administration, indicate that some ranitidine products contain a substance that may be carcinogenic. Providers and patients require additional information on the risks of continuing therapy vs. the benefits of the medication. This article comments on what is currently known about the evolving situation of elevated N‐nitrosodimethylamine levels in ranitidine and the limits of the existing information to assess best practices.
  • 17.

    【2hr】US, EU, and Japanese Regulatory Guidelines for Development of Drugs for Treatment of Alzheimer’s Disease: Implications for Global Drug Development

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    机译 美国，欧盟和日本开发用于治疗阿尔茨海默氏病的药物的监管指南：对全球药物开发的启示
    摘要：Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer’s disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.
  • 18.

    【2hr】Open Data Revolution in Clinical Research: Opportunities and Challenges

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    机译 临床研究中的开放数据革命：机遇与挑战
    摘要：Efforts for sharing individual clinical data are gaining momentum due to a heightened recognition that integrated data sets can catalyze biomedical discoveries and drug development. Among the benefits are the fact that data sharing can help generate and investigate new research hypothesis beyond those explored in the original study. Despite several accomplishments establishing public systems and guidance for data sharing in clinical trials, this practice is not the norm. Among the reasons are ethical challenges, such as privacy of individuals, data ownership, and control. This paper creates awareness of the potential benefits and challenges of sharing individual clinical data, how to overcome these challenges, and how as a clinical pharmacology community we can shape future directions in this field.
  • 19.

    【2hr】Clinical Trial Generalizability Assessment in the Big Data Era: A Review

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    机译 大数据时代的临床试验通用性评估：综述
    摘要：Clinical studies, especially randomized, controlled trials, are essential for generating evidence for clinical practice. However, generalizability is a long‐standing concern when applying trial results to real‐world patients. Generalizability assessment is thus important, nevertheless, not consistently practiced. We performed a systematic review to understand the practice of generalizability assessment. We identified 187 relevant articles and systematically organized these studies in a taxonomy with three dimensions: (i) data availability (i.e., before or after trial ( vs. generalizability)); (ii) result outputs (i.e., score vs. nonscore); and (iii) populations of interest. We further reported disease areas, underrepresented subgroups, and types of data used to profile target populations. We observed an increasing trend of generalizability assessments, but a priori generalizability can be assessed using only study design information (primarily eligibility criteria), it gives investigators a golden opportunity to adjust the study design before the trial starts. Nevertheless, a priori generalizability. With the wide adoption of electronic health records systems, rich real‐world patient databases are increasingly available for generalizability assessment; however, informatics tools are lacking to support the adoption of generalizability assessment practice.
  • 20.

    【2hr】Approach to High Volume Enrollment in Clinical Research: Experiences from an All of Us Research Program Site

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    机译 大量招募临床研究的方法：美国所有人研究计划网站的经验
    摘要：Clinical trials and cohort studies are required to meet target recruitment of study participants within stipulated timelines, especially when the priority is to include populations traditionally unrepresented in biomedical research. By the third quarter of 2019, the University of Arizona‐Banner Health Provider Organization (UA‐Banner HPO) has enrolled > 30,000 core participants into the Research Program ( ), the research cohort of the Precision Medicine Initiative. The majority of enrolled participants meet the criteria for individuals under‐represented in biomedical research. The enrollment goals were calculated based on a target of 20,000 as set by the National Institutes of Health and our health provider organization achieved enrollment numbers between 17% and 86% above the targeted daily enrollment. We evaluated enrollment methods and challenges to enrollments encountered by the UA‐Banner Health Provider Organization into the . Challenges to enrollment centered around the need for high‐touch engagement methods, time investment necessary for stakeholder inclusion, and the use of purely digital enrollment methods especially in populations under‐represented in biomedical research. These challenges occurred at the level of the individual, provider, institutions, and community, and cumulatively impacted participant enrollment. Successful strategies for engagement and enrollment leveraged provider partners as advocates for the program. For high‐volume enrollment in clinical research, it is important to engage leaders in the healthcare setting, patient providers, and tailor engagement and enrollment to potential participant needs. We emphasize the need for precision engagement and enrollment methods tailored to individual needs.
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