Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

Exposure–response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults

The aim of the study was to evaluate the exposure–response (E–R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E–R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E–R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.     

注射用血栓通中三七元素迁移的规律

目的:分析注射用血栓通中三七从原料到成品全过程的元素迁移规律,以便更好地控制成品中元素杂质。方法:采用ICP-MS法全面分析三七药材、三七总皂苷(中间体)和注射用血栓通中21种元素的含量。结果:21种元素的标准曲线相关系数r均在0. 999以上,回收率在92. 71%～107. 07%之间,RSD均在5%以内。三七药材中铝、铁含量较高,铅、砷、汞、镉、铜符合中华人民共和国药典的相关规定,三七总皂苷(中间体)和注射用血栓通中多数元素均未检出或含量极低。结论:注射用血栓通的提取工艺可有效去除三七中大部分元素,重金属及有害元素也降到较低水平。