In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

老年轻度认知障碍患者血清瘦素、甲状腺激素水平与局部脑血流量关系的研究

目的 通过检测老年轻度认知障碍（MCI）患者血清瘦素（LEP）、甲状腺激素水平，分析其与局部脑血流量（rCBF）的关系。方法 选择本院收治的128 例老年MCI 患者，另选健康者128 例作为对照组。检测血清LEP、甲状腺激素、大脑各区域rCBF 水平并分析其相关性。结果 老年MCI 组患者左右侧额叶、右侧颞叶、左侧顶叶、左右侧基底节区域脑血流量[（43.81±8.62）mL/（100 g·min）、（43.24±7.93）mL/（100 g·min）、（45.14±6.98）mL/（100 g·min）、（45.86±6.77）mL/（100 g·min）、（67.95±8.52）mL/（100 g·min）、（68.36±8.34）mL/（100 g·min）]低于对照组[（46.39±8.31）mL/（100 g·min）、（46.52±8.56）mL/（100 g·min）、（47.37±7.04）mL/（100 g·min）、（48.25±6.98）mL/（100 g·min）、（70.34±8.96）mL/（100 g·min）、（70.58±8.57）mL/（100 g·min）]（P＜0.05）。老年MCI 组患者血清LEP、T3、FT3 水平[（4.87±1.56）μg/L、（1.21±0.16）nmol/L、（3.04±0.36）pmol/L]低于对照组[（11.45±3.92）μg/L、（1.68±0.21）nmol/L、（4.82±1.21）pmol/L]（P＜0.05），TSH 水平为（2.78±0.75）IU/mL，高于对照组的（1.13±0.38）IU/mL（P＜0.05）。老年MCI 患者血清LEP 水平与左侧额叶、右侧颞叶、左侧顶叶rCBF 呈正相关（r=0.452、0.537、0.544，P 均＜0.05），T3 水平与左侧额叶、右侧颞叶rCBF 呈正相关（r=0.427、0.521，P 均＜0.05），FT3 水平与右侧颞叶rCBF 呈正相关（r=0.492，P＜0.05），TSH 水平与左侧额叶、右侧颞叶rCBF 呈负相关（r=-0.463、-0.489，P 均＜0.05）。结论 老年MCI 患者血清中LEP、T3、FT3 水平降低，TSH 水平升高，且与不同区域rCBF 有相关性，可通过调控脑血管功能影响rCBF 变化水平。     

Contextualizing the lived experience of quality of life for persons with spinal cord injury: A mixed-methods application of the response shift model

Objective: The objective of this study was to gain greater insight into individuals’ quality of life (QOL) definitions, appraisals, and adaptations following spinal cord injury (SCI).

Design: A mixed-methods design, applying the Schwartz and Sprangers response shift (RS) model. RS is a cognitive process wherein, in response to a change in health status, individuals change internal standards, values, or conceptualization of QOL

Setting: Community-dwelling participants who receive medical treatment at a major Midwestern medical system and nearby Veterans’ Affairs hospital.

Participants: A purposive sample of participants with SCI (N?=?40) completed semi-structured interviews and accompanying quantitative measures.

Interventions: Not applicable.

Outcome Measures: Qualitative data were analyzed using content analysis to identify themes. Analysis of variance were performed to detect differences based on themes and QOL, well-being, and demographic and injury characteristics.

Results: Four RS themes were identified, capturing the range of participant perceptions of QOL. The themes ranged from complete RS, indicating active engagement in maintaining QOL, to awareness and comparisons redefining QOL, to a relative lack of RS. Average QOL ratings differed as a function of response shift themes. PROMIS Global Health, Anxiety, and Depression also differed as a function of RS themes.

Conclusion: The RS model contextualizes differences in QOL definitions, appraisals, and adaptations in a way standardized QOL measures alone do not.     

黄芪活血功效及现代药理学研究进展

黄芪始载于《神农本草经》,有补气升阳、益卫固表,利水消肿,托毒生肌之效。被誉为补气健脾之要药,临床上常用于气虚乏力、脾虚泄泻等疾病,已为医者所熟知。近年来,研究学者围绕其补气、健脾、利水功效机制已有较全面的认识。然陶弘景在《本草经集注》首载黄芪"逐五脏间恶血",表明本品兼有活血作用。目前,对于本品活血作用机制阐释,中医常基于"补气活血""气行血行"理论进行论证,但并不等同于本品无活血作用。通过梳理历代本草文献中对黄芪的记载,发现其活血作用应用广泛。综合传统方剂与现代方剂中有关其活血作用的应用,本品在方中行活血通络、活血利水、活血扶正作用,尤能体现其活血作用。且现代药理学研究在有关瘀血病理指标的分子机制中,黄芪有很好的调控作用,表明黄芪有活血作用,但未深入探究,存在研究价值。该文从历代文献对黄芪活血功效的论述、黄芪活血作用的临床应用及现代药理学研究深入探讨其活血作用机制,以期扩展黄芪的临床应用范围,为临床治疗提供理论指导。     

SI和DBP对女性产后出血的风险预测效果

目的考察休克指数(shock index,SI)和舒张压(diastolic blood pressure,DBP)对女性产后出血的风险预测效果。方法选取2016年1月～2018年12月在我院行产检并分娩的320例产后出血孕妇作为研究组,另外选取同期进行正常分娩的健康孕妇240例作为对照组,比较两组患者的一般临床资料、血红蛋白(hemoglobin,Hb)、舒张压(diastolic blood pressure,DBP)、收缩压(systolic blood pressure,SBP)、心率(heart rate,HR)及休克指数(shock index,SI),并采用Ordinal逻辑回归分析各参数对产后出血的风险预警。结果两组患者在年龄、孕周、BMI及新生儿体重相比,差异无统计学意义(P0.05),而孕次相比,差异具有统计学意义(P0.05);与对照组产后24 h相比,研究组产后24 h患者的DBP、SBP及Hb均显著降低,而HR和SI显著升高(P0.05);与对照组产前相比,产后24 h患者的SBP、HR及SI显著降低(P0.05);与研究组产前相比,产后24 h患者的DBP、SBP、HR及Hb均显著降低,而SI显著升高,差异具有统计学意义(P0.05);Ordinal逻辑回归分析结果显示,休克指数和舒张压对产后出血具有预警作用(P0.05)。结论休克指数和舒张压可作为评估女性产后出血的风险预测指标,临床应密切监护。     

从“血不利则为水”探讨乳腺癌相关淋巴水肿

导致血不利的原因一是不足,即由于气、血、津、液等物质的缺乏致无源行血;一是不通,即水、湿、痰、饮、瘀、食积、火郁、内风、外伤等病理因素阻滞,致血行不畅。血瘀经脉之内,则水亦瘀积脉中,致脉络胀满,形成水肿。乳腺癌术后患者,金刃本已损伤血脉,术后的放疗、化疗又属祛邪之法,故机体元气受损,气虚无力行血,血运行不畅,导致患侧上肢水肿。故治疗乳腺癌相关淋巴水肿时,应当血水同治,即活血利水之法要贯穿始终。先病血而后病水者,可以活血化瘀为主,利水为辅;先病水后病血者,则以利水消肿为主,酌加活血养血之品。但需要注意的是:①临证时切不可拘泥于单纯的活血利水法,而忽视乳腺癌相关淋巴水肿(breast cancer related lymphedema,BCRL)患者机体本身的状况。②临证勿忽视五脏与血、水的关系,以及肺、脾、肾、三焦与水肿的内在关系。③可多种方法联合运用,审证求因,标本同治。BCRL术后宜补气活血,通脉利水;术后兼化疗者可疏肝健脾、利水消肿;早期可在活血利水基础上,侧重利湿消肿,后期多湿聚为痰,治疗侧重化痰软坚。