生脉注射液中人参皂苷Rc在心绞痛患者体内的PK-PD相关性

目的 评价生脉注射液中人参皂苷Rc在心绞痛患者体内的药代动力学-药效动力学（PK-PD）相关性。方法 10名稳定性心绞痛受试者连续静脉滴注生脉注射液14 d,分别于给药后不同时间点采集血浆样品,采用液相色谱-串联质谱（LC-MS）法测定血浆中人参皂苷Rc的血药浓度,绘制药-时曲线,进行非房室模型拟合并计算PK参数;以受试者的收缩压（SBP）、舒张压（DBP）及心率（HR）作为药效指标,进行PK-PD结合模型的拟合,计算PK-PD参数。结果 人参皂苷Rc在心绞痛受试者体内的PK符合二室模型,其降压及加快HR的效应滞后于血药浓度,不与血药浓度直接相关;效应室浓度与药效之间具有良好的相关性,血压和HR的效应模型分别符合Inhibitory Effect Sigmoid I_max和Sigmoid E_max模型。结论 成功建立了生脉注射液中人参皂苷Rc在心绞痛患者体内的PK-PD结合模型,可有效地用于预测其血药浓度和效应,评价药效物质基础。     

甘露醇右旋糖酐40在家兔体内的PK-PD模型研究

目的研究右旋糖酐40甘露醇复方注射剂和甘露醇单方注射剂中甘露醇的药动学及药效学关系,建立其在家兔体内的PK-PD(药动-药效)模型。方法采用气相色谱法测定血样中甘露醇的质量浓度,以规定时间内家兔排尿量作为甘露醇利尿效应指标。结果甘露醇静注给药后其药时曲线符合二室模型,单方组和复方组均出现最大利尿效应滞后于血药质量浓度的现象,复方组药效明显高于单方组;甘露醇的药理效应和效应室质量浓度的关系符合Sigmoid-Emax模型,且该模型所得预测药效值与实测药效值接近。结论建立的PK-PD模型预测所得甘露醇静注给药后的血药质量浓度及药理效应准确可靠,为改善临床应用提供理论依据。     

苦参碱及氧化苦参碱的药代动力学与药效动力学

以QTc延长率为效应指标,用药代动力学-药效动力学结合模型对苦参碱、氧化苦参碱iv后在免体内的处置和效应动力学作定量分析,两药的血浓时程均符合二房室模型,两药的效应与效应室浓度之间的关系均符合S形E_max模型。两药彼此的药动学和药效学性质均有明显差异,但它们各自的劳动学和药效学性质在所用剂量范围内均为非剂量依赖性。     

黄连解毒汤“方证对应”的PK-PD研究和数据挖掘技术的应用

目的:基于"方证对应"理论,探讨黄连解毒汤在药动学和药效学方面的研究思路及方法。方法:查阅近年来国内、外学者在黄连解毒汤药动学和药效学方面的研究成果,论述药动-药效学(PK-PD)结合模型和数据挖掘技术在中药复方物质基础研究和药动学研究中的重要性。结果:通过引入PK-PD结合模型和数据挖掘技术,有助于揭示方剂与证候之间的对应关系。结论:在"方证对应"理论的指导下,黄连解毒汤的药动学和药效学研究还需进一步深入。     

创新课程药动学-药效学模型实验教学实践

作为药动学扩展的创新课程,首次在药学本科学员中开展药动学-药效学模型实验.选用氟比洛芬作为模型药物,HPLC法测定口服给药后家兔的血药浓度.采用内毒素发热家兔模型,考察氟比洛芬的药动学和药效学参数.与传统药物动力学实验相比,药动学-药效学模型实验是培养学生实践能力和创新能力的实验教学新模式.     

厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内药动学-药效学关系研究

目的:应用药动学-药效学结合模型研究厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内单剂量及多剂量用药时的药动学-药效学关系。方法:将SD大鼠制备成2肾1夹型肾性高血压模型,给大鼠单剂量或多剂量灌胃给药,分别于第1天和第8天连续的预定时间点测定血药浓度,同时测定动脉收缩压(SBP)和动脉舒张压(DBP)等药物效应,建立效应室药动学-药效学结合模型并计算相关的药动学和药效学参数。对单用、联用及单剂量、多剂量的药动学-药效学规律进行定量研究。结果:厄贝沙坦的药动学特征呈二室模型,氢氯噻嗪在非稳态和稳态条件下均未改变厄贝沙坦的药动学参数,而在稳态条件下,厄贝沙坦可增高氢氯噻嗪的血药浓度及曲线下面积。厄贝沙坦和氢氯噻嗪联用降压效应优于单用的效应。药物效应和效应室浓度之间符合Sigmoid-Emax药效学模型。单剂量下药物效应与血药浓度间存在滞后现象,多剂量下滞后现象消失。Emax、EC50、Keo等药效学参数在厄贝沙坦组和两药联用组之间的差异有统计学意义。结论:建立了PK-PD定量数学模型研究厄贝沙坦和氢氯噻嗪联用在大鼠体内单剂量和多剂量用药后药动学-药效学(暴露-反应)关系的规律,并提供了相关的药动学和药效学参数,可为临床合理用药提供参考依据。     

尼索地平控释贴剂在自发性高血压大鼠体内的药动学-药效学结合模型的建立

目的:建立尼索地平控释贴剂(NCRP)在自发性高血压大鼠(SHR)体内的药动学-药效学(PK-PD)结合模型。方法:将SHR随机分为贴剂(NCRP)组和片剂(尼索地平片)组,每组6只,植入微透析探针,按尼索地平计每只给药5 mg。收集给药后36 h内的血浆微透析液,采用高效液相色谱法测定尼索地平血药浓度,Win Nonlin 5.3软件计算药动学参数,以心率和血压为药效学指标,进行PK-PD结合模型研究。结果:与尼索地平片比较,NCRP具有控释效果;NCRP药物效应与效应室浓度以Sigmoid-Emax模型拟合,心率和收缩压的PK-PD模型主要参数分别为Emax:(2.65±0.06)、(10.71±0.87),EC50:(83.65±35.25)、(1.29±0.26)ng/ml,γ:(0.83±0.91)、(1.2±0.35),Keo:(0.37±0.53)、(0.91±0.24)h-1。结论:成功建立了NCRP在SHR体内的PK-PD结合模型。     

微透析技术在抗菌药物药动学和药效学中的应用

微透析技术是一项新兴的体内药物分析技术。通过微透析技术与药动学和药效学模型结合,实现对组织或细胞外游离态药物浓度及其相应药理效应的同时研究,不仅有利于进一步明确药物的剂量-效应关系,制定临床最佳给药方案,而且也为个体化给药提供了科学依据。本文综合近年文献,对微透析技术的基本原理以及在抗菌药物药动学和药效学研究中的应用作一综述。     

酮洛芬β-CD包合物在兔体内药代动力学—药效动力学研究

为了解药物经β-CD包合后的生物体内性质建立了HPLC-UV法以测定酮洛芬在家兔体内的血药浓度。用酵母诱导家兔的发热反应,考察酮洛芬β-CD包合物与其单体的药代动力学—药效动力学(PK-PD)。结果表明:建立的HPLC-UV法简便可行;酮洛芬β-CD包合物在分布相T_1/2α为0.4h,而其单体的T_1/2α为0.56h,反映了包合后酮洛芬吸收更快;在效应—浓度—时间曲线上,包合后的酮洛芬早期效应略高;酮洛芬给药后的效应峰值滞后于血药浓度峰值,提示药物的效应室在外周室。     

HPLC—MS（TOF）法测定大鼠血浆中环维黄杨星D的浓度

目的:本文建立了HPLC-MS(TOF)法测定大鼠ig给药后体内环维黄杨星D的浓度,为进一步研究环维黄杨星D的药代动力学提供了可靠的方法。方法:大鼠血浆中加入内标多奈哌齐后碱化,以液-液萑取法提取血浆后采用LC-ESI-MS(TOF)联用技术,以电喷雾(ESI)作为接口技术,选择环维黄杨星D的准分子离子([M H]~ ,m/z 403)和内标多奈哌齐的准分子离子([M H]~ ,m/z 380)作为测定离子,测定大鼠血浆中环维黄杨星D的浓度。HPLC条件:Lichrospher CN柱(4.6 mm×150mm,10μm),甲醇-醋酸盐缓冲液(80:20)为流动相,流速:0.8mL·min~(-1);质谱检测参数:喷嘴电压力5500V;喷管电压为180 V;检测电压为2 225 V;喷管温度为140℃。结果:环维黄杨星D的线性范围为0.5～200 ng·mL~(-1),最低检测限为0.2 ng·mL~(-1),日内精密度RSD为6.1％,日间精密度的RSD为7.6％。结论:该测定方法具有灵敏、专一和快速的优点,应用本法测定了大鼠ig给药环维黄杨星D的血浆浓度。     

Cyclovirobuxine D ameliorates acute myocardial ischemia by K(ATP) channel opening, nitric oxide release and anti-thrombosis

Cyclovirobuxine D is an active compound extracted from Buxus microphylla, which has been used for treating acute myocardial ischemia in China. The present study was to investigate its mechanism on myocardial ischemia. Cyclovirobuxine D significantly increased cardiomyocytes viability injured by oxidation or hypoxia. It significantly reduced the infarct size induced by ligating the coronary artery in rats, and the effect was almost abolished by glibenclamide, a blocker of ATP sensitive potassium channel, but it was not influenced by cyclooxygenase-2 inhibitor celecoxib or estrogen receptor antagonist tamoxifen. In addition, cyclovirobuxine D significantly protected rat aorta endothelial cells against hypoxia and enhanced nitric oxide (NO) release from endothelial cells, which was inhibited by nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). Furthermore, cyclovirobuxine D significantly decreased the weight of venous thrombus in rats. In conclusion, the action mechanism of cyclovirobuxine D on myocardial ischemia may be related with its cytoprotection, K(ATP) channel opening, NO generation stimulating and venous thrombosis inhibiting.     

蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

A Population Analysis of Nebulized (R)-albuterol in Dogs Using a Novel Mixed Gut-Lung Absorption PK-PD Model

Purpose. The objectives of this study were to 1) construct a pharmacokinetic-pharmacodynamic (PK-PD) model, and 2) determine the PKs and PDs of (R)-albuterol when given by nebulization to 8 dogs for 7 consecutive days. Methods. Four doses were evaluated (0.002, 0.02, 0.1, and 0.4 mg/kg/day). Blood samples were obtained after drug administration on days 1 and 7. Heart rates (HR) were obtained during treatment days 1, 4 and 7. All (R)-albuterol plasma concentrations were fitted using a mixed gut-lung absorption 2-compartment PK model. Day-1, 4, and 7 HR data were co-modeled using a direct response model with Hill-type equations, including a necessary tolerance phenomenon. The population PK-PD analysis was performed with an iterative 2-stage methodology (IT2S). Results. No chiral inversion was seen, and double absorption peaks on the plasma concentration versus time curves were observed in the majority of dogs. These were hypothesized to be the result of combined gut and lung absorption of (R)-Albuterol. Results indicated that 67% (range: 57-89%) of (R)-albuterol systemic exposure after nebulized administration is due to gut absorption. Mean population PK parameters were KaGI (10±5.7 h^–1), KaLUNG (21±9.5 h^–1), CLc/F (0.6±0.2 L/h/kg), CLd/F (1.4±0.5 L/h/kg), Vc/F (1.4±0.9 L/kg), and Vp/F (4.8±2.4 L/kg). (R)-albuterol administration was associated with an increase in the dogs heart rates. A tolerance effect related to the cumulative dose was observed and modeled. Conclusions. The presented PK-PD model appears to differentiate gut from lung absorption when (R)-albuterol is given by 15-minute nebulization to dogs. These results agree with the accepted hypothesis that most of the systemic exposure of (R)-albuterol after nebulized administration is due to gut absorption.     

Power Spectral Analysis of Heart Rate Variability in Rats as a Quantitative Tool in the PK-PD Analysis of the Parasympatholytic Activity of Atropine

Purpose. To utilize power spectral analysis (PSA) of heart rate variability (HRV) as a pharmacodynamic (PD) measure of atropine parasympathetic effect, and to model the kinetics of action. Methods. Heart rate data was collected following atropine administration to rats and was analyzed off-line for high frequency peaks by PSA of HRV as a measure of parasympathetic tone. A temporal cumulative approach (TCA) detected transient changes in parasympathetic activity. The pharmacokinetics (PK) was analyzed and linked to both direct and indirect PK-PD models. Results. TCA enabled a quantitative measure of atropine parasympathetic activity. A simultaneous fit of the indirect PK-PD model to the experimental data of all three atropine doses successfully captured the experimental data. Conclusions. TCA can be used as a quantitative measure of parasympathetic tone. Our work has established a preclinical model to investigate the kinetics of drug action on the autonomic nervous system.     

冠心病患者氯吡格雷群体药动学-药效学模型研究

目的 建立冠心病患者氯吡格雷群体药动学-药效学模型,为尽早诊断和干预氯吡格雷抵抗提供临床依据.方法 前瞻性收集使用双联抗血小板治疗冠心病的患者101例,分别以患者体内氯吡格雷活性代谢产物(clopidogrel active metabolite,Clop-AM)浓度和血小板最大聚集率(maximum platelet...     

环维黄杨星D的前药改造及生物活性研究

目的通过对植物活性单体——环维黄杨星D的前药改造，以寻求疗效更好、治疗安全范围更宽的心血管药物。方法根据前药设计原理，设计合成目标化合物，并研究其生物活性。结果获得7个环维黄杨星D新衍生物，并经光谱证明其结构。结论选取部分环维黄杨星D新衍生物进行抗心律失常药理实验，结果表明部分化合物药理效果优于环维黄杨星D。     

健康志愿者单次和多次口服美敏伪麻缓释胶囊的药动学研究

目的研究美敏伪麻缓释胶囊经单、多次给药后的药动学特征,评估其在健康志愿者体内的安全性。方法 22例受试者随机、开放试验设计,研究单、多次给药药动学特征。血浆中氯苯那敏、伪麻黄碱、右美沙芬、右啡烷采用LC-MS/MS法测定,药动学参数采用Win Nonlin软件计算。安全性特征以记录到的所有不良事件来进行评价。结果整个研究过程中没有严重不良事件报告。单次口服美敏伪麻缓释胶囊后,伪麻黄碱、氯苯那敏、右美沙芬和右啡烷均在3~5 h达峰,t1/2分别为6.30±1.17、23.3±6.91、10.4±2.19、8.62±3.04 h,Cmax分别为203±40.4、5.05±1.39、4.29±3.95、1.95±0.72 ng/m L,AUClast分别为2 050±559、137±47.5、61.3±67.5、17.2±6.58μg·h/L,AUCinf分别为2 140±570、161±63.8、17.6±6.65、62.8±69.3μg·h/L。在2次/d,连续给药4 d后基本达到稳态血药浓度,伪麻黄碱、氯苯那敏、右美沙芬和右啡烷的Cmax、Cmin、AUCtau,ss与单次给药比较均有不同程度的升高,波动系数的平均值为107%~271%。结论美敏伪麻缓释胶囊多次给药后4 d达到稳态血药浓度,暴露均较单次给药后有所增高,在健康志愿者体内安全性良好。     

滁菊总黄酮对异丙肾上腺素致大鼠急性心肌缺血的影响

目的 观察滁菊总黄酮对异丙肾上腺素（ISO）致急性心肌缺血模型大鼠的保护作用。方法 将大鼠皮下注射ISO复制大急性心肌缺血模型,观察滁菊总黄酮对模型大鼠心电,血清肌酸激酶（CK）、乳酸脱氢酶（LDH）、心肌组织超氧物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）含量的影响。结果 滁菊总黄酮能够抑制急性心肌缺血模型大鼠心电图J点抬高,降低血清CK、LDH活性,升高心肌组织SOD、CAT活性,降低MDA含量。结论 滁菊总黄酮对ISO致心肌缺血模型大鼠有保护作用。     

黑龙江地产山里红叶醇提液对异丙肾上腺素诱导大鼠急性心肌缺血关键酶的影响

摘 要 目的： 观察山里红叶醇提液对异丙肾上腺素诱导的大鼠急性心肌缺血的保护作用并初步探讨其作用机制。方法: 皮下多点注射异丙肾上腺素造成大鼠急性心肌缺血模型,测定血清中谷草转氨酶(AST)、血清肌酸激酶(CK)、乳酸脱氢酶(LDH)、羟丁酸脱氢酶(HBDH)、超氧化物歧化酶(SOD)的活性及血清丙二醛(MDA)水平。结果: 山里红叶醇提液能抑制异丙肾上腺素诱导的大鼠中血清中AST、CK、LDH、HBDH的活性及升高血清SOD活性,降低血清MDA含量。结论: 山里红叶醇提液对大鼠异丙肾上腺素引起心肌缺血的关键酶有一定的保护作用。