应用人工神经网络评估大剂量甲氨蝶呤化疗后的骨髓抑制

目的：研究建立人工神经网络模型用于评估大剂量甲氨蝶呤(HDMTX)化疗后的骨髓抑制程度,促进个体化用药。方法：收集180例急性淋巴细胞白血病(ALL)患儿行HDMTX化疗的临床资料。将所有资料随机分成两组,训练组(n=150)：以化疗后中性粒细胞总数(NEU)减少率为输出目标,采用遗传算法配合动量法训练后建立人工神经网络;测试组(n=30)：用建立的人工神经网络预测测试组患儿的NEU减少率,通过计算平均预测误差(MPE)、权重残差(WRES)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)和均方根预测误差(RMSE)来验证模型。结果：人工神经网络的MPE 为(-2.05±7.41)%,WRES为(23.20±29.74)%,MAE为(6.12±4.53)%,MSE为(57.26±64.46)(%)₂,RMSE为 7.57%,有76.67%的病例相对预测误差在±20%以内。人工神经网络预测的准确度及精密度均优于多元线性回归模型(逐步回归法)。结论：本研究建立的人工神经网络预测性能较好,可用于预测HDMTX化疗后骨髓抑制程度以指导个体化用药。     

肝移植受者他克莫司血药浓度早期预测方案及评估

目的:建立人工神经网络用于估算他克莫司血药浓度。方法:收集36例肝移植受者口服他克莫司的150份稳态全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络。结果:人工神经网络平均预测误差(MPE)与平均绝对误差(MAE)分别为0.05±3.01ng·mL-1和2.09±2.12ng·mL-1,78.3%血药浓度数据绝对预测误差≤3.0ng·mL-1。人工神经网络准确性及精密度优于多元线性回归。结论:人工神经网络预测可用于预测他克莫司血药浓度。     

肝移植患者他克莫司个体化给药研究

目的:建立人工神经网络用于估算他克莫司血药浓度.方法:收集26例肝移植患者口服他克莫司的94份全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络.结果:人工神经网络平均预测误差(MPE)与平均绝对预测误差( MAE)分别为(-0.11±2.81) ng/mL和(2.14±1.72) ng/mL,78.6％血药浓度数据绝对预测误差≤3.0 ng/mL.多元线性回归 MPE与 MAE分别为(0.56±2.70) ng/mL和(2.15±1.63) ng/mL,9例次(9/14,64.3％)绝对预测误差≤3.0 ng/mL.人工神经网络准确性及精密度优于多元线性回归.结论:人工神经网络预测可用于预测他克莫司血药浓度,指导个体化给药.     

人工神经网络预测肝移植术受者他克莫司血药浓度

建立人工神经网络用于估算他克莫司血药浓度。收集37例肝移植受者口服他克莫司的176份稳态全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络。人工神经网络平均预测误差(MPE)与平均绝对误差(MAE)分别为(0.02±2.40)ng.mL 1和(1.93±1.37)ng.mL 1,84.6%血药浓度数据绝对预测误差≤3.0 ng.mL 1。人工神经网络的准确性及精密度优于多元线性回归。结果表明,人工神经网络预测的相关性、准确性和精密度较好,简便迅捷,可用于预测他克莫司血药浓度。     

GA-BP神经网络、多元线性回归预测新疆癫痫患儿拉莫三嗪血药浓度

摘要：目的:建立遗传算法-反向传播（GA-BP）神经网络模型、多元线性回归模型预测新疆癫痫患儿拉莫三嗪血药浓度。方法:回顾性收集自治区人民医院2015年8月～2021年10月份就诊的296例癫痫患儿口服拉莫三嗪的稳态血药浓度以及临床资料,建立GA-BP人工神经网络模型、多元线性回归模型预测拉莫三嗪血药浓度,比较两种方法对拉莫三嗪血药浓度的预测能力。结果:多元线性回归分析结果显示影响拉莫三嗪血药浓度的因素有民族、合并用药、给药剂量、疗效以及部分生化指标（P＜0.05）;GA-BP神经网络模型对60个验证组浓度预测误差均小于10%,误差小于15%的比率是100.00%,平均预测误差（MPE）为0.000 72%,平均绝对误差（MAE）为0.45%,血药浓度预测值与实测值之间的相关系数r=0.999 8,预测结果较理想。多元线性回归模型60个浓度预测误差小于15%的比率是20.00%,MPE为2.54%,MAE为4.74%,血药浓度的预测值与实测值之间的相关系数r=0.225 2,预测结果较差。结论:与多元线性预测模型相比,GA-BP神经网络预测模型根据患者临床资料可较好的预测新疆癫痫患儿拉莫三嗪血药浓度。     

左乙拉西坦在癫痫患儿中的群体药动学研究

目的建立癫痫患儿口服左乙拉西坦的群体药动学(PPK)模型,并用此模型探讨左乙拉西坦在儿童患者群体内的药动学特征。方法收集344例癫痫患儿口服左乙拉西坦后的血药浓度数据和临床资料。将患儿随机分为两组,模型组(n=259)采用NLME程序进行PPK分析,建立一房室药动学模型(个体间变异采用指数模型,残差变异采用加法模型表示),考察各协变量对参数Ka、Vd和CL的影响。用拟合优度、自举法对最终模型的性能进行内部验证。采用最终模型预测验证组(n=85)患儿的血药浓度,计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)和均方根预测误差(RMSE)对最终模型进行外部验证。结果 PPK最终模型为:Ka(h-1)=1.01×eηKa,Vd(L·kg-1)=[0.42+0.000 35×(AGE-56)]×eηVd,CL(L·kg-1·h-1)=[0.05-0.009 5×(ln WT-2.83)]×eηCl;年龄(AGE)正相关影响Vd,体重的自然对数值(ln WT)负相关影响CL。拟合优度、自举验证的评价结果表明最终模型稳定、预测结果可靠。外部验证最终模型结果为:MPE=0.01 mg·L-1,MAE=0.91 mg·L-1,MSE=1.16(mg·L-1)2,RMSE=1.08 mg·L-1。血药浓度实测值和最终模型的个体预测值的决定系数R2=0.990 6。外部验证说明最终模型预测准确度高。结论本研究成功建立了癫痫患儿口服左乙拉西坦后的PPK模型,模型结构表明左乙拉西坦体重校正的清除率随患儿年龄和体重的增加有下降趋势。     

人工神经网络模型在肾移植患者西罗莫司个体化给药中的应用

目的:建立人工神经网络用于估算西罗莫司血药浓度的方法。方法:收集56例肾移植患者口服西罗莫司的182份全血浓度数据,采用遗传算法配合动量法优化网络参数,建立人工神经网络,并对测试数据进行处理,验证测试结果。结果:人工神经网络平均预测误差(MPE)与平均绝对误差(MAE)分别为(0.31±1.14)、(0.89±0.77)ng·mL-1,32例/次(88.9%)血药浓度数据绝对预测误差≤2.0ng·mL-1。人工神经网络模型准确性及精密度优于多元线性回归及非线性混合效应模型。结论:人工神经网络模型可用于预测西罗莫司血药浓度,指导个体化给药。     

万古霉素在新生儿和小婴儿患者中的群体药动学研究

目的建立万古霉素在新生儿和小婴儿患者的群体药动学(PPK)模型,为临床个体化用药提供参考。方法收集85例新生儿科患者静脉注射使用万古霉素后的血药浓度数据和临床资料。将患者分为两组,模型组(n=71)采用Phoenix~NLME~(TM)1.3软件进行PPK分析,建立一房室药动学模型(个体间变异采用指数模型,个体内变异采用混合误差模型),考察各协变量对参数V和CL的影响。用拟合优度、自举法对最终模型的性能进行内部验证。采用验证组(n=14)患者的血药浓度,计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差均方(MSPE)对最终模型进行外部验证。结果 PPK最终模型为V(L)=3.167,CL(L·h~(-1))=0.413×(WT/3.32)~(0.747)×(PNA/25)~(0.402)×e~(ηCL),体重(WT)和产后日龄(PNA)对CL有影响。拟合优度、自举验证的结果表明最终模型稳定、预测结果可靠。外部验证最终模型计算MPE、MAE和MSPE值分别为(-0.843±1.347)、(1.462±1.175)和(2.432±4.293)mg·L~(-1)。血药浓度实测值和最终模型的个体预测值的决定系数R=0.955,外部验证说明最终模型预测准确度较好。结论本研究建立的万古霉素新生儿和小婴儿患者的PPK模型预测能力和稳定性良好,可为其个体化给药方案的制订提供参考。     

采用遗传-反向传播人工神经网络法构建新疆地区癫痫患儿拉考沙胺血药浓度预测模型

目的:利用遗传-反向传播(GA-BP)人工神经网络法构建新疆地区癫痫患儿拉考沙胺(LCM)血药浓度的预测模型。方法:采用超高效液相色谱法测定400例癫痫患儿的LCM稳态血药浓度,收集患儿临床资料,提取相关数据,采用GA-BP人工神经网络法构建LCM血药浓度的预测模型。结果:模型验证结果显示,80例预测浓度的平均预测误差(MPE)绝对值均<10%,预测误差(PE)绝对值<20%的比例是100%,PE绝对值<10%的比例是92.50%,平均预测绝对误差(MAE)为2.28%,提示GA-BP模型预测的准确度和精密度均较好,预测浓度和实测浓度的相关系数为0.998,预测结果较理想。结论:应用GA-BP人工神经网络法预测LCM血药浓度是可行的,可应用于LCM个体化给药研究,促进临床合理用药。     

万古霉素群体药代动力学模型在临床应用中的预测性能的评估

目的评估万古霉素群体药代动力学(PPK)模型在临床应用中的预测性能。方法收集广西医科大学第一附属医院静脉应用万古霉素治疗的成人住院患者,根据万古霉素PPK模型,通过贝叶斯反馈法求出给定剂量下的稳态谷浓度和稳态峰浓度个体预测值,与实测值比较,评估模型的预测效能。结果共纳入271例患者697个血药浓度值,其中稳态谷浓度417个,稳态峰浓度280个。谷浓度和个体预测值均值分别为(11.85±7.14)和(11.08±6.81)mg·L^-1,峰浓度和个体预测值均值分别为(18.42±9.61)和(17.61±7.37)mg·L^-1。谷浓度的平均预测误差、平均相对预测误差、平均绝对误差和均方根误差分别为-0.77 mg·L^-1,-2.53%,1.63 mg·L^-1和2.38 mg·L^-1,峰浓度的平均预测误差、平均相对预测误差、平均绝对误差和均方根误差分别为-0.81 mg·L^-1,1.53%,2.28 mg·L^-1和3.32 mg·L^-1,相对预测误差在±30%以内的血药浓度值约占92%。结论建立的万古霉素PPK模型在临床应用中具有较高的预测性能,可用于指导万古霉素的个体化给药。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Hyperkalaemia in patients in hospital

A survey of all laboratory blood specimens with a plasma potassium concentration greater than or equal to 5.5 mmol/L was conducted over a three month period. Of 331 specimens with hyperkalaemia, 71 were excluded because the specimens was haemolysed, old or contaminated. The laboratory served a population of 348,561 and during this time measured the plasma potassium on 25,016 occasions. Sixty-six outpatients and 20 neonates were not evaluated. The survey was undertaken on 86 of 102 inpatients (46 males), 48 of whom were over 66 years of age. Fifty-seven patients were admitted under a medical service and 29 under a surgical service. Fifty-nine had a single episode of hyperkalaemia. Thirty-two underwent a surgical procedure. The commonest contributing factor was impaired renal function which was present in 71 (83%) patients. Although a definitive causative role for drugs could be identified in only five patients, in 52 (60%) patients drugs were a contributing factor (potassium supplements 24, ACE inhibitors 16, nonsteroidal antiinflammatory drugs 12). Thirty-five of the 86 (41%) patients died during their hospital admission. Nineteen of the 35 deaths occurred within three days of the hyperkalaemia being recorded. A normal plasma potassium was eventually documented in 50 of the 86 patients. Of the remaining 36 patients, 25 (69%) subsequently died. In general the treatment of patients with hyperkalaemia focused on identifying and treating the underlying cause. Hyperkalaemia must always be considered seriously and regard given to the overall clinical status of the patient, with particular attention to drug therapy, renal and cardiac function, acid base status and the possibility of sepsis.