冰片对卡马西平在家兔体内药代动力学的影响

目的观察冰片对卡马西平(carbam azep ine,CBZ)及10,11-环氧化卡马西平(10,11-epoxide carbam azep ine,ECBZ)在家兔体内药动学过程的影响。方法CBZ和冰片灌胃给药,高效液相法检测家兔血浆和脑脊液中CBZ及ECBZ的浓度,并计算药动学参数。结果冰片和CBZ合用可使CBZ的药动学参数T12(ka)、Tpeak、AUC增大而Ka和CL减少;ECBZ的药动学参数T12(ke)和Tpeak增大而Ke减少;ECBZ的脑血比提高。结论冰片可提高CBZ的生物利用度,减慢代谢,并促进血脑屏障对ECBZ的通透性。     

川芎对天麻苷元大鼠脑内药动学的影响

目的建立大鼠脑组织中天麻苷元的HPLC测定方法,并研究川芎对天麻苷元在大鼠脑内药动学的影响。方法 144只SD大鼠随机分为天麻单用组(灌胃给予天麻提取物0.945 mg.kg-1)和天麻-川芎配伍组(灌胃给予天麻提取物0.945 mg.kg-1和川芎提取物3.78 mg.kg-1),于给药后不同时间点取脑组织。采用HPLC法测定大鼠脑组织中天麻苷元的浓度,以DAS2.0药动学软件计算药动学参数。结果天麻苷元在0.125～8 mg.L-1(r=0.999 6)范围内线性关系良好,绝对回收率为86.54%～89.96%,日内及日间精密度均低于5%。天麻-川芎配伍组中天麻苷元脑内药物浓度曲线下面积为天麻单用组的1.66倍;平均滞留时间延长,清除率为天麻单用组的64.58%,与天麻单用组相比有显著差异(均P<0.05)。结论川芎可提高天麻苷元在大鼠脑内的生物利用度,减缓天麻苷元在大鼠脑内的消除速度。     

黄连对栀子中栀子苷的药物代谢动力学影响

目的研究传统药黄连-栀子配伍后黄连对栀子在家兔体内药物代谢动力学的影响。方法栀子组和黄连-栀子组(1:1)分别灌胃给药,采用反相高效液相色谱法测定栀子苷的血药浓度,DAS 2.0软件对结果进行统计分析。结果栀子单独给药、药对黄连-栀子配伍给药,栀子苷在家兔体内代谢模型均呈二室开放模型;配伍组栀子苷的t1/2α、t1/2Ka缩短,tmax和V1/F减小,K21和CL/F增加。结论黄连中的化学成分可对栀子苷的吸收、分布和消除过程产生影响。该研究可为传统药对体内协同作用机制的研究提供思路。     

白芍煎剂在大鼠体内的药物动力学

采用高效液相色谱法测定大鼠静脉注射芍药苷和灌胃给予白芍煎剂后血浆中芍药苷浓度,静脉注射后的数据经3P87处理,灌胃后的数据以非隔室模型处理.结果表明大鼠静脉注射芍药苷(15mg/kg)后,血药浓度时间曲线符合二室模型,药动学参数为T1/2α=26min,T1/2β=274min.大鼠灌胃白芍煎剂(相当于芍药苷850mg/kg)后,生物利用度为F=312%,Tmax=102min,Cmax=993mg/L.大鼠灌胃白芍煎剂后芍药苷的绝对生物利用度仅为3%,提示芍药苷有可能发生了生物转化.     

栀子大黄汤配伍变化对栀子中京尼平苷药动学的影响

目的：通过测定栀子、栀子-大黄、栀子-大黄-枳实和栀子大黄汤4种汤剂中京尼平苷在大鼠体内的药动学参数,考察栀子大黄汤配伍的变化对栀子中京尼平苷药动学的影响。方法：将SD大鼠随机分为4组,分别灌胃给予栀子、栀子-大黄、栀子-大黄-枳实、栀子大黄汤汤剂7．7、6．9、7．3、8．2mL·kg^-1,采用HPLC法测定各汤剂给药后5、10、20、30、60、90、120、240、360和480分钟时的血药浓度,并用BAPP2．0软件计算药动学参数。结果：栀子、栀子-大黄、栀子-大黄-枳实和栀子大黄汤组中京尼平苷的Gmax分别为（2．47±0．47）、（2．15±0．49）、（3．95±0．18）、（3．31±0．86）mg·L^-1;t1／2分别为（163±24）、（176±14）、（282±16）、（227±41）min;AUC0-t分别为（369±38）、（348±61）、（814±74）、（549±58）mg·L^-1·min^-1。与栀子组相比,栀子-大黄组中京尼平苷的Cmax和AUC0-t略有下降,栀子-大黄-枳实组和栀子大黄汤组中京尼平苷的Cmax和AUC0-t均显著升高,但栀子大黄汤组中京尼平苷的AUC0-t显著低于栀子-大黄-枳实组（P〈0．05）。结论：栀子大黄汤药材不同配伍对京尼平苷的药动学存在不同的影响,大黄可使京尼平苷的生物利用度略微下降,枳实可显著增加京尼平苷的生物利用度,淡豆豉则可显著降低京尼平苷的生物利用度。     

黄芩苷及其含药血清在大鼠体内的药动学、药效学相关性研究

目的:以黄芩苷含药血清对PC12细胞氧化损伤的保护作用为药效指标,研究黄芩苷的体内药动学及药效学过程的相关性。方法:大鼠灌胃后,测定不同取血点血清样本中的黄芩苷含量,运用血清药理学方法,观察血清样本对H2O2诱导PC12细胞氧化损伤模型的保护作用,对浓度-时间、效应-时间曲线进行相关分析,建立药动-药效结合模型;观察不同浓度黄芩苷溶液的保护作用,获得黄芩苷体外抗氧化作用的量效关系。结果:黄芩苷含药血清对PC12细胞氧化损伤有明显保护作用,且具有时间依赖性。效应-时间曲线的Emax为98%,tmax为15min;浓度-时间曲线的Cmax为9.39μg.ml-1,tmax亦为15min,以Log(AUC)-AUE作图,图形近似呈“S”形。体外实验中,黄芩苷浓度在0.16~10μg.ml-1范围内有抑制作用,且作用随剂量增加而增大。结论:黄芩苷体内、外均具有抗氧化作用,且效应的时效关系与血清中黄芩苷的时量关系呈正相关。     

栀子柏皮汤不同配伍在大鼠体内的药代动力学研究

目的：探讨栀子柏皮汤不同配伍对栀子苷体内药代动力学的影响。方法将30只SD大鼠随机分为5组,每组6只。分别灌胃含等量栀子苷的栀子苷单体溶液及栀子、栀子-炙甘草、栀子-黄柏、栀子-黄柏-炙甘草汤剂,采用HPLC方法测定给药后不同时间血药浓度,比较药代动力学参数。结果汤剂组AUT及T1/2显著高于栀子苷单体组,栀子-炙甘草、栀子-黄柏及栀子黄柏-炙甘草组T1/2、AUT0-t及AUT0-∞均显著高于栀子组,栀子-黄柏-炙甘草组AUT0-t、AUT0-∞、T1/2、Tmax及Cmax均高于其他组,组间比较差异有统计学意义(P<0.05)。结论栀子柏皮汤药材间相互作用有助于促进栀子苷吸收,从而提高药物生物利用度。     

栀子苷4种不同给药途径的药动学研究

目的:研究栀子苷(geniposide)经4种不同途径给药后在大鼠体内的药动学过程,比较各个途径的生物利用度,揭示栀子苷的体内动态变化规律,为栀子苷的临床应用提供理论依据。方法:分别灌胃(ig)、滴鼻(ns)、肌注(im)、尾静脉(iv)给予栀子苷50,8,8和8 mg.kg-1,不同时间点眼眶取血。应用外标法和反相高效液相色谱法(RP-HPLC)测定血浆中栀子苷的含量,应用DAS统计软件模拟计算,得出相应的药动学参数。结果:ig及im给药符合一室模型,ns给药符合二室模型,iv给药符合三室模型。ig给药的t1/2,Cmax和AUC0~t与其他方式相比,存在显著性差异。不同给药途径的绝对生物利用度分别为F(ig)=9.74%,F(ns)=49.54%,F(im)=72.69%。结论:药动学参数及绝对生物利用度表明,栀子苷在ig,ns,im 3种给药途径的体内生物利用度为im>ns>ig。     

大鼠体内大豆苷元及其代谢物分布影响因素研究

目的研究大鼠灌胃给予大豆苷元后,多剂量与性别对大豆苷元及其代谢物在大鼠血浆中分布的影响。方法雌、雄大鼠分别单次或多次灌胃给予大豆苷元1.0 mg·kg-1,血浆样品经沉淀蛋白处理,采用LC-MS/MS方法测定血浆样品中大豆苷元及其II相代谢物的质量浓度,采用Winnolin6.4计算各化合物的主要药动学参数,并对获得的药动学参数进行统计分析。结果大鼠多次灌胃给予大豆苷元后,血浆中大豆苷元及其代谢物的AUC_(0-24)明显高于单次给药。多次给药后雌鼠血浆中大豆苷元主要以大豆苷元-7-葡萄糖醛酸结合物和大豆苷元-7-硫酸结合物形式存在,雄鼠血浆中主要以大豆苷元-7-葡萄糖醛酸结合物、大豆苷元-7-硫酸结合物和大豆苷元-7-葡萄糖醛酸-4'-硫酸结合物形式存在。结论多次给药及性别差异明显影响大豆苷元在大鼠血浆中的分布。     

RP-HPLC法测定血浆中栀子苷浓度及药动学研究

目的:建立反相高效液相色谱法测定血浆中栀子苷的浓度,研究比较栀子药材及其制剂加味逍遥丸和清开灵注射液中栀子苷在小鼠体内的药动学行为。方法:血浆样品用甲醇沉淀蛋白后,采用Kromasil C18色谱柱(250 mm×4.6 mm,5μm),柱温:室温;流动相:乙腈-水(10:90);流速:1.0 mL·min-1;检测波长238 nm,进样量20μL。结果:线性范围1.02-51.0μg·mL-1(r=0.9992);最低检测浓度0.255μg·mL-1;回收率分别为93.14％,91.90％,108.2％;日内和日间精密度RSD均小于10％。小鼠灌胃栀子提取液和加味逍遥丸提取液后栀子苷的药动学行为均符合一室模型,而小鼠静脉注射栀子提取液和清开灵注射液后栀子苷的药动学行为均符合二室模型。结论:2种不同的提取液以相同途径给予栀子苷后,药材和制剂中栀子苷的房室模型没有改变,但灌胃加味逍遥丸比栀子药材的分布及消除半衰期长,达峰时间长,达峰浓度低;静注清开灵注射液比栀子药材的分布及消除半衰期短、消除速率快。     

冰片对川芎嗪血药浓度和在脑中分布的影响

目的：探讨冰片对川芎嗪血药浓度和在脑中分布的影响。方法：经股静脉单用或复合冰片给予大鼠川芎嗪10mg／kg，采用高效液相色谱法测定不同时间的血浆和脑组织中川芎嗪药物浓度。结果：川芎嗪复合冰片后，血浆药物浓度发生明显变化，在所观察的时间里，血浆药物浓度比单用川芎嗪低；但川芎嗪复合冰片后能提高川芎嗪在脑组织中的含量。结论：冰片可促进川芎嗪在脑中的分布，川芎嗪复合冰片治疗脑血管疾病时临床显效可能更快。     

Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration

Both borneol and gastrodin are bioactive substances derived from traditional Chinese medicine. In this paper, the effect of borneol on the distribution of gastrodin to the brain in mice via oral administration was investigated. Gastrodin concentrations in plasma and gastrodigenin (active metabolite of gastrodin) concentrations in the brain of mice were determined by reversed-phase high-performance liquid chromatography, after intragastric administration of gastrodin (200 mg kg(-1)) alone or combined with different doses (200, 400 and 600 mg kg(-1)) of borneol simultaneously or the same dose (400 mg kg(-1)) of borneol given 20 and 40 min beforehand, respectively. Compared with the administration of gastrodin alone, gastrodin coadministrated with borneol could have been rapidly absorbed from the gastrointestinal tract; the peak time of gastrodin in the plasma became shorter (5-15 vs. 30 min); the bioavailability of gastrodigenin in the brain was increased by 33.6-108.8%; and obvious brain-targeting effect was observed. The enhancing effect was attenuated when the dose of borneol was too high (600 mg kg(-1)), or the time interval between the administration of borneol and gastrodin was longer than 40 min. The results indicate that borneol can accelerate the absorption of gastrodin in the gastrointestinal tract and promote its distribution to the brain. Therefore, borneol is a promising promoter for oral brain-targeting drug delivery.     

Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration

Both borneol and gastrodin are bioactive substances derived from traditional Chinese medicine. In this paper, the effect of borneol on the distribution of gastrodin to the brain in mice via oral administration was investigated. Gastrodin concentrations in plasma and gastrodigenin (active metabolite of gastrodin) concentrations in the brain of mice were determined by reversed-phase high-performance liquid chromatography, after intragastric administration of gastrodin (200 mg kg^{? 1}) alone or combined with different doses (200, 400 and 600 mg kg^{? 1}) of borneol simultaneously or the same dose (400 mg kg^{? 1}) of borneol given 20 and 40 min beforehand, respectively. Compared with the administration of gastrodin alone, gastrodin coadministrated with borneol could have been rapidly absorbed from the gastrointestinal tract; the peak time of gastrodin in the plasma became shorter (5–15 vs. 30 min); the bioavailability of gastrodigenin in the brain was increased by 33.6–108.8%; and obvious brain-targeting effect was observed. The enhancing effect was attenuated when the dose of borneol was too high (600 mg kg^{? 1}), or the time interval between the administration of borneol and gastrodin was longer than 40 min. The results indicate that borneol can accelerate the absorption of gastrodin in the gastrointestinal tract and promote its distribution to the brain. Therefore, borneol is a promising promoter for oral brain-targeting drug delivery.     

冰片及其制剂对大鼠胃粘膜刺激作用的研究

目的研究冰片及其制剂对大鼠胃粘膜的刺激作用。方法采用雄性Wistar大鼠,灌胃给药,剂量80mg·kg-1,连续给药7d,按Guth标准评估溃疡指数。结果和空白组相比,冰片组溃疡指数有显著性差异,各制剂组溃疡指数和冰片组相比有显著性差异。结论冰片能够对雄性大鼠胃粘膜造成刺激,形成损伤,冰片制剂能够在一定程度上减轻这种刺激。     

冰片注射液对小鼠脑缺血再灌注后学习和记忆行为的影响

目的观察冰片对小鼠脑缺血复灌后学习记忆行为的影响。方法采用小鼠夹闭双侧颈总动脉,脑缺血15 min后复灌造模,动物分组给药,人工常规饲养7 d后,检测小鼠跳台错误次数、回避反应和Y型迷宫试验,观察小鼠学习记忆行为的改变。结果冰片可以减少小鼠跳台试验及回避反应中的错误次数,延长Y型迷宫试验中的潜伏期,缩短逃避时间。结论脑缺血复灌损伤可以导致记忆障碍,冰片对小鼠脑缺血后的记忆障碍具有改善作用。     

冰片滴鼻对豚鼠鼻粘膜血管和脑血管通透性的影响研究

目的:研究不同浓度冰片滴鼻后对豚鼠鼻粘膜血管和脑血管通透性的影响。方法:将豚鼠随机分为系列浓度冰片(0.5%、1.0%、2.0%)组、组胺组和液体石蜡组,滴鼻给药后静脉注射2%伊文思蓝(EB),10min后处死豚鼠,取鼻粘膜和脑组织,测定并计算鼻粘膜和脑组织中EB含量。结果:与液体石蜡组比较,系列浓度冰片组鼻粘膜和脑组织中EB含量更高(P<0.05或P<0.01),并以2.0%冰片组最为明显。结论:冰片滴鼻可以明显增加豚鼠鼻粘膜血管和脑血管的通透性。     

冰片对大鼠经鼻腔给药灯盏花素体内药动学的影响

目的:探索冰片对大鼠经鼻腔给药灯盏花素体内药代动力学的影响。方法:采用同位素标记法125I检测实验大鼠经过尾静脉注射、单纯鼻腔给药和鼻腔给药联合冰片三种途径摄入0.4mg/kg灯盏花素以后的药代动力学,测定1、5、10、30、60、90、120、150、180、210、270min的血浆中灯盏乙素的浓度,绘制药时曲线并比较三种途径的药代动力学参数。结果:经鼻腔给药联合冰片组大鼠的tmax为22min短于单纯鼻腔给药组的tmax30min,差异有统计学意义(t=5.73,P=0.025);经鼻腔联合冰片组和单纯鼻腔给药组的Cmax分别为0.55、0.52μg/mL,绝对生物利用度分别为53.21%和53.71%,差异没有统计学意义。结论:冰片可以在一定程度上影响大鼠经鼻腔灯盏花素给药,使其血浆灯盏乙素浓度的达峰时间缩短,但是对灯盏乙素的绝对生物利用度没有明显影响,可以为灯盏花素新制剂的研究提供新方向。     

Borneol,a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood–brain barrier (BBB). Borneol is a naturally occurring compound in a class of ‘orifice-opening’ agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the ‘orifice-opening’ effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol’s chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery.     

Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer

Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain. However, stomach irritation may occur when high doses of borneol are used. In the present work, gastrodin, the main bioactive ingredient of the traditional Chinese drug “Tianma” (Rhizoma Gastrodiae) was used as a model drug to explore reasonable application of borneol. Sustained-release solid dispersions (SRSDs) for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder. The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffractometry. The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form. Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model. Subsequently, gastric mucosa irritation and the brain targeting of the SRSDs were evaluated. Compared with the free mixture of gastrodin and borneol, brain targeting of SRSDs was slightly weaker (brain targeting index: 1.83 vs. 2.09), but stomach irritation obviously reduced. Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery.KEY WORDS: Borneol, Gastrodin, Oral drug delivery, Brain-targeting, Gastric mucosa irritation, Sustained-release     

Multiple regulation and targeting effects of borneol in the neurovascular unit in neurodegenerative diseases

Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords ‘borneol’, ‘neurovascular unit’, ‘endothelial cell’, ‘astrocyte’, ‘neuron’, ‘blood–brain barrier’, ‘neurodegenerative diseases’ and ‘brain disease’ in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood–brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.