人体中伊曲康唑及其活性代谢产物羟基伊曲康唑的整合药代动力学研究

目的:羟基伊曲康唑(OH-ITZ)为目前临床一线抗真菌药伊曲康唑(ITZ)的主要活性代谢产物,其与ITZ有着相似的抗菌活性,且血药浓度较母体药物高,因此OH-ITZ的体内过程对临床疗效的影响研究不容忽视。本文旨在建立灵敏、快速的液相色谱-串联质谱法同时测定人血浆中ITZ及OH-ITZ,并应用整合药代动力学模型进行整体评价。方法:血浆样品经沉淀蛋白后,以乙腈(甲酸0.1%)-水(甲酸0.1%)为流动相梯度洗脱,Zorbax XDB C18柱分离,采用电喷雾电离源,以多反应监测(MRM)方式进行正离子检测。定量分析所用的离子反应分别为m/z705→m/z392(ITZ),m/z 721→m/z 408(OH-ITZ)和m/z386→m/z122(内标,丁螺环酮)。结果:测定血浆中ITZ及OH-ITZ的线性范围均为0.50~500ng/mL,日内、日间精密度(RSD)均小于12.4%,准确度(RE)均在±7.5%以内;整合药动学研究结果显示综合浓度药-时曲线符合口服给药药物消除规律,整合后主要药动学参数t1/2和AUC0-∞分别为19.5h,5754ng·h·mL-1。结论:本方法运行时间短、选择性强、灵敏度高、操作简便、血浆用量少,适用于ITZ及OH-ITZ的临床药代动力学研究;其整合药动学模型研究所获参数能够表征ITZ和OH-ITZ的整体处置规律,符合经典药代动力学模型特征。     

兰索拉唑在正常及溃疡模型家兔体内药代动力学研究

目的:建立高效液相色谱法分析兔血浆中兰索拉唑的含量,并比较兰索拉唑在正常及溃疡模型家兔体内药代动力学行为的差异。方法:家兔于20℃水中浸泡8小时建立胃溃疡模型,耳缘静脉给予兰索拉唑注射剂后,分别在不同时间点收集血样,HPLC法测定,采用DASS2.0软件计算给药后的药物动力学参数。结果:兰索拉唑浓度在20~2000 ng.mL-1范围内线性关系良好,最低检测浓度为20 ng.mL-1。低、中、高3个浓度的提取回收率均大于85%,批内、批间相对标准差低于10%。与正常兔比较,溃疡模型家兔给予兰索拉唑药物后体内AUC(0-6.5)明显增加[(916.84±338.61)vs(522.72±172.16)μg.h.L-1,P<0.05]、体内平均滞留时间延长MRT(0-6.5)[(0.824±0.203)vs(0.69±0.13)h,P<0.05]、血浆消除半衰期增大[(0.88±0.44)vs(0.53±0.28)h,P<0.05]、血浆清除率显著减小[(2.74±1.70)vs(6.23±2.21)L.h-1,P<0.05]、最大血药浓度增大[(1091.31±348.94)vs(682.20±234.56)μ...     

注射用兰索拉唑在中国健康人体内的药动学

目的:研究注射用兰索拉唑在健康人体内的药动学特征。方法:30名健康受试者随机分为3组,男女各半,分别静脉滴注兰索拉唑15,30,60mg,进行低、中、高单剂量药动学研究。30mg剂量组并进行多剂量药动学研究。采用LC-MS/MS测定血浆中兰索拉唑的浓度。应用DAS2.1.1软件计算药动学参数。结果:30名健康受试者分别单次静脉滴注注射用兰索拉唑15,30,60mg的主要药动学参数如下tmax为(0.67±0.00),(0.67±0.00),(0.73±0.09)h;Cmax为(857.1±251.2),1 738.5±263.8),(3 609.4±421.6)μg.L-1;AUC0-12为(2 873.9±2 065.4),(3 366.2±1 138.9),(12 321.1±5 632.5)μg.h.L-1;t1/2为(2.5±1.8),(1.4±0.4),(3.0±1.8)h。多次给药的主要药动学参数如下tmax为(0.70±0.07)h;Cmax为(1 530.2±305.1)μg.L-1;AUC0-12为(3 048.1±1 181.0)μg.h.L-1;AUCSS为(3 048.1±1 181....     

西洛他唑片在人体的药动学研究

目的研究西洛他唑片在人体内的药动学。方法12名健康男性志愿者单剂量口服100 mg西洛他唑片,采用高效液相色谱法测定血浆中西洛他唑浓度,数据用3P97软件统计处理。结果西洛他唑片药-时曲线符合二室模型,其Cm ax为(769.5±228.2)μg.L-1,Tm ax为(3.004±1.204)h,T1/2α为(4.72±3.38)h,T1/2β为(25.95±12.22)h,AUC0-72为(12525±3077)μg.h.L-1,AUC0-为(13003±3206)μg.h.L-1。结论西洛他唑在人体内药动学过程符合二室开放模型,本研究可为临床用药提供药动学参数。     

西洛他唑片在健康志愿者体内的药动学及生物等效性

目的:研究国产西洛他唑片在人体的药动学和生物等效性.方法:20名男性健康志愿者随机交叉单剂量口服西洛他唑受试和参比制剂(Pletaal)100mg,采用反相高效液相色谱法测定其血药浓度,计算其药动学参数和相对生物利用度,评价两种制剂的生物等效性.结果:西洛他唑受试和参比制剂的主要药动学参数:t1/2分别为(11.9±4.6)h和(11.2±3.0)h,Tmax分别为(3.7±1.2)h和(4.0±1.2)h,Cmax分别为(749.2±348.7)μg·L-1和(655.2±222.1)μg·L-1,AUC0-48分别为(10 088.5±4 606.1)μg·L-1·h和(9 259.0±3 511.8)μg·L-1·h,AUC0-∞分别为(10 926.3±4 713.6)μg·L-1·h和(10 183.4±3 540.7)μg·L-1·h,西洛他唑受试制剂的相时生物利用度为(107.5±14.9)%.结论:经统计学分析,两种制剂具有生物等效性.     

西洛他唑片的健康人体药动学研究

目的研究国产西洛他唑片在人体内的药动学。方法12名健康男性志愿者单剂量口服100 m g西洛他唑片,采用高效液相色谱法测定血浆中西洛他唑浓度,并用3P 97软件统计处理。结果西洛他唑片药-时曲线符合二室模型,其Cm ax,Tm ax,T1/2,AUC0-72,AUC0-∞分别为(937.10±238.10)μg.L-1,(3.4±0.8)h,(20.4±10.5)h,(12194±4024)μg.h.L-1,(12689±4325)μg.h.L-1。结论西洛他唑在人体内药动学过程符合二室开放模型,本研究可为临床用药提供药动学参数。     

盐酸阿夫唑嗪缓释片人体内生物利用度

目的:比较盐酸阿呋唑嗪缓释片和进口阿呋唑嗪普通片的人体生物利用度和生物等效性。方法:20名男性健康受试者自身交叉口服单剂量盐酸阿呋唑嗪缓释片和进口普通片5mg,用高效液相色谱(HPLC)法测定人血浆中盐酸阿呋唑嗪的浓度,计算药动学参数,以方差分析与双向单侧t检验进行统计学分析。结果:盐酸阿呋唑嗪缓释片和进口普通片的Cmax分别为(28.9±9.6)μg.L-1和(32.9±10.2)μg.L-1,tmax分别为(2.7±0.6)h和(1.4±1.0)h,AUC0→∞分别为(221.1±59.5)μg.L-1.h和(245.7±67.2)μg.L-1.h。两药各药动学参数间均无统计学差异。盐酸阿呋唑嗪缓释片的相对生物利用度为(92.2±13.2)%。结论:两种制剂具有生物等效性。     

利奈唑胺滴眼液在兔眼角膜内的药动学

目的探讨利奈唑胺滴眼液单次滴兔眼后在角膜中的药动学特征。方法 40只新西兰大白兔,局部滴入利奈唑胺滴眼液50μL,采用高效液相色谱法测定兔眼角膜中利奈唑胺的药物浓度,用DAS 2.1.1软件计算药动学参数。结果给药后0～120 h,利奈唑胺在兔眼角膜中的最高浓度为(58.62±15.48)μg.g 1,消除半衰期t1/2为(38.09±11.59)h,药时曲线下面积AUC0 t为(2 459.02±508.95)μg.h.g 1,AUC0∞为(2 834.13±578.96)μg.h.g 1。结论利奈唑胺滴眼液单次滴兔眼后在角膜中具有良好的药代动力学特征和组织通透性。     

西洛他唑片在人体的药动学研究

目的研究西洛他唑片在人体内的药动学.方法 12名健康男性志愿者单剂量口服100 mg西洛他唑片,采用高效液相色谱法测定血浆中西洛他唑浓度,数据用3P97软件统计处理.结果西洛他唑片药-时曲线符合二室模型,其Cmax为(769.5±228.2)μg·L-1,Tmax为(3.004±1.204)h,T1/2α为(4.72±3.38)h, T1/2β为(25.95±12.22)h,AUC0-72为(12525±3077)μg·h·L-1,AUC0-为(13003±3206) μg·h·L-1.结论西洛他唑在人体内药动学过程符合二室开放模型,本研究可为临床用药提供药动学参数.     

国产西洛他唑片的健康人体药动学

目的:研究国产西洛他唑片在人体内的药动学。方法:18名健康男性志愿者单剂量口服100mg西洛他唑片,采用高效液相色谱法测定血浆中西洛他唑浓度,并用3P97软件统计处理。结果:西洛他唑片药-时曲线符合二室模型,其Cm ax,tm ax,t1/2,AUC0-72,AUC0-∞分别为(901.9±221.2)μg.L-1,(4.1±1.2)h,(20.4±9.9)h,(12 722±3 709)μg.L-1.h,(1 3247±3 847)μg.L-1.h。结论:西洛他唑在人体内药动学过程符合二室开放模型,本实验可为临床用药提供药动学参数。     

Role of itraconazole metabolites in CYP3A4 inhibition.

Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.     

经不同静脉快速灌注4℃ 0.9%氯化钠溶液对兔降温的效果研究

目的比较分别经股静脉与耳缘静脉快速灌注4℃0.9%氯化钠溶液对兔降温效果。方法 10只家兔随机分为两组:股静脉组(n=5)和耳缘静脉组(n=5),均采用电子输液泵以3ml.kg-1.min-1的速度输注4℃0.9%氯化钠溶液,观察其达到目标温度(34℃)所需时间、所需液体容量,降温前后的心率、中心静脉压以及平均动脉压的变化。结果股静脉组体温降到目标温度所需时间比耳缘静脉组所需时间短,差异有统计学意义(P<0.01)。股静脉组所需灌注液体容量比耳缘静脉组少,差异有统计学意义(P<0.01);达到目标温度后,耳缘静脉组的中心静脉压和平均动脉压均比降温之前升高,差异有统计学意义(P<0.01)。结论经中心静脉(股静脉)灌注低温0.9%氯化钠溶液诱导亚低温的速度比经外周静脉(耳缘静脉)的速度快,且对血流动力学影响较小。     

Rapid and sensitive high performance liquid chromatographic method for the determination of itraconazole and its hydroxy-metabolite in human serum

Published high performance liquid chromatographic (HPLC) methods for the determination of itraconazole (ITZ) in biological matrices are labor intensive, extraction-based procedures which operate at a pH approaching the limit of column tolerance, and unless modified, cannot measure its hydroxy-metabolite (OH-ITZ). A protein precipitation-based method requiring no solvent extraction and utilizing a base-deactivated C18 analytical column to minimize peak tailing is described herein. Calibration curves for OH-ITZ and ITZ were linear from 25–1500 ng ml⁻¹ (r²≥0.999). Intra-assay relative standard deviations (R.S.D.) were below 12%. Inter-assay R.S.D. were below 14%. This method provides a rapid means for the accurate and precise determination of both OH-ITZ and ITZ concentrations in human serum.     

姜黄素对兔心肌缺血再灌注损伤的影响

目的:探讨姜黄素(curcumin)预处理对兔心肌缺血再灌注损伤(ischemia-reperfusion injury,IRI)的影响。方法:将40只新西兰大白兔随机分为两组:处理组(20只)于术前2h将60mg/kg的姜黄素静脉注射;对照组(20只)静脉注射等体积的DMSO。"二线二结"法结扎心脏左前降支动脉30min,然后恢复心肌灌注。两组分别于结扎前与再灌注后1.0h从股静脉取血2ml,测定血浆心肌肌钙蛋白I(cardiac troponin I,cTnI)与超氧化物岐化酶(superoxide dismutase,SOD)含量。结果:再灌注1.0h后,兔血浆cTnI较结扎前明显升高(P<0.05),SOD含量较结扎前降低(P<0.05),处理组cTnI水平较对照组明显降低(P<0.05),SOD含量较对照组明显增加(P<0.05)。结论:姜黄素对兔心肌IRI有保护作用,其机制可能与提高SOD含量、减少氧自由基生成有关。     

Tanshinone IIA protects rabbits against LPS-induced disseminated intravascular coagulation (DIC)

Aim:

To evaluate the effects of tanshinone IIA (Tan IIA), a lipophilic diterpene from the Chinese herb Salvia miltiorrhiza, on lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) in rabbits.

Methods:

LPS-induced DIC model was made in adult male New Zealand rabbits by continuous intravenous infusion of LPS (0.5 mg/kg) via marginal ear vein for 6 h. The animals were simultaneously administered with Tan IIA (1, 3 and 10 mg/kg) or heparin (500 000 IU/kg) through continuous infusion via the contralateral marginal ear vein for 6 h. Before and 2 and 6 h after the start of LPS infusion, blood samples were taken for biochemical analyses.

Results:

Continuous infusion of LPS into the rabbits gradually impaired the hemostatic parameters, damaged renal and liver functions, increased the plasma TNF-α level, and led to a high mortality rate (80%). Treatment of the rabbits with Tan IIA dose-dependently attenuated the increase in activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrin-fibrinogen degradation products (FDP); ameliorated the decrease in plasma levels of fibrinogen and platelets; and reversed the decline in activity of protein C and antithrombin III. Meanwhile, the treatment significantly suppressed the increase in the plasma levels of aminotransferase, creatinine and TNF-α, and led to much lower mortality (46.7% and 26.7% for the medium- and high-dose groups). Treatment of the rabbits with the high dose of heparin also effectively improved the hemostatic parameters, ameliorated liver and renal injuries, and reduced the plasma level of TNF-α, and significantly reduced the mortality (33.3%).

Conclusion:

Tan IIA exerts a protective effect against DIC in rabbits.     

Influence of endotoxin-induced fever on the pharmacokinetics of theophylline in the rabbit model

To assess fever-induced changes in theophylline pharmacokinetics in the rabbit model, six healthy, male, New Zealand white rabbits were studied using a randomized, matched-pair design. In treatment 1, 15 mg/kg of theophylline was infused into the left marginal ear vein, and several blood samples were collected from the opposite ear for 10 hours. Treatment 2 was conducted in an identical manner, except 20 to 40 micrograms/kg of Escherichia coli endotoxin was injected into the left marginal ear vein to induce fever. The majority of the rabbits had slight decreases in the slowest disposition rate constant and increases in the volume of distribution at steady state; however, total body clearance was only minimally (5%) changed. No statistically significant differences were noted between these values (Hotelling T2 = 0.32). Given the sample and methods, fever apparently does not affect theophylline pharmacokinetics.     

两种浓度臭氧对实验兔股动脉和股静脉影像学及病理学的影响

目的观察两种浓度的臭氧(O3)对实验兔股动脉和股静脉影像及病理学的变化,以评估臭氧对股动脉和股静脉的氧化程度。方法20只实验兔随机分为A、B两组。给予氯胺酮30 mg/kg肌内注射麻醉后,随机选择一侧股动脉和股静脉腹股沟处,在神经刺激器引导下,注射臭氧-氧气混合气体A组浓度50μg/mL 5 mL,B组浓度30μg/mL 5 mL。注射后2 h在实验兔耳缘静脉建立通道,给予氯胺酮10 mg/kg静脉注射麻醉后,再静脉注射碘佛醇2 mL/kg,立即行CT扫描(TOSHIBA AQUILION MULTI)。随后处死实验兔,取注射点腹股沟处股动脉和股静脉2 cm作病理学光镜检查。对侧相应部位作为空白对照。结果与空白对照比较,A、B两组的CT扫描结果显示,注射点腹股沟处股静脉显影正常,未见狭窄或扩张;A、B两组的股静脉直径差异无统计学意义(P>0.05)。50倍和100倍光镜结果显示,注射点腹股沟处股动脉、股静脉结构正常,血管壁完整。结论在股动脉和股静脉旁注射臭氧进行镇痛治疗是安全的。     

地奥心血康在兔体内对环孢素药动学的影响

目的: 研究地奥心血康(DAX)对环孢素(CsA)血药浓度及其药动学参数的影响.方法: 采用高效液相色谱法(HPLC)对单用CsA(组Ⅰ)及DAX与CsA合用(组Ⅱ)后家兔体内CsA全血浓度进行测定,并对两组药动学参数进行统计学分析.结果: DAX可使CsA的 Cmax、AUC显著增大(P＜0.05),其余药动学参数无显著变化.结论: CsA与DAX合用时,需对CsA进行血药浓度监测.     

五步蛇毒纤溶酶FⅡ对LPS诱导的肾纤维蛋白沉积的作用

目的观察五步蛇毒纤溶酶FⅡ对LPS诱导的兔肾纤维蛋白沉积的作用。方法用脂多糖(LPS)诱导的兔肾血栓模型作为本实验的研究方法。生理盐水作阴性对照组;尿激酶作阳性对照组。兔肾组织学检查及测定血浆FDP含量以观察五步蛇毒纤溶酶FⅡ对兔肾纤维蛋白沉积的溶解作用。结果阴性对照组,给药2、6h后,兔肾组织有大量的纤维蛋白的沉积,FDP含量分别为(7821±479)%和(8427±621)%;阳性对照组,给药2、6h后,肾组织有少量纤维蛋白的沉积,FDP含量分别为(13334±427)%和(21017±542)%。FⅡ分别以01mg·kg-1·h-1(低)、03mg·kg-1·h-1(中)、06mg·kg-1·h-1(高)3个剂量滴注。低剂量组的兔肾组织有纤维蛋白的沉积,但比阴性对照组减少;中剂量组的兔肾组织有少量纤维蛋白的沉积;高剂量组的兔肾组织几乎无纤维蛋白的沉积;血浆FDP含量在低、中和高剂量组均比阴性对照组增加,并有量效关系(P<005)。结论步蛇毒纤溶酶FⅡ对LPS诱导的兔肾纤维蛋白沉积有良好的降解作用。     

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0–t) and C_max of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0–t) and C_max similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5–104.1%) and 101.3% (97.9–104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling.