Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.     

The transactional model of stress and coping as guidance for understanding adolescent patients' experience with thalassemia: Case report

Purpose : This case report investigated the transactional model of stress and coping as guidance for nursing care of an adolescent patient with thalassemia. Sources Used : A case study of a 15‐year‐old female patient with β‐thalassemia major. Data were collected using patient medical records, an interview with the patient and physical examination. Results : Four issues related to coping were isolated: Worsening physical symptoms; psychosocial consequences, coping process, and building supportive networks. These issues and the patient's adaption are explored via the transactional model. Conclusions : Having thalassemia was cognitively appraised by the patient as a stressful and taxing situation with detrimental consequences, such as changes in physical appearance, stigmatization, and depression. Nurses should evaluate each patient's physical and psychosocial needs, utilizing appropriate theoretical models for designing a suitable care plan. As the case study demonstrates, the transactional model was an effective guide for nurses in planning care of an adolescent patient with thalassemia.     

胰腺囊性肿瘤恶性风险预测模型研究

目的 明确与恶性胰腺囊性肿瘤（PCN）相关的术前危险因素，建立准确的预测模型，并予以验证。方法 纳入2013年1月至2020年5月复旦大学附属华东医院经术后病理检查证实的114例PCN病例，分为模型组（n=80）和验证组（n=34）。回顾性分析模型组术前的临床资料并探索与恶性PCN相关的影响因素，建立PCN恶性风险预测模型，绘制受试者工作特征（ROC）曲线和校正曲线评价模型，最后基于验证组数据对模型进行临床验证。结果 单因素回归分析提示临床症状、CA19-9水平升高、中性粒细胞淋巴细胞比值（NLR）、淋巴细胞单核细胞比值（LMR）、肿瘤最大直径、胰管扩张和实性成分与恶性PCN显著相关，进一步行多因素回归分析确定了NLR≥2.146、CA19-9水平升高、胰管扩张是恶性PCN的独立预测因素。基于多因素回归分析结果建立恶性PCN预测模型，绘制模型的ROC曲线，计算AUC为0.921（95%CI 0.863~0.979），Youden指数最大时取得最佳临界预测值为0.203，此时相对应的特异度为83.3%，敏感度为92.9%，准确率为85%。同时校正曲线显示模型具有较好的拟合度，最后代入验证组数据显示模型预测准确率为82.4%，特异度81.2%，敏感度100%。结论 CA19-9水平升高、NLR升高以及胰管扩张是恶性PCN的高危因素，基于此建立的恶性胰腺囊性肿瘤的预测模型具有较好的准确率，可为今后的临床诊疗提供辅助参考。     

Model-assisted estimators for time-to-event data from complex surveys

We develop model-assisted estimators for complex survey data for the proportion of a population that experienced some event by a specified time t. Theory for the new estimators uses time-to-event models as the underlying framework but have both good model-based and design-based properties. The estimators are compared in a simulation to traditional survey estimation methods and are also applied to a study of nurses' health. The new estimators take advantage of covariates predictive of the event and reduce standard errors compared to conventional alternatives.     

基于药动学与药效学相关联的养阴通脑颗粒主要有效部位正交配伍研究

目的探讨养阴通脑颗粒主要有效部位(总生物碱、总黄酮、总皂苷、总酚酸)配伍后在脑缺血再灌注模型大鼠体内药物浓度及其药动学与药效学变化。方法采用正交试验法组成上述主要有效部位用量配比不同的9个组方,供脑缺血再灌注模型大鼠ig给药,高效液相色谱-二极管阵列检测器(HPLC-DAD)测定不同时间点血浆中的葛根素、阿魏酸和川芎嗪血浆药物浓度。DAS 3.2.6软件以非房室模型拟合药动学参数,并运用总量统计矩法和综合评分法对整体药动学特征进行评价。同时采用酶联免疫吸附测定(ELISA)法测定大鼠血浆中超氧化物歧化酶(SOD)和过氧化氢酶(CAT)的含量。最后进行药动学-药效学(PK-PD)模型研究,获得各药物浓度与药效之间的定量方程。结果葛根素、阿魏酸和川芎嗪在模型大鼠体内的药动学特征有所差异。总量统计矩和综合评分研究表明不同配伍对总量零阶矩、总量平均滞留时间、综合评分等参数影响不一。主要有效部位正交配伍给药后,一定程度上会抑制脑缺血再灌注大鼠血浆中SOD和CAT的降低。各PK-PD模型均采用Sigmoid-Emax模型,拟合结果与实测数据之间相关性良好,R值均大于0.85。结论养阴通脑颗粒主要有效部位配伍对模型大鼠体内的药动学行为和抗氧化指标具有一定影响;中药复方多成分药物代谢动力学可采用总量统计矩和综合评分法进行研究;PK-PD结合模型可用于中药复方多成分药动学与药效学之间相关性的评价与预测。     

Understanding and adjusting for the selection bias from a proof-of-concept study to a more confirmatory study

It has long been noticed that the efficacy observed in small early phase studies is generally better than that observed in later larger studies. Historically, the inflation of the efficacy results from early proof-of-concept studies is either ignored, or adjusted empirically using a frequentist or Bayesian approach. In this article, we systematically explained the underlying reason for the inflation of efficacy results in small early phase studies from the perspectives of measurement error models and selection bias. A systematic method was built to adjust the early phase study results from both frequentist and Bayesian perspectives. A hierarchical model was proposed to estimate the distribution of the efficacy for a portfolio of compounds, which can serve as the prior distribution for the Bayesian approach. We showed through theory that the systematic adjustment provides an unbiased estimator for the true mean efficacy for a portfolio of compounds. The adjustment was applied to paired data for the efficacy in early small and later larger studies for a set of compounds in diabetes and immunology. After the adjustment, the bias in the early phase small studies seems to be diminished.     

Progressive rehabilitation of the sprained ankle: A novel treatment method

ObjectivesThis randomised, single blinded cohort study was designed to assess the immediate effect of manual fascial manipulation on walking pain and the range of ankle dorsiflexion within the first 4 days after ankle trauma.MethodsMeasurements were taken from 19 subjects, 5 female and 14 male, who presented with grade I–III ankle sprains. Ankle dorsiflexion was photographed in a standardised position and calculated by means of the Dartfish® Advanced Video Analysis Software and SPSS® (version 17) was used to compare the pre- and post-treatment data.ResultsAfter one treatment session 13 of the 19 subjects were walking pain free and 3 of the 19 where walking with only little pain. The highly significant (p < 0.001) mean improvement of ankle dorsiflexion was 7.9° (±5.8°). All, apart from one subject, whom were walking pain free after treatment showed a minimum of 4° increased dorsiflexion.ConclusionEarly fascia work around the injured ankle improves ankle dorsiflexion and reduces walking pain. It may reduce the delay of tissue healing and, thus, optimise further rehabilitation of the sprained ankle which may also reduce socio-economic costs.