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.     

Do painters need their whole brain to excel?

ABSTRACT

Skilled professional artists are sometimes able to maintain their talents while other cognitive functions deteriorate due to brain diseases. The objective of this study is to asses the preserved artistry of a professional painter in spite of the presence of strokes affecting brain areas implicated in art expression. She had a neurologic evaluation and brain imaging after the stroke; painter-curators analyzed and compared the painter’s pictorial artwork created before and after the stroke. In spite of cerebellar, visuospatial, motor, cognitive, and functional deficits likely related to strokes affecting bilateral cerebellar, left occipital, and right temporal-occipital areas, the patient was able to maintain most of their artistic painting skills.. After a short period of functional recovery, our patient showed discrepancy among their impaired cerebellar cerebral functions in day activities and their preserved painting abilities.     

中药酊剂临床外用技术规范(草案)

基于对中药酊剂外用技术的数据挖掘,结合临床实际应用研究,经外治学会专家多次论证,形成中药酊剂临床外用技术规范(草案),包括临床适用范围、操作步骤以及外用酊剂的方法、剂量、频率、时间、注意事项、不良反应及护理要点。以期规范中药外用酊剂的临床应用,提高其疗效并减少不良反应。     

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.     

经皮肺穿刺肺癌兔应用化疗药物对肿瘤细胞沿针道转移率影响的研究

目的探究化疗药物对已进行经皮肺穿刺肺癌兔术后肿瘤细胞沿针道转移率的影响。方法将成功建立的肺癌兔模型分为治疗组24只,对照组20只,所有患兔在计算机断层扫描(CT)引导下成功进行细针吸取细胞学检查(FNAC)5次,治疗组在进行穿刺后保留套管拔出针芯,边给予化疗药物边撤出套管。沿针道搜集组织并进行病理细胞学检测。结果治疗组中,3个不同部位5次穿刺均未发现阳性转移的发生率比较,差异无统计学意义(P﹥0.05);对照组中,脏层胸膜5次穿刺均未发现阳性转移的发生率分别低于壁层胸膜和胸壁组织,差异均有统计学意义(P﹤0.05);治疗组脏层胸膜5次穿刺均未发现阳性转移的发生率高于对照组,差异有统计学意义(P﹤0.05)。穿刺后,治疗组脏层胸膜肿瘤细胞转移阳性率明显低于对照组,差异有统计学意义(P﹤0.01);两组壁层胸膜及胸壁组织的肿瘤细胞转移阳性率比较,差异均无统计学意义(P﹥0.05)。结论经皮肺穿刺肺癌兔使用化疗药物可降低肿瘤细胞沿针道的阳性转移率。     

米非司酮在子宫肌瘤治疗中的临床效果分析

目的分析探讨子宫肌瘤患者行米非司酮治疗的临床价值。方法采用回顾性分析形式对我院于2018年1月-2019年1月期间所收治的54例子宫肌瘤患者进行研究,所有患者均予以米非司酮治疗,治疗前后均予以彩色超声检查测定指标。结果用药前子宫平均体积和最大肌瘤分别为(328.25±41.63)cm^3、(132.51±31.25)cm^3;用药后上述指标分别为(240.11±12.22)cm^3、(71.97±16.37)cm^3。组间对比差异有统计学意义(P<0.05);用药后FSH、LH、E2以及P的平均水平较比用药前有所降低(P<0.05),T和PRL用药前后差异无统计学意义(P>0.05),用药过程中尿常规和肝功能指标正常。结论米非司酮治疗子宫肌瘤的效果显著,不良反应小。