以药效法测定四物汤药动学参数的研究

以血小板聚集抑制率作为药理效应指标，研究了四物汤的药物动力学参数，同时以探索中药及复方的药动学研究方法为目的，对药理效应法研究药动学进行了比较研究。结果：家兔口服四物汤后符合开放一房室模型，药效吸收、消除半衰期是0.37h、0．40h，tp=0．56h，效应维持时间1．9h。建议应同时考察效量、药效、表观三种半衰期，在研究设计时应重视体现药动学和药效的双重性。     

用药物的量效关系和时效关系计算中药和中药制剂的半衰期

因多数药物都有随着剂量加大作用增强,作用达峰值后,随着时间延长作用减弱。所以在一定条件下,药物的量效关系和时效关系均可用直线回归方程表达。本文根据药物的量效关系和时效关系,研究了党参水溶性部分抑制小鼠自主活动和灭炎灵对小鼠退热作用的效量半衰期,药效半衰期(或半效期)以及它们在不同时间内的体存量,并依据体存量求其表观半衰期。结果表明,药物的上述三种半衰期都比较接近。其中以药效半衰期最长。     

药物累积法研究热痹清片的药物动力学

目的:研究热痹清片在小鼠体内的药物动力学过程。方法:采用药物累积法,以小鼠急性死亡率为指标,测定小鼠灌胃给药后不同时间的药物体存量,估算表观药物动力学参数。结果:药物毒性效应呈一级动力学过程,符合二房室模型。其动力学参数为:分布速率常数α和消除速率常数β分别为2.2272h-1及0.2031h-1;其分布半衰期t1/2α和消除半衰期t1/2β分别为0.3112h和3.4121h。结论:热痹清片小鼠灌胃给药易于吸收,毒性较大,分布快,但消除较慢。其表观药物动力学参数可为临床合理用药作参考。     

麝香保心pH依赖型梯度释药微丸和麝香保心丸的药效动力学

目的 探讨麝香保心pH依赖型梯度释药微丸和麝香保心丸的药效动力学参数。方法 以大鼠心肌营养性血流量为效应指标进行测定。结果 麝香保心丸在大鼠体内呈一室模型特征，其最低起效剂量为0.54mg/kg，效应呈现半衰期为0.53h，效应消除半衰期为1.21h，药效作用期为3.48h，效应达峰时间为1.13h，效量吸收半衰期为0.23h，消除半衰期为1.47h,达峰时间为0.88h,统计矩结果表明麝香保心pH依赖型梯度释药微丸和麝香保心丸的平均效应维持时间分别为5.05h和2.33h,效量平均滞留时间分别为7.70h和3.21h,麝香保心pH依赖型梯度释药微丸的效量相对生物利用度为104.03%.结论 麝香保心丸在体内具有吸收快,消除快和作用维持时间较短的特点,耐麝香保心pH依赖型梯度释药微丸在体内具有起效迅速,药效持久,缓和的特征.     

马钱子碱镇痛作用及其药效动力学研究

目的:探讨马钱子碱的镇痛作用及其药效动力学.方法:用热板法测定小鼠疼痛的的潜伏期为痛阈指标,以吗啡为阳性对照药,进行马钱子碱腹腔注射给药的量效关系和时效关系的研究,以一次给药后药效强度变化的经时过程进行房室模型拟合和药效动力学参数计算.结果:马钱子碱ip具有显著的镇痛作用,其镇痛作用强度与给药剂量呈正相关,其20mg·kg-1ip的药效强度与吗啡10mg·kg-1ip相当.其药效的消除呈一级动力学过程并符合二房室开放模型,消除相速率常数β为0.00498 min-1,半衰期t1/2β为2.32h,其分布相速率常数α为0.05201min-1,半衰期t1/2α为13.33min,药效曲线下面积AUC为17101.2△E%min,其药效持续时间Tc约为8h.结论:马钱子碱具有肯定的镇痛作用,其药效强度较高,维持时间较长.     

射干提取物止咳药效动力学研究

目的:探讨三种射干提取物止咳作用的强弱及其药效动力学过程。方法:采用一次性灌胃给药,以浓氨水雾化诱咳的方法,观察记录小鼠的咳嗽潜伏期和2分钟内咳嗽次数,建立相应的时间-效应方程及剂量-效应方程,计算相关药效动力学参数。结果:三种射干提取物在小鼠体内均呈一室模型特征,2号、6号、7号止咳效应半衰期分别为1.314h、2.149 h、0.538 h,效应消除半衰期分别为8.226h、3.971 h、8.026 h,药效作用期分别为5.73h、7.74 h、7.38 h,效应达峰时间分别为为1.0h、2.0h、2.0h;2号、6号、7号延长咳嗽潜伏期效应半衰期分别为0.272h、8.427h、0.553h;效应消除半衰期分别为2.579h、8.428h、5.259h;药效作用期分别为4.14h、6.64 h、7.29 h,效应达峰时间分别为1.0h、1.0h、2.0h;2号、6号、7号延长咳嗽潜伏期最低起效剂量分别为24.83、1.02、2.12mg/kg,抑制咳嗽次数的最低起效剂量分别为5.06、0.34、0.41mg/kg。结论:三种射干提取物均具有明显的止咳作用,并且起效剂量低、起效迅速、药效作用时间持久。     

复方马钱子碱的镇痛作用及其药效动力学初步观察

目的探讨复方马钱子碱的镇痛作用及其药效动力学规律。方法①小鼠腹腔注射不同剂量的复方马钱子碱,于药前和药后测定痛阈(热板法),计算痛阈增加率,以各组最大药效进行量效关系计算,并与吗啡进行平行比较。②小鼠腹腔注射32.6mg/kg复方马钱子碱,药前和药后不同时间测定小鼠痛阈,绘制时间-效应曲线。根据时效曲线进行房室拟合并计算药效动力学参数。结果复方马钱子碱3个剂量均有明显的镇痛作用,其中32.6mg/kg的镇痛作用超过吗啡,差异有显著性意义。复方马钱子碱腹腔注射吸收速率常数(Ka)=0.09477/min,吸收相半衰期(T1/2a)=7.3min,消除速率常数(Ke)=0.00203/min,消除相半衰期(T1/2e)=341.4min,起效时间(Tb)=1.3min,达峰时间(Tmax)=41.4min,峰强度(Emax)=238.5,失效时间(Te)=598.7min,药效持续时间(Tc)=597.4min。结论复方马钱子碱腹腔注射有明显的镇痛作用,且起效迅速,作用强而持久。     

两种方法测定麻黄汤体内过程的比较

目的:以毒理效应法和药理效应法分别测定麻黄汤的体内过程,比较两法的异同。方法:毒理效应法以小鼠死亡率为指标,不同时间先后2次ip麻黄汤19.69 g·kg-1测定其表观药动学参数;药理效应法采用大鼠酵母致热模型,以解热效应为指标,ig给予麻黄汤11.2 g·kg-1测定表观药动学参数。DAS 2.1.1程序拟合表观药动学数据并计算参数。结果:毒理效应法测得麻黄汤体内呈二室开放模型,主要药动学参数t1/2β=9.36 h,AUC=46.80 g·kg-1.h,CL=0.32(g·kg-1)/(h·g·kg-1)。药理效应法测得麻黄汤体内呈一室模型,主要药动学参数t1/2=4.15 h,AUC=55.01 g·kg-1.h,CL=0.27(g·kg-1)/(h·g·kg-1)。结论:2法测得参数存在一定差异,毒理半衰期长于效应半衰期。生物效应法可用于探讨中药方剂体内过程,但所得参数意义及数值均与经典药动学有差异。     

以药物体内累积法再探麻黄汤、桂枝汤、银翘散、桑菊饮的药物动力学

以药物累积法估测了麻黄汤、桂枝汤、银翘散、桑菊饮四个解表方剂的药物动力学参数。结果除桑菊饮呈一房室模型分布外,其他三方均属二房室模型分布,四个方剂基本上均按一级动力学消除。麻黄汤的最小有毒剂量为15.73g/kgip,表现消除半衰期为23.41小时,表观分布半衰期为3.76小时。桂枝汤相应为11.94g/kg,17.10和1.19小时。银翘散相应为7.28g/kg,13.86和0.76小时。桑菊饮相应为9.72g/kg,9.72和0.86小时。对药物累积法估测中药复方药物动力学的研究方法作了讨论。     

三越麻黄颗粒小鼠药物动力学研究

目的:对三越麻黄颗粒的体内药动学进行研究。方法:在药效学实验的基础上以制剂对小鼠腹腔毛细血管通透性的影响为指标,采用药理效应法考察了该颗粒剂在体内的药动学指标。结果:三越麻黄颗粒体内的药动学指标符合一室模型,采用药理效应法计算后得到以下药动学参数:体存相当药量的吸收速度常数(Ka)为1.06h-1,达峰时(Tmax)为1.57 h,t1/2(Ka)为0.656 h,消除速度常数(ke)为0.628 h-1,t1/2(Ke)为1.10 h;采用效应半衰期法计算得到以下药动学参数:消除速度常数(ke)为0.537 h-1,t1/2(Ke)为1.29 h;根据效应—时间曲线得到以下效应动力学参数:药物效应起效速度常数(Ka)为2.149 h-1,达峰时(Tmax)为1.36 h,t1/2(Ka)为0.32 h,消除速度常数(ke)为0.139 h-1,t1/2(Ke)为5.0 h。结论:三越麻黄颗粒剂起效较快而消除较慢,体存相当药量的药动学参数仅为表观参数,需结合药效的变化来讨论其具体的意义。     

亚胺培南治疗院内常见耐药菌血流感染给药方案结合蒙特卡洛模拟的药物经济学评价

目的 探讨亚胺培南不同给药方案治疗院内常见耐药菌血流感染的经济学效果。方法 调查中山市人民医院2019—2020年应用亚胺培南治疗院内常见耐药菌血流感染病例共151例,按照实际给药分为A方案：0.5 g/次,每12小时给药1次（q12h）;B方案：0.5 g/次,每8小时给药1次（q8h）;C方案：1 g/次,q12h;D方案：1 g/次,q8h;E方案：1 g/次,每6小时给药1次（q6h）。分别进行蒙特卡洛模拟（MCS）,计算各方案的累积反应分数（CFR）,进行成本效果分析（CEA）。结果 5组方案的成本效果比（C/E）分别为68.5、68.2、100.4、82.6、93.1,以A方案为参照,余下4种方案的增量成本效果比（△C/△E）分别为65.9、845.1、147.2、201.8。结论 C/E最小的B方案对多重耐药鲍曼不动杆菌（MDR-AB）、耐碳青霉烯类铜绿假单胞菌（CRPA）和耐碳青霉烯类肠杆菌科（CRE）的抗菌活性较差,并非院内常见耐药菌血流感染最理想的方案,应结合临床耐药菌种选择给药方案。D方案的药物经济学评价效果优于C方案和E方案,且更多给药频次的E方案并未体现出更高收益。     

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??Tacrolimus is widely used as a first-line immunosuppressant after adult liver transplantation. However, because of narrow treatment window and pharmacokinetic individual differences, it is difficult to formulate individualized dosing regimens in short term. Pharmacokinetic parameters that estimated by population pharmacokinetics(PPK) can provide a preliminary individualized regimen for early postoperative patients. This paper collected literatures on PPK modeling of orally administered tacrolimus in adult liver transplantation patients through literature search. And multiple influencing factors of PPK model was mainly summarized, such as demographic characteristics, blood biochemical index, combined medication, liver and kidney function, genetic factors, postoperative time and dosage. It will provide literature support for the development of individualized dosing regimens for oral tacrolimus recipients using the PPK protocol for adult liver transplantation.     

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??OBJECTIVE To establish a population pharmacokinetics(PPK) model of vancomycin in adult patients and investigate the factors influencing vancomycin clearance.METHODS The nonlinear mixed-effect model(NONMEM) was used to investigate the population characteristics of vancomycin in adult patients and the serum cystatin C was used as a marker of renal function. The final model was built by forward inclusion approach and backward elimination method. Fitting effect of the model was evaluated by the goodness of fit plots(GOFs). Nonparametric Bootstraps and normalized prediction distribution errors(NPDE) were performed to evaluate the robustness and predictive efficacy of the final model. External model evaluation was conducted using an independent dataset to evaluate the model predictability. RESULTS Vancomycin PPK model was set up via 147 serum trough concentration data from 95 adult patients. The estimated population typical values of clearance rate and apparent volume of distribution were 3.57 L??h^-1 and 63.30 L, respectively. The main factor influencing clearance was renal function. The GOFs showed that the final model was stable and effective, and the fitting degree of the final model was better than that of the base model. The robust rate verified by Bootstrap was 99.45%. All of the relative biases between the median of parameters validated by Bootstrap and the estimated parameters of final model were within ??3%, and the 95% confidence intervals of these validated parameters did not include zero. The NPDE followed the N(0,1) distribution with a global adjust P value of 0.334, which indicated that the model had a high predictive accuracy. External evaluation was performed via an independent dataset of 40 concentration data from 20 patients. The mean prediction error(MPE) and mean absolute prediction error(MAPE) based on population predictions(PRED) was -1.90% and 24.34%, respectively. CONCLUSION Vancomycin PPK model established in the study is of as a good stability and high predictive accuracy, as a reference for developing individualized administration regimens.     

肝移植患者霉酚酸酯的应用与环孢素A监测

 目的探讨肝移植术后免疫抑制剂的应用及环孢素A血药浓度监测。方法特异性单克隆荧光偏振免疫法(mAFPIA)测定环孢素A血药浓度,肝移植术后免疫抑制方案：环孢素A+霉酚酸酯+泼尼松。结果霉酚酸酯与环孢素A对排异有协同作用，减少环孢素A的用量并减少环孢素A引起的肝、肾毒性；环孢素A的全血谷浓度在(160±30) ng·mL^-1可作为肝移植术后环孢素A剂量调整的依据。结论有霉酚酸酯的新三联免疫抑制方案对肝移植术后是安全、有效的，对临床治疗效果有重要意义。mAFPIA法对应用环孢素A患者的血药浓度监测简便、快速、稳定。     

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??OBJECTIVE To provide reference for the industry, introduce the experimental design of animal efficacy studies and human dosage extrapolating strategy about drugs and biological products (including vaccines) approved by FDA under animal rule. METHODS This article provides an overview catalogued by the indications of drugs (including vaccines), on experimental grouping, dosage regimen, critical efficacy endpoints and other elements in the adequate and well-controlled animal efficacy studies, and further analyses the strategy of extrapolating animals efficacy data. RESULTS The regulations commonly known as the animal rule allow for the licensure of drugs and biological products developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances, when human efficacy studies are not ethical and field trials to study the effectiveness of drugs or biological products are not feasible. CONCLUSION Under the animal rule, drug efficacy can be established based on adequate and well-controlled studies in animal models and the human dosing regimens can be extrapolated based on the animal data.     

临床药动学给药个体化系统的研制及应用

 目的：为利用临床常规监测的血药浓度数据估算病人的个体药动学参数，优化给药方案，设计、研制了临床药动学给药个体化系统（CPKDP程序）。方法：依据群体药动学原理及Bayes公式，CPKDP程序用FOXPRO 2.6和BORLAND C++ 3.1开发，在希望汉字系统UCDOS 5.0平台上运行。结果：CPKDP程序适用于具有不同药动学特征的多种药物，适用于不同给药途径的单剂量或多剂量给药。在群体药动学参数的基础上，结合病人个体特征，以1，2血药浓度作为反馈，即可拟合估算个体药动学参数，优化给药方案。结论：经初步应用，CPKDP程序是应用Bayes反馈法开展临床个体化给药工作非常实用的工具。     

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??OBJECTIVE To evaluate and optimize the treatment regimen of cephalosporins based on Monte Carlo simulation and the pharmacokinetics/pharmacodynamics (PK/PD) model.METHODS The treatment regimens of cefradine, cefuroxime, ceftriaxone and cefepime are 0.75 g qid, 1 g qid, 2 g bid and 2 g tid. And a total of 903 strains from eight species were collected. The minimum inhibitory concentration (MIC) was measured by trace broth dilution method. Monte Carlo simulation was used to simulate the regimens against Escherichia coli, Bacillus, Klebsiella pneumoniae, Acinetobacter baumannii, Citrobacter, Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa. Then,the cumulative fraction of response (CFR) was calculated.RESULTS Cefhradine and cefuroximes?? rates of resistance were higher (47.31%-100%), the cumulative reaction scores(CFR) were all less than 90%. Cefuroxime has desirable regimen for Escherichia coli, Klebsiella pneumoniae, Citrobacter and Streptococcus pneumoniae. Cefepime has at least one dose regimen??s CFR for more than 90%, and cephalosporins is consistent with time-dependent drug characteristics.CONCLUSION For the treatment of infectious diseases, the choice of cephalosporins should be used to follow the principles of antibiotics. Target therapy should be used to test the pathogen susceptibility test, according to the value of MIC to simulate the corresponding dosing regimen, to achieve individualized administration.     

滋阴解毒祛瘀法对系统性红斑狼疮激素用量影响的随机双盲对照试验

目的系统评价滋阴解毒祛瘀法治疗系统性红斑狼疮对激素治疗用量的影响。方法采用随机、对照、双盲的临床研究设计方案,收集60例肝肾阴虚、热毒血瘀证轻中度活动SLE患者,按随机法分为治疗组和对照组;两组均给予相同西医基础治疗(糖皮质激素+羟氯喹或环磷酰胺),其中治疗组加用滋阴解毒祛瘀方,并根据临床症状随症加减;对照组采用中药安慰剂。结果经过24周治疗后,两组患者在中医证候积分、SLE-DAI积分及糖皮质激素用量均明显降低(P<0.01);治疗组降低中医证候总分与糖皮质激素治疗用量明显优于对照组(P<0.01),治疗组降低SLE-DAI积分优于对照组(P<0.05)。结论滋阴解毒祛瘀法治疗系统性红斑狼疮,在改善临床症状、降低SLE-DAI积分、控制病情的同时,能有效减少糖皮质激素用量,且安全性较好。     

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??OBJECTIVE To introduce two commonly used algorithms for warfarin individualized medication????multiple regression analysis(MRA)and maximum a posterior Bayesian (MAPB), and provide reference for individualized medication of warfarin in clinical practice. METHODS The principles of MRA and MAPB for warfarin individualized medication, as well as the decision support tools to realize MRA and MAPB, were introduced. The function of MAPB tool, including formulating an initial dosage regimen, adjusting the regimen and its application in special clinical situations, was described by five typical cases.RESULTS AND CONCLUSION MLR is simple to calculate, however, it can only be used to formulate the initial dosage regimen and dose adjustment cannot be carried out, which limits it clinical application in a certain extent. The application of MAPB can not only develop individualized medication of warfarin and adjust dose according to international normalized ratio(INR) with satisfactory prediction performance, but also be applied in special cases with better flexibility, such as judging medication adherence and instructing withdrawal. It could serve as an effective decision support tool to be promoted vigorously, which has a promising prospect.