Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment—A case study of troglitazone

In vitro to in vivo extrapolation (IVIVE) for next-generation risk assessment (NGRA) of chemicals requires computational modeling and faces unique challenges. Using mitochondria-related toxicity data of troglitazone (TGZ), a prototype drug known for liver toxicity, from HepaRG, HepG2, HC-04, and primary human hepatocytes, we explored inherent uncertainties in IVIVE, including cell models, cellular response endpoints, and dose metrics. A human population physiologically-based pharmacokinetic (PBPK) model for TGZ was developed to predict in vivo doses from in vitro point-of-departure (POD) concentrations. Compared to the 200–800 mg/d dose range of TGZ where liver injury was observed clinically, the predicted POD doses for the mean and top one percentile of the PBPK population were 28–372 and 15–178 mg/d respectively based on C_max dosimetry, and 185–2552 and 83–1010 mg/d respectively based on AUC. In conclusion, although with many uncertainties, integrating in vitro assays and PBPK modeling is promising in informing liver toxicity-inducing TGZ doses.     

99mTc-DTPA核素肾动态显像评价主动脉夹层患者术后肾功能受损研究

目的:应用99mTc-DTPA肾动脉显像评价Stanford不同分型主动脉夹层患者术后左、右侧肾功能及总体肾功能受损程度,帮助临床制定进一步的治疗方案,改善患者预后。方法:回顾性分析2018年3月8日至2019年7月19日,在本院核医学科行99mTc-DTPA肾动态显像的主动脉夹层术后患者48例,评价患者双肾血流灌注、总肾小球滤过率(GFR)和分肾的GFR,比较Stanford主动脉夹层A型(简称A型)患者和主动脉夹层B型(简称B型)患者之间总肾功能及分肾功能,血肌酐、血尿素氮及血尿酸水平的差异。结果:B型患者术后总GFR低于A型患者(67.5 vs.80.6 m L/min,P<0.05),其中以左肾功能受损为著(30.9 vs.40.3 m L/min,P<0.05),差异有统计学意义。结论:肾动态显像对主动脉夹层术后患者早期评价肾功能有重要价值。主动脉夹层B型患者GFR较A型减低,且左侧肾GFR减低更明显,临床可以早期采取干预措施,改善主动脉夹层患者预后。     

去肾交感神经术治疗难治性高血压

难治性高血压(resistant hypertension, RH)是指在改善生活方式基础上应用可耐受的足够剂量且合理的3种降压药物(包括一种噻嗪类利尿剂)治疗至少4周后, 诊室和诊室外(包括家庭血压或动态血压监测)血压值仍在目标水平之上, 或至少需要4种降压药物才能使血压达标, 目前尚缺乏有效的治疗方案。去肾交感神经术(renal sympathetic denervation, RDN)作为RH的一种治疗手段, 在病理生理机制上已被基础实验证实。早期Ⅰ代RDN的临床试验结果并不统一, Ⅱ代RDN改进了消融技术并在最近的高血压临床试验应用中得到了阳性结论, 同时RDN用于治疗其他疾病的临床试验也产生了阳性结果。但由于目前尚无对肾交感神经活动的具体评估方法, 无法准确筛选出适宜行RDN的人群, 故其临床应用仍存在争议。     

Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitisation potency. Part 2. The biological variability of the murine Local Lymph Node Assay (LLNA) for skin sensitisation

The Local Lymph Node Assay (LLNA) is the most common in vivo regulatory toxicology test for skin sensitisation, quantifying potency as the EC3, the concentration of chemical giving a threefold increase in thymidine uptake in the local lymph node. Existing LLNA data can, along with clinical data, provide useful comparator information on the potency of sensitisers. Understanding of the biological variability of data from LLNA studies is important for those developing non-animal based risk assessment approaches for skin allergy. Here an existing set of 94 EC3 values for 12 chemicals, all tested at least three times in the same vehicle have been analysed by calculating standard deviations (SD) for logEC3 values. The SDs range from 0.08 to 0.22. The overall SD for the 94 logEC3 values is 0.147. Thus the 95% confidence limits (2xSD) for LLNA EC3 values are within a factor of 2, comparable to those for physico-chemical measurements such as partition coefficients and solubility. The residual SDs of Quantitative Mechanistic Models (QMMs) based on physical organic chemistry parameters are similar to the overall SD of the LLNA, indicating that QMMs of this type are unlikely to be bettered for predictive accuracy.     

Comparison between a new platelet count drop method PL-11, light transmission aggregometry,VerifyNow aspirin system and thromboelastography for monitoring short-term aspirin effects in healthy individuals

Platelet function has been described by many laboratory assays, and PL-11 is a new point-of-care platelet function analyzer based on platelet count drop method, which counts platelet before and after the addition of agonists in the citrated whole blood samples. The present study sought to compare PL-11 with other three major more established assays, light transmission aggregometry (LTA), VerifyNow? aspirin system and thromboelastography (TEG), for monitoring the short-term aspirin responses in healthy individuals. Ten healthy young men took 100?mg/d aspirin for 3-day treatment. Platelet function was measured via PL-11, LTA, VerifyNow and TEG, respectively. The blood samples were collected at baseline, 2 hour, 1 day during the aspirin treatment and 1 day, 5?±?1 days, 8?±?1 days after the aspirin withdrawal. Moreover, 90 additional healthy subjects were recruited to establish a reference range for PL-11. Platelet function of healthy subjects decreased significantly 2 hours after 100?mg/d aspirin intake and began to recover during 4–6 days after the aspirin withdrawal. Correlations between methods were PL-11 vs. LTA (r?=?0.614, p?<?0.01); PL-11 vs. VerifyNow (r?=?0.829, p?<?0.01); PL-11 vs. TEG (r?=?0.697, p?<?0.001). There was no significant bias between PL-11 and LTA at baseline (bias?=?1.94%, p?=?0.804) using Bland-Altman analysis, while the data of PL-11 were significantly higher than LTA (bias?=?24.02%, p?<?0.001) during the aspirin therapy. The reference range for PL-11 in healthy young individuals was from 66.8 to 90.5% (95%CI). When aspirin low-responsiveness was defined as LTA?>?20%, the cut-off values for each method were, respectively: PL-11?>?50%, VerifyNow?>?533 ARU, TEG?>?60.2%. The results of different platelet function assays were uninterchangeable for monitoring aspirin response and correlations among them were also varied. Correlations among PL-11 and other three major assays suggested the ability of PL-11 to assess the treatment effects of aspirin. But a large cohort study is needed to confirm the cut-off value of aspirin response detected by PL-11.