中毒剂量与治疗剂量克仑特罗在兔体内的药动学研究

目的研究克仑特罗在引起不良反应的大剂量下兔体内的药动学,探讨中毒剂量与治疗剂量的药动学参数存在的差异。方法新西兰兔单剂量灌胃(ig)中毒剂量(150μg·kg^-1)与治疗剂量(5μg·kg^-1)的盐酸克仑特罗溶液,采用酶标免疫分析(ELISA)测定不同时间的血浆药物浓度。两组试验数据采用3P97程序拟合处理,求得不同剂量的药动学参数。结果两组剂量的浓度-时间曲线均符合一室开放模型。中毒剂量与治疗剂量的Ke分别为(0.39±0.08)h^-1和(0.18±0.07)h-1;t_1/2(ke) 分别为(1.82±0.34)h和(4.30±1.61)h;t1/2(ka)分别为(0.67±0.28)h和(1.05±0.28)h;t_(max)分别为(1.48±0.39)h和(2.70±0.22)h;C_max分别为(71.37±37.76)ng·mL^-1和(1.56±0.98)ng·mL^-1;AUC分别为(310.28±115.00)ng·h·mL^-1和(14.28±7.22)ng·h·mL^-1;MRT分别为(3.74±0.51)h和(8.82±2.78)h。结论两组剂量在Ke(P<0.01),t_1/2(ke) (P<0.05),t_1/2(ke) (P<0.05)、t_max(P<0.01),MRT(P<0.01)等存在显著差异;C_max,AUC随剂量增加而增加,C_max/D₀、AUC/D₀无显著性差异(P>0.05),为临床抢救中毒病人提供参考。     

酒石酸美托洛尔片在中国健康人体的药代动力学

目的　研究单剂量和多剂量酒石酸美托洛尔片在中国健康人体的药代动力学。方法　22名健康受试者口服酒石酸美托洛尔片50mg,用HPLC-荧光检测法测定血浆中美托洛尔的浓度。结果　所得药代动力学参数如下。单剂量:AUC0-t为(395. 6±298. 95)ng·h·mL-1,AUC0-∞为(433. 83±342. 94)ng·h·mL-1,Cmax为(63. 06±34. 61)ng·mL-1,tmax为(1. 573±0. 52)h,MRT为(7. 40±2. 31 )h;多剂量:AUCss0-t为( 504. 67±322. 35 )ng·h·mL-1,Cmax为(77. 72±45. 69)ng·mL-1,tmax为(1. 7±0. 6)h,Cmin为(4. 12±1. 57)ng·mL-1,平均稳态血药浓度Cav是( 21. 03±13. 43 )ng·mL-1,血药浓度波动度DF为(367. 29±112. 56)%。结论　酒石酸美托洛尔片单剂量和多剂量给药后,安全性良好。     

复方烟酸缓释片与烟酸普通片在犬体内药代动力学的比较研究

目的比较复方烟酸缓释片与烟酸普通片中烟酸及其代谢物烟尿酸在Beagle犬体内的药代动力学。方法6只Beagle犬采用随机交叉给药方案,单剂量口服500mg复方烟酸缓释片或烟酸普通片后,用RP-HPLC法同时测定Beagle犬血浆中烟酸及其主要代谢物烟尿酸的药物浓度,计算药动学参数和相对生物利用度。结果Beagle犬单剂量口服500mg复方烟酸缓释片和烟酸普通片后,烟酸主要药代动力学参数tmax分别为(2.17±0.61)h和(1.04±0.49)h,Cmax分别为(30.85±4.50)mg·mL-1和(68.05±20.48)mg·mL-1,t1/2分别为(0.69±0.43)h和(0.43±0.10)h,MRT分别为(2.12±0.62)h和(1.72±0.40)h,AUC0-12h分别为(62.17±21.13)mg·h·L-1和(138.67±44.86)mg·h·L-1;烟尿酸主要药代动力学参数tmax分别为(2.42±0.49)h和(1.50±0.45)h,Cmax分别为(0.76±0.34)mg·mL-1和(1.66±0.63)mg·mL-1,t1/2分别为(1.74±1.24)h和(1.64±1.03)h,MRT分别为(2.42±0.62)h和(1.79±0.38)h,AUC0-12h分别为(1.55±0.76)mg·h·L-1和(3.25±1.16)mg·h·L-1。结论单剂量口服复方烟酸缓释片,测得的Cmax、tmax和AUC与烟酸普通片均有显著性差异,受试缓释片的tmax长于参比普通片,Cmax低于参比普通片,说明受试缓释片无突释现象,有一定缓释效果。     

单剂量口服阿德福韦酯片人体药动学研究

目的:研究单剂量口服阿德福韦酯片在健康人体中的药动学。方法:采用随机、开放、三交叉设计试验,12名健康志愿者随机分为3组,在3周期里单次空腹口服阿德福韦酯片5、10、30mg,用高效液相色谱-质谱串联法测定血浆药物浓度,计算药动学参数。结果:单剂量口服阿德福韦酯片5、10、30mg后阿德福韦的主要药动学参数Cmax分别为(11·4±3·7)、(25·4±8·2)、(76·3±23·0)ng·mL-1,tmax分别为(1·69±1·41)、(0·90±0·56)、(0·94±0·50)h,AUC0～t分别为(102·7±51·7)、(235·0±82·3)、(715·4±267·6)ng·h·mL-1,AUC0～∞分别为(168·7±30·7)、(266·2±83·7)、(741·5±273·9)ng·h·mL-1。结论:阿德福韦酯吸收迅速,Cmax、AUC与剂量呈正相关。健康志愿者单剂量口服阿德福韦酯片5～30mg较安全。     

西嗪伪麻缓释片多次给药后伪麻黄碱的人体药动学研究

目的:研究健康受试者多次口服国产西嗪伪麻缓释片后伪麻黄碱的药动学特点。方法:10名健康受试者(男女各半),每次空腹口服西嗪伪麻缓释片(含伪麻黄碱120mg)1片,bid,连续6d。应用液-质联用(LC-MS)法测定血浆中伪麻黄碱浓度,所测数据用DASver2.0程序处理,然后进行药动学研究。结果:多次口服西嗪伪麻缓释片后伪麻黄碱主要药动学参数为t1/2(6.06±0.67)h,tmax(3.90±0.99)h,Cmax(272.03±52.56)ng·mL-1,CL(58.70±16.80)L·h-1,Vd(255.30±71.20)L,AUC0～36(3419.70±750.80)ng·h·mL-1,AUC0～∞(3422.20±751.00)ng·h·mL-1,MRT0～36(9.45±0.61)h,MRT0～∞(9.47±0.61)h。多次口服受试制剂3d后,伪麻黄碱血药浓度达稳态,其稳态药动学参数为Cssmax(272.03±52.56)ng·mL-1,Cssmin(104.99±37.15)ng·mL-1,Cssav(198.55±38.95)ng·mL-1,DF(0.86±0.20),AUCss(2382.61±467.44)ng·h·mL-1。以上参数男女比较均无显著性别差异,另多次和单次给药所得药动学参数比较均无统计学意义。受试者服药期间未出现明显不良反应。结论:西嗪伪麻缓释片中伪麻黄碱有明显的缓释效果;多次给药后伪麻黄碱的药动学过程无明显改变,在正常人体内无蓄积。     

复方盐酸曲马多人体药动学研究

目的:研究复方盐酸曲马多的人体药动学。方法:10名健康志愿者口服复方盐酸曲马多1片(每片含盐酸曲马多37.5mg,对乙酰氨基酚325mg),用高效液相色谱-荧光法测定血浆中曲马多的浓度,计算药动学参数。结果:口服复方盐酸曲马多片1片后AUC0~24为(1361.61±441.79)ng·h·mL-1,AUC0~∞为(1555.04±582.51)ng.·h·mL-1,Cmax为(134.81±33.96)ng·mL-1,tmax为(1.9±0.57)h,t1/2为(7.63±2.02)h。结论:本方法可用于复方盐酸曲马多人体药动学研究。     

2种左甲状腺素钠片的人体生物等效性研究

目的:研究2种左甲状腺素钠片的人体生物等效性。方法:按照两制剂两周期随机交叉设计,26名男女健康受试者分别单剂量口服受试制剂(Berlthyrox)或参比制剂(雷替斯)6片(每片含左甲状腺素钠100μg)。采用放射免疫法测定血清中T4、T3浓度,并计算药动学参数,评价2种制剂的生物等效性。结果:受试制剂与参比制剂的T4主要药动学参数分别为:cmax(138.54±16.22)、(147.45±16.92)ng·mL-1,tmax(2.4±1.0)、(2.3±2.2)h,t1/2(253.58±155.94)、(467.97±638.97)h,AUC0～48h(5550.27±679.50)、(5817.83±649.35)ng·h·mL-1,AUC0～∞(48065.79±28322.17)、(85248.31±113292.36)ng·h·mL-1;T3的主要药动学分别为:cmax(1.56±0.23)、(1.55±0.18)ng·mL-1,tmax(39.7±16.5)、(35.4±18.8)h,t1/2(117.55±107.94)、(105.29±65.78)h,AUC0～48h(64.09±7.52)、(65.06±7.60)ng·h·mL-1,AUC0～∞(330.15±250.21)、(307.33±126.61)ng·h·mL-1。受试制剂与参比制剂T4、T3的相对生物利用度分别为(95.9±11.6)%、(99.2±12.6)%。结论:2种左甲状腺素钠片生物等效。     

高效液相色谱法测定人血浆中卡托普利和人体药动学的研究

目的　建立简便的测定人血浆中卡托普利血药浓度的高效液相色谱法 ,研究卡托普利在健康人体中的药动学参数。方法　以对溴苯乙酰基溴为紫外衍生化试剂 ,采用高效液相色谱紫外检测法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度。结果　卡托普利的血药浓度标准曲线的线性范围为 2 5～ 12 0 0ng·mL- 1 ,其最低定量限为 2 5ng·mL- 1 ,日内及日间RSD均小于 8%。应用所建立的血药浓度检测方法测定 18名健康志愿受试者口服单剂量卡托普利受试制剂和参比制剂 ( 5 0mg)后血药浓度 ,并计算药动学参数。结果表明口服受试制剂或参比制剂后的tmax分别为( 0 6 4± 0 18)h和 ( 0 82± 0 4 1)h ;Cmax分别为 ( 6 0 0 2± 194 3)ng·mL- 1 和 ( 5 82 7± 175 3)ng·mL- 1 ;AUC0→ 8h分别为 ( 14 4 8 5± 4 83 7)ng·h·mL- 1 和 ( 1389 9± 392 5 )ng·h·mL- 1 ;AUC0→∞ 分别为 ( 186 9 4± 70 1 6 )ng·h·mL- 1 和 ( 1781 8± 6 15 5 )ng·h·mL- 1 。结论　本方法操作便捷 ,灵敏度高 ,为血药浓度监测及药代动力学研究提供了方法学基础     

多剂量口服硝苯地平缓释片的药动学及生物等效性研究

目的研究多剂量口服硝苯地平缓释片在人体内的药动学特点和两种硝苯地平缓释片的生物等效性.方法22名健康男性志愿者采用双周期交叉、自身对照试验设计.以尼群地平为内标,采用高效液相色谱-大气压化学源-质谱联用(HPLC-MS)的方法,测定人血浆中硝苯地平的浓度.将22名受试者的经时血药浓度录入DAS(ver 1.0)程序,得到药代动力学参数,并进行统计分析和生物等效性评价.结果多剂量口服 20 mg×7 d 受试和参比制剂后血浆中硝苯地平的Cmax分别为 52.5±27.4、54.0±31.2 ng·ml-1,Cmin分别为 5.4±4.1、6.2±5.9 ng·ml-1,Cav分别为 16.8±9.2、19.3±12.4 ng·ml-1,Tmax分别为 3.7±0.9、4.1±1.1 h,t1/2分别为 8.9±4.9、8.5±3.1 h,AUC0-τ分别为 403.4±221.0、461.9±296.6 ng·h·ml-1,AUC0-36h分别为 444.4±256.1、503.1±330.9 ng·h·ml-1,AUC0-∞分别为 482.1±268.9、542.3±348.4 ng·h·ml-1 ,DF分别为(299.8±117.7)%、(279.2±97.5)%.Tmax进行非参数秩和检验,Cmax、Cmin、Cav、DF、AUC0-τ、AUC0-36h、AUC0-∞经对数转换后做方差分析,并经双向单侧t检验,两制剂的Tmax、Cmax、Cmin、Cav、DF、AUC0-τ、AUC0-36h、AUC0-∞均无显著性差异(P＞0.05),受试制剂的Cav、DF、AUC0-36h、AUC0-τ、AUC0-∞的90%可信限落在参比制剂的80%～125%范围内;Cmax、Cmin的90%可信限落在参比制剂的70%～143%范围内.两种制剂的相对生物利用度为(100.6±38.6)%(AUC0-36h,T/AUC0-36h,R×100%).结论两种制剂具有生物等效性.     

国产酒石酸唑吡坦片剂人体生物等效性研究

目的:研究国产酒石酸唑吡坦片剂和进口酒石酸唑吡坦片剂的人体生物等效性。方法:采用高效液相荧光检测法,测定18例男性健康受试者单剂量口服10 mg国产和进口酒石酸唑吡坦片剂的唑吡坦血浆浓度。采用3p97程序对主要的药动学参数Cmax,AUC0-12h,Tmax进行统计分析。结果:国产和进口酒石酸唑吡坦片剂的Cmax、分别为(113．73±11．40)和(116．58±16．13)ng·mL-1,Tmax分别为(1．01±0．25)和(1．03±0．24)h,t1/2 ke分别为(3．02±0．29)和(2．92±0．42)h,AUC0-12 h分别为(413．81±61．64)和(434．0±62．20)ng·h·mL-1。2种制剂的Cmax,AUC0-12h和Tmax无显著性差异。国产酒石酸唑吡坦片剂相对生物利用度为(95．50±7．50)％。结论:国产和进口酒石酸唑吡坦片剂两种制剂具有生物等效性。     

Weibull分布:药物最小致死量的理论分布

基于药物的最小致死量服从Ｗｅｉｂｕｌ分布的假设，以Ｗｅｉｂｕｌ分布为模型计算药物的ＬＤ５０及一般的ＬＤＫ．通过所得计算结果与对数正态分布的对比分析来证实这一假设，探讨两种统计分布模型的差异，阐述以Ｗｅｉｂｕｌ分布为药物最小致死量理论分布的意义，并提出以复相关系数评价两种理论分布对实验数据的拟合良度．     

老年人用药剂量的商榷

从20060张门诊处方调查中发现老年人处方占门诊处方24％,急诊处方占34.9％。而处方中按年龄给予调整剂量者仅占1.4％。提出应按老年人生理,病理情况,随药物的性质和年龄的增长来调整用药剂量,以使药物能发挥最大疗效,和最小不良反应。     

苯二氮类负荷剂量法与逐日递减法治疗戒酒综合征的对照研究

目的 :比较苯二氮 艹卓 类负荷剂量法与逐日递减法治疗戒酒综合征的有效性和安全性。方法 :111例AWS总分≥ 7分、符合CCWD - 2 -R戒酒综合征诊断标准的患者 ,随机分为两组进行对照研究 ,分别采用负荷剂量法和逐日递减法治疗 ,以AWS减分率为疗效评定指标 ,以TESS为评价不反应指标。结果 :苯二氮 艹卓 类负荷剂量法治疗戒酒综合征 ,2周末有效率 96 % ,与逐日递减法比较 ,无显著性差异 (P >0 0 5 )。但负荷剂量法在治疗d1、d2就能较全面控制戒断症状 ,其AWS的减分率较逐日递减法有非常显著性差异 (P <0 0 1) ,并且负荷剂量法能较快改善震颤、焦虑、激越、幻觉、定向力等症状 ,AWS上述各因子分明显低于逐日递减法 (P <0 0 5 ,P <0 0 1)。 2周后负荷剂量法的不良反应的发生率明显低于逐日递减法 (P <0 0 5 ,P <0 0 1) ,其不良反应的程度亦明显较低 (P <0 0 1)。结论 :苯二氮 艹卓 类负荷剂量法治疗戒酒综合征简便、有效、安全 ,值得临床应用     

中毒剂量与治疗剂量克仑特罗在兔体内的组织分布

目的：研究中毒剂量与治疗剂量克仑特罗在兔体内的组织分布,分析比较两者差异.方法：新西兰兔单剂量灌胃中毒剂量（150μg·kg^-1）与治疗剂量（5 μg·kg^-1）的盐酸克仑特罗溶液,给药后24 h处死,采用酶标免疫分析测定克仑特罗在心、肝、肾、肺、眼、肌肉的含量.结果：中毒剂量组以肝、肾组织中药物含量为最高,治疗剂量组以肺、肝组织中药物含量为最高.结论：中毒剂量组与治疗剂量组在24 h的组织分布存在差异.     

肿瘤放疗中剂量测量用热释光探测器的基本特性研究

目的研究肿瘤放疗剂量测量用热释光探测器(TLD)的基本特性,为临床照射剂量测量提供可靠依据。方法应用TLD、NE-Farmer2581-A电离室剂量仪,热释光剂量读出系统,AECL-780C钴-60治疗机,用线性相关、t检验统计分析,了解剂量测量用TLD的质量、敏感度、剂量响应性、剂量重复性。结果 TLD表面洁净、光滑,直径、厚度分别为3.00、0.80mm,精度为±0.01%,面积重量为(29.4±0.9)mg/cm2,敏感度因子(Si)为1.00±0.09,在1 000cGy范围内读出发光值与辐射剂量呈线性关系,r值为0.99,在cGy剂量级重复使用10次,读出值变化0.66%。结论 TLD质量好、性能稳定、线性相关性强、重复测量精度高,符合国际推荐标准,可用于肿瘤放疗剂量测定。     

The clinical pharmacokinetics of phenytoin

Procedures for estimating the variability in dosage requirements of phenytoin to achieve steadystate plasma concentrations of 10–20 mg/liter and for estimating the plasma concentrations produced on a fixed dose are given. Further, a method is proposed for estimating the dosage required to achieve a desired steady-state plasma phenytoin concentration when a steady-state value on a known daily dose has been measured, A method is also described for estimating dosage requirements when two or more plasma concentrations have been measured. These methods are derived from data obtained on administering phenytoin in four to five different dosage regimens until steady state was achieved in each of nine volunteers. The drug was administered orally as a suspension every 8 hr, starting with about 100mg/day. The daily dose was increased in steps, and maintained at each daily dose rate for 6–14 days, or longer. Blood samples were drawn 4 and 8 hr after the last dose on 2 successive days at the end of each step and analyzed for phenytoin concentration. The average of these values was used to estimate the steady-state plasma concentration, C_pss. For each subject the C_pss values were fitted to a rearranged Michaelis-Menten equation C_pss =K_mR/(V_m-R). In this equation R is the dosing rate, V_m is the maximum rate of metabolism, and K_m is a constant equal to the plasma concentration at which the metabolism rate is one-half maximum. The average values found for V_m and K_m were 10.3 mg/kg/day and 11.54 mg/liter, respectively. The individual values of V_m and K_m appear to be constant over time, but there is considerable interindividual variability: coefficients of variation are 25% and 50%, respectively.Supported in part by grants (GM-16496, GM-01791, and GM-00001) from the National Institutes of Health. Dr. Martin was a recipient of a grant from the Swiss National Research Foundation.     

A hand-held calculator program for individualized dosage adjustment of intravenous theophylline in acute asthma

Summary Despite general development of drug assay services and increasing interest in pharmacokinetics, proper dosage regimen calculations are not often made in routine clinical practice. This could be due, in part, to unfamiliarity with pharmacokinetic theory, the consequent difficulty of collaboration and the inevitable delay while data are processed on a computer. The present program for a hand-held calculator (TI-59) was written to minimize these problems, and was designed for the use of intravenous theophylline in the management of acute asthma, where there is a need for individualisation of dosage. Calculations are based on the one compartment open model. With 3–4 plasma drug concentrations taken early in the treatment, the program gives a measure of goodness of fit, the elimination rate constant (k_el), the volume of distribution (V_d) and the suggested infusion rate to achieve a given steady-state level. Data from 10 severe acute asthmatic patients were used to test the model and the estimated parameters were: V_d=0.26±0.029 l/kg (mean±SEM) and k_el=0.20±0.045 h^–1. The average standard deviation (s) for differences between the model and observations was 0.96±0.21 mg/l, of which at least 0.5 mg/l was due to assay error. In seven patients where the infusion period was extended, the predicted steady state plasma concentration agreed reasonably with that observed (r=0.83, df=5, 0.01<p<0.05).     

辅料在各种剂型中的作用

辅料在药物制剂中一般都无药效,但如选用、调配得当,也可起重要作用。不仅能使加工顺利和保证产品质量,且能改进主药的药代动力学作用。本文以辅料所起作用为重点,综述了各类辅料在常规剂型、延效剂型,控释剂型与靶向剂型中应用的理论与实践。     

Distribution of clomipramine,citalopram, midazolam,and metabolites in skeletal tissue after chronic dosing in rats

In recent years, the use of skeletal tissue as an alternative matrix in forensic toxicology has received new interest. In cases where extreme decomposition has taken place, analysis of skeletal tissue is often the only option left. In this article, a fully validated method is presented and the distribution of clomipramine, citalopram, midazolam, and metabolites after chronically administration is examined within skeletal tissue. Rats were chronically dosed with respectively clomipramine, citalopram, or midazolam. Extracts were quantitatively analyzed using liquid chromatography?electrospray ionization?tandem mass spectrometry (LC?ESI?MS/MS). Clomipramine, citalopram, and metabolites, respectively desmethylclomipramine and desmethylcitalopram are shown to be detectable in all bone types sampled. Midazolam and its metabolite α‐OH‐midazolam could not be detected. The absence of midazolam in extracts gives an indication that drugs with pKa values under physiological pH are badly or not incorporated in bone tissue. Bone and post‐mortem blood concentrations were compared. A range of different bone types was compared and showed that the concentration is strongly dependent on the bone type. In concordance with previous publications, the humerus shows the highest drug levels. Skeletal tissue concentrations found ranged from 1.1 to 587.8 ng/g. Comparison of the same bone type between the different rats showed high variances. However, the drugs?metabolite ratio proved to have lower variances (<20%). Moreover, the drugs?metabolite ratio in the sampled bones is in close concordance to the ratios seen in blood within a rat. From this, we can assume that the drugs?metabolite ratio in skeletal tissue may prove to be more useful than absolute found concentration.     

Chlorpromazine dosage and duration of tonic immobility: biphasic effects

Five groups of 2-1/2 to 3 week old chickens were injected with an average of 3.4, 7.4, 18.2, 46.3, 89.4 mg/kg of chlorpromazine (CPZ). Low doses of the drug produced a significant enhancement of tonic immobility but high doses depressed the reaction relative to control subjects. Other investigators have found only enhanced immobility with CPZ, creating a paradox of a tranquilizer potentiating what is thought to be a fear reaction. This report extends the dose-response curve and resolves the paradox.