丹参注射液对大鼠体内稳态华法林药动学和药效学参数的影响

目的 探讨丹参注射液对大鼠体内稳态华法林药动学和药效学参数的影响. 方法 采用平行、随机的实验设计. 丹参注射液 5 g.kg^-1腹腔注射给药,bid,连续9 d ; 华法林0.2 mg.kg^-1.d^-1灌胃给药,每天1次连续9 d. 分别在给药的第1,6和10天从尾动脉抽取血样测定血药浓度和凝血酶原时间（PT）. 结果 丹参对PT值没有影响（P>0.05）,当丹参和华法林合用时,丹参增加华法林的血药浓度（P<0.05）,改变华法林的药动学参数（P<0.05）和药效学主要参数INR（P<0.05）. 结论 丹参和华法林联合用药时发生相互作用,可能导致出血,应注意监测.     

复方丹参滴丸对华法林在人体内药动学和药效学的影响

目的研究复方丹参滴丸对华法林在人体内药动学和药效学的影响,以及单独服用复方丹参滴丸4周后对凝血酶原时间(PT)和活化部分凝血活酶时间(APTT)的影响。方法采用随机、单盲、双周期交叉、安慰剂对照试验设计。12名男性健康志愿者随机分为2组(6人/组),连续5周每日分别服用复方丹参滴丸(10片,每天3次)或安慰剂(10片,每天3次);d29口服单剂量华法林5 m g;第2周期2组交叉服用安慰剂或复方丹参滴丸,其余给药方案不变。按要求收集志愿者血样,分别以高效液相色谱法(H PLC)测定华法林的血药浓度以及半自动血凝仪测定常见凝血指标。结果合用复方丹参滴丸后,华法林的药动学参数cmax、AUC0~144、AUC0~∞、t1/2显著增加(P<0.05),CL/F显著减小(P<0.05),tmax和V/F没有显著变化;华法林的药效学参数发生显著变化。单独服用复方丹参滴丸4周后,PT和APTT均发生显著变化。结论复方丹参滴丸可影响华法林的药动学和药效学;单独服用复方丹参滴丸4周对凝血功能有显著影响。     

大豆异黄酮对华法林在人体内药动学和药效学的影响

目的:研究大豆异黄酮对华法林在人体内药动学和药效学的影响。方法:采用随机、单盲、双周期交叉、安慰剂对照试验设计。12名健康志愿者(男女各半)随机分为2组,连续5 wk每日分别服用大豆异黄酮胶囊(75 mg)或安慰剂1粒;d 29口服单剂量华法林5 mg;第2周期2组交叉服用安慰剂或大豆异黄酮胶囊,其余给药方案不变。按要求收集志愿者血样,分别以高效液相色谱(HPLC)法测定华法林的血药浓度以及半自动血凝仪测定常见凝血指标。结果:合用大豆异黄酮后,华法林的药动学参数c_(max)、AUC_(0～144)、AUC_(0～∞)、t_(1/2)显著增加(P<0.05),CL(F)显著域小(P<0.05),t_(max)和V_d(F)没有显著变化;华法林的药效学参数均无显著变化。单独服用大豆异黄酮4 wk后,凝血酶原时间(PT)和活化部分凝血活酶时间(APTF)无显著变化。结论:大豆异黄酮可影响华法林的药动学,但不影响华法林的药效学;单独服用大豆异黄酮4 wk对凝血功能无明显影响。     

克拉霉素对替硝唑大鼠体内药动学的影响

目的探讨克拉霉素对替硝唑大鼠体内药动学过程的影响。方法大鼠随机分为两组,每组5只,其中一组大鼠灌胃给药替硝唑后测定血浆中药物的质量浓度,另一组灌胃给药克拉霉素,连续5 d,于第6天联合给药替硝唑与克拉霉素,而后测定血浆中替硝唑药物质量浓度,计算药动学参数。用DAS软件程序进行数据处理并采用SPSS软件进行统计学分析。结果单独给药替硝唑组的主要药动学参数为:ρmax为(27.08±2.98)mg.L-1,t1/2为(2.16±0.76)h,AUC0-24 h为(138.04±5.84)mg.h.L-1。联合给药组的替硝唑主要药动学参数为:ρmax为(32.73±8.37)mg.L-1,t1/2为(2.76±1.69)h,AUC0-24 h为(160.45±7.83)mg.h.L-1。其中,两组间AUC及Cl/F存在显著性差异(P<0.05)。结论克拉霉素对替硝唑大鼠体内药动学过程影响较小。     

阿哌沙班在大鼠体内药动学/药效学研究

目的 考察阿哌沙班大鼠体内药动学并评价其与药效学的相关性。方法 采用超高效液相色谱-串联质谱（UPLC-MS/MS）测定不同时间阿哌沙班血药浓度并绘制血药浓度-时间曲线,同时测定各时间点凝血酶原时间（PT）延长倍数并绘制药效-时间曲线,对药动及药效进行相关性分析。结果 阿哌沙班以2 mg/kg剂量iv给予大鼠,血药浓度时间曲线下面积（AUC_0-∞）、半衰期（t_1/2z）分别为（4 016.07±1 160.46）μg·h/L、（2.95±1.59）h;以10 mg/kg剂量ig给药,AUC_0-∞、t_1/2z、峰浓度（C_max）、达峰时间（t_max）、生物利用度（F）分别为（17 973.48±3 145.30）μg·h/L、（1.52±0.36）h、（4 949.12±615.38）μg/L、（1.00±0.71）h、89.5%。阿哌沙班以10 mg/kg剂量ig给药后0.5~2.0 h可显著延长PT,以各时间点PT延长倍数对血药浓度作图呈良好的线性关系。结论 阿哌沙班大鼠ig给药F高,吸收迅速,延长PT的效应与血药浓度呈现良好的相关性。     

阿奇霉素在中国健康人体血浆中的药动学研究

目的研究阿奇霉素在健康中国人体中的血浆药动学,为临床用药提供参考。方法10名健康志愿者单剂量口服阿奇霉素500mg后,高效液相色谱-紫外检测法测定血浆药物浓度。采用F检验结合AIC法判别房室模型,DAS药动学程序计算药动学参数。结果最佳房室模型为二室模型(Wi=1/C2,AICmin=-7.4821),主要的药动学参数:α为(0.29±0.13)h-1,β为(0.02±0.003)h-1,Ka为(0.72±0.22)h-1,t1/2β为(38.93±7.74)h,tmax为(2.60±0.49)h,cmax为(434.74±47.65)μg.L-1,AUC0～144和AUC0～∞分别为(12179.42±3001.11)μg.h.L-1和(13338.35±3062.56)μg.h.L-1。结论阿奇霉素片在中国健康人体中的血浆药动学参数与国内外文献报道基本一致。     

阿奇霉素在中国健康人体血浆中的药动学研究

OBJECTIVE To study the pharmacokinetics of azithromycin tablet in Chinese healthy volunteers.METHODS 10 healthy volunteers were given a single oral dose of 500mg azithromycin tablet.The plasma concentrations of azithromycin were determined by HPLC-UV.The     

阿奇霉素在中国健康人体血浆中的药动学研究

目的研究阿奇霉素在健康中国人体中的血浆药动学,为临床用药提供参考。方法10名健康志愿者单剂量口服阿奇霉素500mg后,高效液相色谱-紫外检测法测定血浆药物浓度。采用F检验结合AIC法判别房室模型,DAS药动学程序计算药动学参数。结果最佳房室模型为二室模型(W_i=1/C²,AIC_min=-7.4821),主要的药动学参数:α为(0.29±0.13)h^-1,β为(0.02±0.003)h^-1,K_a为(0.72±0.22)h^-1,t_1/2β为(38.93±7.74)h,t_max为(2.60±0.49)h,c_max为(434.74±47.65)μg·L^-1,AUC_0～144和AUC_0～∞分别为(12179.42±3001.11)μg.h·L^-1和(13338.35±3062.56)μg·h·L^-1。结论阿奇霉素片在中国健康人体中的血浆药动学参数与国内外文献报道基本一致。     

药动学-药效学结合模型的研究进展

本主要对近年来药动学．药效学结合模型在模型建立、药理学、毒理学、临床应用及新药研发等方面的进展进行了综述，并展望其发展前景。     

Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects

Aims

This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects.

Methods

Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured.

Results

An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin.

Conclusions

Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity.     

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin

AIM: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. RESULTS: Lasofoxifene had no clinically meaningful effect on R- or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration-time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/*1, respectively. The mean PT AUC and Cmax ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar. CONCLUSIONS: Lasofoxifene has no clinically meaningful effect on the pharmacokinetics of warfarin. Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during lasofoxifene introduction and discontinuation, consistent with warfarin's label.     

The Effects of Danshen (Salvia miltiorrhiza) on Warfarin Pharmacodynamics and Pharmacokinetics of Warfarin Enantiomers in Rats

The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats. After a single oral dose of racemic warfarin (2 mg kg^?1), treatment with oral Danshen extract (5 g kg^?1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0·2 mg kg^?1 day^?1 for 5 days) the 3-day treatment of Danshen extract (5 g kg^?1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin. The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.     

氢化可的松琥珀酸钠口服结肠靶向pH敏感型水凝胶的药动学与药效学研究

目的 对氢化可的松琥珀酸钠(hydrocortisone sodium succinate,HSS)口服结肠靶向pH敏感型水凝胶(oral colon targeted pH-sensitive hydrogel of HSS,HSS-GEL)进行药动学与药效学研究。方法 考察HSS-GEL与HSS在大鼠体内血药浓度变化;建立2,4,6-三硝基苯磺酸(2,4,6-trinitrobenzene sulfonic acid,TNBS)诱导小鼠溃疡性结肠炎(ulcerative colitis,UC)模型,以小鼠疾病活动指数(disease activity index,DAI)、结肠长度、髓过氧化酶活性(myeloperoxidase,MPO)和脏器指数为指标,考察了HSS-GEL的结肠炎治疗作用。结果 HSS-GEL的T_max、C_max和AUC与HSS比较均有统计学差异(P<0.01),其中HSS-GEL的T_max比HSS明显延长,药物吸收入血时间明显延后;HSS-GEL组C_max与HSS的C_max相比明显降低;HSS-GEL组AUC是同等剂量HSS的39.38%,表明将HSS制成HSS-GEL口服后药物入血量明显减少;造模后小鼠由于炎症反应,DAI、MPO活性和脏器指数均升高,结肠缩短,给予HSS-GEL治疗后,小鼠DAI、MPO活性和部分脏器指数与TNBS组相比均明显降低(P<0.05或P<0.01);而TNBS+HSS-GEL组小鼠MPO活性和部分脏器指数降低程度明显大于TNBS+HSS组,表明HSS-GEL对TNBS诱导的小鼠UC有很好的治疗作用,且效果优于HSS。结论 制备的HSS-GEL具有良好的结肠靶向性与结肠炎治疗效果。     

Effects of Baicalin on Oral Pharmacokinetics of Caffeine in Rats

Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC₅₀ values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.     

阿奇霉素微球干混悬剂的研制及其药动学

按不同处方制备阿奇霉素-乙基纤维素(EC)微球并进行质量评价。再将微球制成干混悬剂,考察其在12名健康志愿者体内的药动学情况。结果表明,微球的优化处方为药物-EC重量比2∶1,EC浓度50mg/ml,水油相比15∶1,用其制成的干混悬剂口感好、无苦味。自制干混悬剂和参比干混悬剂的药-时曲线形状相似,AUC0～96h分别为(7.61±1.31)和(7.45±1.66)μg·h·ml-1。     

Facilitation of Pulmonary Insulin Absorption by H-MAP: Pharmacokinetics and Pharmacodynamics in Rats

Purpose. Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. Methods. Aliquots (100 l) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. Results. The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (C_max) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG_0t) was achieved for H-MAP/insulin combination (66 ± 5 %) compared to insulin alone (47 ± 10 %). Conclusion. H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.     

阿奇霉素开始治疗时间对肺炎支原体肺炎临床转归的影响

目的：评价阿奇霉素不同开始时间对肺炎支原体肺炎（MPP）临床转归的影响。方法：选择2016-2017年在我院就诊的MPP患儿335例,按照阿奇霉素开始治疗时间分为早期干预组（发病≤72 h）109例和晚期干预组（发病>72 h）226例,均给予阿奇霉素干混悬剂10 mg/（kg·d）晨起顿服,先口服3~5 d,停药3~4 d,再口服3 d,疗程9~12 d。比较两组患儿的临床转归情况及肺外并发症发生率。结果：两组的总病程及严重MPP、肺不张、胸腔积液比例比较差异均无统计学意义（P均>0.05）,而早期干预组肺外并发症发生率为17.43%,低于晚期干预组的28.32%（χ2=4.677,P<0.05）。治疗后随访结果显示,两组患儿的WBC、CRP、肺不张、胸腔积液复常率比较差异均无统计学意义（P均>0.05）。结论：阿奇霉素早期使用并不能进一步改善MPP的临床症状及预后,但可以降低肺外并发症的发生率。