Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide

1.?A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro.

2.?The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127–acrylamide–bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20?mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software.

3.?The predicted in vivo clearance of CP at concentrations of 5, 10 and 20?mM was 11.36, 10.12 and 10.68?mL/min/kg, respectively, within two-fold differences compared with the reported 11.1?mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced.

4.?This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.     

Being overweight or obese as a risk factor for acute liver injury secondary to acute acetaminophen overdose

Purpose

Increased incidences of hepatotoxicity have been observed in obese patients with acute acetaminophen overdose. We evaluate whether the status of being overweight or obese is associated with increase in the development of hepatotoxicity and acute liver injury (ALI) in patients with acute acetaminophen overdose.

Methods

This was a retrospective cohort study comparing the risk of hepatotoxicity and ALI between overweight or obese patients (body mass index [BMI] ≥ 25) and normal BMI patients (BMI ≤ 24.9) presenting with acute acetaminophen overdose at Siriraj Hospital during January 2004 to June 2012. All patients were treated with intravenous N‐acetylcysteine. Psi parameters were calculated. High psi was defined as psi of ≥5.0 mM‐hour. Data were analyzed using multinomial logistic regressions, odds ratio (OR), stratified OR, and 95% confidence interval (CI).

Results

There were 197 patients who fulfilled the criteria for analysis, 35 (17.8%) were obese, 24 (12.2%) were overweight, and 138 (70%) were normal BMI cases. Hepatotoxicity and ALI developed in 25 (12.7%) and 40 (20.3%) cases, respectively. Multinomial logistic regression revealed that the overweight‐obesity status and log₁₀(psi value) were significant risk factors of ALI, with OR (95% CI) of 2.68 (1.21‐5.95) and 1.74 (1.27‐2.38), respectively, while only log₁₀(psi) was a significant risk factor of hepatotoxicity with OR (95% CI) 378.51 (39.49‐3627.99). From stratification, overweight‐obesity had significant odds ratios for ALI in strata with low acetaminophen concentration, early initiation of N‐acetylcysteine and low psi.

Conclusion

We conclude that being overweight or obese is an independent risk factor of ALI in acute acetaminophen overdoses.     

精液参数对宫腔内人工授精妊娠结局的影响

目的探讨精液参数对宫腔内人工授精妊娠结局的影响,为需要IUI患者提供参考。方法回顾性分析2010年7月-2016年10月在吉林大学第一医院接受IUI治疗的511对不孕症夫妇,共完成1090个周期。比较分析男女双方年龄、不孕年限、原发性或继发性不孕、处理前精子的活力、浓度、总数、前向精子运动总数(TMS)及处理后前向运动精子活动总数(PTMS)与IUI临床妊娠率间的关系。结果1090个IUI周期共获得130个妊娠周期,周期妊娠率为11.93%,女方年龄、不孕年限在妊娠组与非妊娠组中比较差异有统计学意义(P<0.05)。处理前精子的活力、浓度、总数、TMS、PTMS等参数比较差异无统计学意义(P>0.05),多因素Logistic回归分析结果显示精液常规各项参数与临床妊娠率均无明显相关性(P>0.05)。结论在IUI中女方年龄、不孕年限可影响IUI临床妊娠率;各项精液参数与IUI临床妊娠率无明显相关性,不能有效预测此类型患者IUI的临床妊娠结局。     

一种简易可行的血液流变学参数处理方法

本文通过理论分析及冠心病患者的流变学数据观察说明只要测得全血在观粘度、血浆粘度及血细胞压积，即可通过简单的计算得到较全面、较理想地反映血液流变特性变化的指标。     

丹参提取过程动力学研究:模型建立及关键工艺参数考察

该研究以Fick第一扩散定律、分配平衡来表示丹参药材宏观层面内、外传质过程,建立传质模型,并将药材比表面积融合在传质阻力中,从而有效避免了药材形状不规则问题,扩大了模型适用范围。同时进一步将传质模型与酚酸降解动力学模型结合,建立丹酚酸B、紫草酸和丹参素的提取动力学模型。将模型应用于丹参提取过程研究,敏感性分析结果表明,在最大提取率(320 min)附近,模型预测相对误差在5%以内,模型预测性能较好。不同工艺参数考察结果表明,搅拌会显著加快丹酚酸B传质速率;溶剂倍量对丹酚酸B传质和降解无明显影响;温度的倒数与传质阻力对数值线性关系良好,决定系数为0.996,温度与传质阻力符合阿伦尼乌斯公式。研究结果表明,在较高提取温度(358 K以上)下,紫草酸和丹参素浓度变化受传质影响较弱,只需考虑降解对其浓度变化的影响。该研究为中药提取的工艺优化和质量控制提供了基础。     

The relationship between spinopelvic parameters and clinical symptoms of severe isthmic spondylolisthesis: a prospective study of 64 patients

Purpose

To investigate the relationship between spinopelvic parameters and clinical symptoms for patients with severe isthmic spondylolisthesis.

Methods

A series of spinopelvic parameters were measured in 64 patients with L5 severe isthmic spondylolisthesis. The patients were divided into two groups according to Oswestry score obtained preoperatively, i.e. mild or severe low back pain group. T test was used to compare parameters between two groups, and multiple linear regression analysis was employed to investigate the association between parameters and Oswestry score.

Results

Compared with two group patients, parameters of spondylolisthesis grade, pelvic tilt (PT), lumbar lordosis (LL), T9 tilting angle (T9TA), sacro-femoral horizontal distance (SFHD), distance between perpendicular line through C7 and sacrum (SC7D), pelvic tilt/sacral slope (PT/SS), sacro-femoral horizontal distance/vertical distance (SFHD/SFVD), and lumbar lordosis/thoracic kyphosis (LL/TK) were significantly increased in severe low back pain group, while SS and SFVD were significantly decreased, and no significant difference was found for pelvic incidence (PI) and TK. The statistical analysis showed that spondylolisthesis grade, PT, SC7D, LL, SFHD, PT/SS, SFHD/SFVD, and LL/TK had a significant positive correlation with Oswestry score, with an order of spondylolisthesis grade > PT/SS > SC7D > PT > SFHD/SFVD > SFHD > LL/TK > LL. No significant correlation was found for PI, TK, T9TA with Oswestry score, while SS and SFVD had a significant negative correlation with Oswestry score, with an order of SS > SFVD.

Conclusions

The spinopelvic parameters (spondylolisthesis grade, SS, PT, SC7D, LL, SFVD, SFHD, PT/SS, SFHD/SFVD, LL/TK) are significantly correlated with clinical symptoms of severe isthmic spondylolisthesis in patients. The association of the exacerbation of low back pain with SS (correlation coefficient −0.981, strong) and SFVD (correlation coefficient −0.802, strong) is the most significant correlation.     

高龄非ST段抬高型急性冠状动脉综合征患者经皮冠状动脉介入术前强化他汀类药物治疗对围术期血小板相关参数的影响

目的：探讨经皮冠状动脉介入（ PCI）术前短期、强化他汀类药物治疗对高龄非ST段抬高型急性冠状动脉综合征患者血小板相关参数的影响。方法选取首都医科大学附属北京安贞医院因不稳定型心绞痛或非ST段抬高型心肌梗死行PCI的患者138例。 PCI术前12 h用随机数字表法分为2组：他汀常规治疗（阿托伐他汀20 mg/d）组70例,强化治疗（阿托伐他汀80 mg负荷剂量,随之40 mg/d）组68例。入院后检测基线血小板参数[血小板计数、平均血小板体积（ MPV）、血小板分布宽度（ PDW）、大血小板比例（P-LCR）]。 PCI术后第1、5天复查血小板参数,检测花生四烯酸（AA）和二磷酸腺苷（ADP）诱导的血小板聚集率。结果2组患者入院后基线、PCI术后第1、5天的血小板计数、MPV、PDW、P-LCR比较,差异均无统计学意义（均P＞0．05）。与基线比较,常规治疗组PCI术后第1天血小板计数下降,MPV、PDW和P-LCR增加,差异均有统计学意义[（206±62）×10^9/L比（210±60）×10^9/L、（10．8±0．9）fL比（10．6±0．9）fL、（12．8±1．9）％比（12．5±1．9）％、（32±8）％比（30±8）％]（P＜0．05）;常规治疗组PCI术后第5天血小板计数、MPV、PDW、P-LCR与基线比较,差异无统计学意义（P＞0．05）。强化治疗组PCI术后第1天血小板计数、MPV、PDW及P-LCR与基线比较,差异无统计学意义（ P＞0．05）;PCI术后第5天MPV及P-LCR与基线比较,差异有统计学意义[（10．6±1．0）fL比（10．8±1．0）fL、（30±9）％比（31±8）％]（P＜0．05）。2组PCI术后第1、5天AA和ADP诱导的血小板聚集率比较,差异无统计学意义（P＞0．05）;组内AA和ADP诱导的血小板聚集率比较,差异无统计学意义（ P＞0．05）。结论对于高龄非ST段抬高型急性冠状动脉综合征患者,强化他汀类药物治疗能有效抑制PCI术后MPV、L-PCR等的升高,抑制介?     

不同体位肺复张对重症肺炎患者的临床治疗效果和安全性对比探讨

目的探讨不同体位肺复张对重症肺炎患者的临床治疗效果和安全性。方法选取本院收治的87例重症肺炎患者为研究对象,将患者分为仰卧位肺复张组和俯卧位肺复张组,分别使用不同的肺复张方法进行治疗,比较两组的临床效果。结果复张后5 min、1 h,两组患者的HR、CI、MAP与复张前比较,差异无统计学意义（P〉0.05）,复张后5 min的CVP与复张前比较,差异有统计学意义（P〈0.05）,复张后1 h与复张前比较,差异无统计学意义（P〉0.05）;复张后5 min、1 h的Pa O2/Fi O2高于复张前,差异有统计学意义（P〈0.05）。俯卧位肺复张组复张后5 min、1 h的Pa O2/Fi O2与仰卧位肺复张组比较,差异有统计学意义（P〈0.05）。在肺复张前后无一例患者出现气胸、皮下气肿等并发症;两组患者复张后5 min、1 h的胃黏膜p H与复张前比较,差异无统计学意义（P〉0.05）,两组患者复张后5 min、1 h的胃黏膜p H比较,差异无统计学意义（P〉0.05）。结论两种肺复张方法均能有效改善患者的血氧参数和呼吸功能,且俯卧位肺复张的效果稍显优势,需结合临床进行选择。     

An Exploratory Study on Resistance Spot Welding of Titanium Alloy Ti-6Al-4V

Resistance spot welding (RSW) is one of the most effective welding methods for titanium alloys, in particular Ti-6Al-4V. Ti-6Al-4V is one of the most used materials with its good ductility, high strength, weldability, corrosion resistance, and heat resistance. RSW and Ti-6Al-4V materials are often widely used in industrial manufacturing, particularly in automotive and aerospace industries. To understand the phenomenon of resistance spot weld quality, the physical and mechanical properties of Ti-6Al-4V spot weld are essential to be analyzed. In this study, an experiment was conducted using the Taguchi L9 method to find out the optimum level of the weld joint strength. The given optimum level sample was analyzed to study the most significant affecting RSW parameter, the failure mode, the weld nugget microstructure, and hardness values. The high heat input significantly affect the weld nugget temperature to reach and beyond the β-transus temperature. It led to an increase in the weld nugget diameter and the indentation depth. The expulsion appeared in the high heat input and decreased the weld nugget strength. It was caused by the molten material ejection in the fusion zone. The combination of high heat input and rapid air cooling at room temperature generated a martensite microstructure in the fusion zone. It increased the hardness, strength, and brittleness but decreased the ductility.     

非肥胖型与肥胖型非酒精性脂肪性肝病患者代谢特征和肝脂肪变程度比较*

目的 比较非肥胖型与肥胖型非酒精性脂肪性肝病(NAFLD)患者代谢特征和肝脂肪变程度差异。方法 2015年1月～2021年6月我院诊治NAFLD患者274例,根据体质指数(BMI)=25 kg/m²,将其分为非肥胖型66例和肥胖型208例。计算胰岛素抵抗指数(HOMA-IR),行磁共振仪检查,应用仪器自带软件计算肝脏脂肪含量(LFC)和腹部皮下脂肪厚度(ASFT),使用FibroTouch测量肝脏受控衰减参数(CAP),使用多普勒超声诊断仪检测颈动脉内膜中层厚度(CIMT),将肝脂肪变分为Ⅰ级、Ⅱ级和Ⅲ级。结果 非肥胖型NAFLD患者BMI为(23.4±1.4)kg/m²、血清丙氨酸氨基转移酶水平为24.2(19.6,35.8)U/L,天冬氨酸氨基转移水平为25.0(18.7,32.3)U/L,甘油三酯为(1.9±0.4)mmol/L,高密度脂蛋白为(1.3±0.4)mmol/L,空腹血糖为(5.0±0.7)mmol/L,空腹胰岛素为7.0(4.8,9.4)μU/mL,HOMA-IR为1.6(1.1,2.3),尿酸为376.5(294.3,430.5)μmol/L,与肥胖型组【分别为(28.6±3.0)kg/m²、88.4(55.4,160.5)U/L、71.5(64.4,141.6)U/L、(2.8±0.6)mmol/L、(1.1±0.3)mmol/L、(5.8±0.8)mmol/L、10.4(7.7,14.2)μU/mL、2.5(1.8,3.4)和442.3(346.4,484.5)μmol/L】比,差异显著(P<0.05); LFC为8.2(6.2,13.4)%,ASFT 为(19.2±5.7)mm,CAP为(233.2±40.5)dB/m和CIMT为0.6(0.6,0.7)mm,与肥胖型组【分别为14.6(10.0,18.6)%、(24.6±8.2) mm、(284.6±46.0) dB/m和0.8(0.6,0.9)mm】比,差异显著(P<0.05);Ⅰ级肝脂肪变发生率为43.9%,显著高于肥胖型组的26.0%,而Ⅲ级肝脂肪变发生率为22.7%,显著低于肥胖型组的40.4%(P<0.05)。结论 与肥胖型NAFLD患者比,非肥胖型患者代谢紊乱程度和肝脂肪变程度显著较轻。因此,在临床实践中如何加强对这部分患者的监管仍需要进一步研究。