黄芩汤中黄芩苷的大鼠在体肠吸收特性研究

目的通过大鼠在体单向肠灌流实验研究黄芩汤中黄芩苷在体肠吸收特性。方法建立大鼠在体单向肠灌流模型,采用质量法计算黄芩苷吸收速率常数(Ka)和有效渗透系数(Peff)。结果黄芩汤中黄芩苷在十二指肠、空肠、回肠的吸收速率和程度都存在一定差异。其中黄芩苷在十二指肠的吸收速率显著高于空肠段,差异具有统计学意义(P<0.05),略高于回肠段但差异无统计学意义;黄芩苷在十二指肠的吸收程度明显高于空肠段且差异具有统计学意义(P<0.05),略高于回肠段但差异无统计学意义。结论黄芩汤中黄芩苷在十二指肠的吸收速度和吸收程度较好,表明黄芩汤中黄芩苷在体吸收具有肠道部位依赖特性。     

马洛替酯单向灌流法大鼠在体肠吸收机制研究

目的:考察马洛替酯在大鼠体内肠吸收机制。方法:采用大鼠在体单向灌流法进行肠吸收实验,利用高效液相色谱法测定灌流流出液中马洛替酯的浓度,按重量法计算动力学参数。结果:马洛替酯在十二指肠、空肠、回肠和结肠的吸收速率常数(Ka)、有效渗透系数(Peff)差异均有统计学意义(P<0.05);供试液的浓度对十二指肠的Ka值和Peff值差异无统计学意义(P>0.05)。结论:马洛替酯在大鼠体内肠吸收机制为被动扩散,不存在饱和吸收,且以肠道中上部的吸收为主。     

溴吡斯的明在大鼠离体肠的吸收动力学

目的观察溴吡斯的明在各肠段的吸收动力学特征。方法采用大鼠外翻肠囊模型,反相离子对色谱法测定不同浓度(25、50、100 mg.L-1)的溴吡斯的明在各肠段的吸收量,计算吸收速率常数(Ka)和表观渗透系数(Papp),并考察P-糖蛋白抑制剂(环孢素和维拉帕米)对药物吸收的影响。结果在25、50、100 mg.L-1溴吡斯的明条件下,Ka按十二指肠、空肠、回肠、结肠依次减小,不同浓度溴吡斯的明对同一肠段的Ka无显著影响(P>0.05),十二指肠、空肠、回肠间的Ka无显著差异(P>0.05),在50、100 mg.L-1溴吡斯的明条件下,结肠的Ka与十二指肠、空肠、回肠比较有显著差异(P<0.05,P<0.01)。随着溴吡斯的明浓度增加,各肠段Papp显著降低,不同肠段间的Papp有显著差异(P<0.05,P<0.01)。P-糖蛋白抑制剂对溴吡斯的明吸收无影响(P>0.05)。结论溴吡斯的明在十二指肠有较好吸收,在空肠和回肠有一定吸收,在结肠中吸收较少。     

穗花杉双黄酮大鼠在体肠吸收动力学的研究

采用大鼠在体单向肠灌流实验模型,用HPLC-UV法测定灌流液中药物浓度,研究穗花杉双黄酮肠吸收动力学。结果表明穗花杉双黄酮在十二指肠、空肠、回肠和结肠的吸收速率常数（Ka）、药物表观渗透系数（Papp）差异无统计学意义（P>0.05）,提高药物浓度的吸收速率常数基本保持不变。在大鼠各肠段均有吸收,无特定吸收部位,吸收机制为被动扩散。     

去氢骆驼蓬碱衍生物DH-004大鼠在体肠吸收动力学研究

目的考察去氢骆驼蓬碱衍生物DH-004大鼠在体肠吸收动力学特征,探讨其可能的吸收机制。方法建立UPLC法测定灌流液中DH-004浓度,用大鼠在体单向肠灌流模型考察不同质量浓度的DH-004在不同肠段的吸收特征。结果 DH-004在全肠段均有吸收。20.0μg·mL^-1 DH-004在十二指肠、空肠、回肠和结肠的吸收速率常数(K_a)分别为(11.66±3.84)×10^-2,(10.85±2.65)×10^-2,(7.48±1.70)×10^-2和(4.75±1.14)×10^-2 min,药物表观渗透系数(P_app)分别为(1.47±0.33)×10^-2,(1.55±0.20)×10^-2,(1.25±0.10)×10^-2和(0.98±0.22)×10^-2 cm·min^-1。DH-004在十二指肠段与空肠段的K_a均明显大于其在回肠和结肠的K_a(均P<0.05)。结论 DH-004在大鼠小肠全段有不同程度地吸收,十二指肠和空肠可能为其主要吸收部位。     

水飞蓟素肠溶聚乳酸-羟基乙酸共聚物纳米粒在大鼠在体肠灌流模型及Caco-2细胞模型中的吸收研究

目的:研究水飞蓟素肠溶聚乳酸-羟基乙酸共聚物(PLGA)纳米粒在大鼠在体肠灌流模型及结肠腺癌Caco-2细胞模型中的吸收特性。方法:采用高效液相色谱法测定水飞蓟素含量,考察水飞蓟素混悬液、水飞蓟素PLGA纳米粒和水飞蓟素肠溶PLGA纳米粒在大鼠在体肠灌流模型十二指肠、空肠、回肠和结肠的吸收速率常数(Ka)和表观吸收系数(Kapp)及其含低、中、高质量浓度(20、40、60μg/m L)水飞蓟素时在Caco-2细胞模型中的表观渗透系数(Papp)。结果:与水飞蓟素混悬液比较,水飞蓟素PLGA纳米粒和水飞蓟素肠溶PLGA纳米粒在十二指肠、空肠、回肠和结肠的Ka、Kapp均增加(P<0.05);与对应浓度水飞蓟素混悬液比较,含低、中、高质量浓度水飞蓟素的肠溶PLGA纳米粒和PLGA纳米粒在Caco-2细胞模型中的双向Papp均增加(P<0.05),其中水飞蓟素的肠溶PLGA纳米粒与PLGA纳米粒间差异无统计学意义(P>0.05)。结论:水飞蓟素肠溶PLGA纳米粒可有效增加水飞蓟素肠内吸收及Caco-2细胞摄取和跨膜转运速率。     

在体肠灌流模型研究灵仙新苷的大鼠肠吸收特性

目的:研究灵仙新苷在大鼠肠段的吸收特征。方法:以酚红为标示物,采用在体单向肠灌流模型,LC-MS/MS测定灵仙新苷在体肠灌流的浓度变化,研究灵仙新苷的吸收部位和吸收动力学特征。结果:灵仙新苷在大鼠小肠各肠段的吸收速率常数(Ka)、有效渗透系数(Peff)是十二指肠>空肠≈回肠,且十二指肠的Ka和Peff值与其他肠段存在显著性差异(P<0.05);灌流液中同一肠段不同浓度灵仙新苷的Ka和Peff均无统计学显著差异;盐酸维拉帕米和环孢素A均显著性降低对灵仙新苷的吸收(P<0.05)。结论:灵仙新苷在小肠有不同程度的吸收,其中在十二指肠吸收最好,药物浓度对灵仙新苷的Peff和Ka值无影响,其吸收机制为被动扩散,灵仙新苷可能不是P-糖蛋白底物。     

在体单向灌流法研究加巴喷丁的大鼠肠吸收

采用在体单向灌流法考察加巴喷丁的大鼠肠吸收特性.结果表明,加巴喷丁在小肠各段(十二指肠段、空肠段和回肠段)和结肠均有吸收.低、中浓度(1和10 mmol/L)时药物在小肠各段的吸收速率常数(Ka)和有效渗透系数(Peff)显著大于结肠段(P＜0.05),高浓度(50 mmol/L)时十二指肠段的吸收显著大于结肠段(P＜0.05).加巴喷丁浓度对其在小肠各段的吸收有显著影响,低浓度组小肠各段药物的Ka和Peff显著大于高浓度组(P＜0.05),而药物浓度对结肠段的吸收无显著影响.     

在体单向灌流法研究β-蜕皮甾酮大鼠在体肠吸收特性

目的考察β-蜕皮甾酮的肠道吸收特性,探究β-蜕皮甾酮生物利用度低的原因。方法采用大鼠在体单向肠灌流模型,运用HPLC法测定药物浓度。分别考察小肠吸收部位(十二指肠、空肠、回肠、结肠),药物浓度,灌流液pH值,肠道菌群对β-蜕皮甾酮吸收的影响。结果β-蜕皮甾酮在不同肠段的吸收速率常数(K_a)由高到低依次为回肠、结肠、空肠、十二指肠;以β-蜕皮甾酮浓度为50、100、200μg·mL~(-1)的含药缓冲液在空肠进行吸收实验,K_a和小肠有效渗透系数(P_(eff))差异无统计学意义;药物的吸收程度在空肠随pH值升高而增加;大鼠肠道菌群失衡会干扰β-蜕皮甾酮的吸收。结论β-蜕皮甾酮在各个肠段均有吸收,但在肠道下部吸收较好;吸收机制为被动扩散;药物在碱性环境下吸收较好;肠道菌群对β-蜕皮甾酮吸收有显著影响。     

单向灌流法研究姜黄素的大鼠在体肠吸收

目的 研究姜黄素在大鼠肠内的吸收特性.方法 采用大鼠在体肠段单向灌流模型,HPLC法对药物的质量浓度进行检测,分别研究药物不同质量浓度、不同时间点以及吸收部位姜黄素吸收的情况.结果 姜黄素质量浓度对ka有显著性影响(P＜0.05),而对Kapp无显著性影响;姜黄素的肠吸收速率随时间出现周期性的波动,且在灌肠达到稳态后1h,ka的大小顺序为:40、20、80μg/ml;姜黄素在各肠段的ka和Kapp比较均无明显差异(P＞0.05),各肠段的ka(h-1)为十二指肠＞回肠＞空肠＞结肠;Kapp为十二指肠＞空肠＞回肠＞结肠.结论 姜黄索在吸收过程中存在高浓度饱和现象,初步判断姜黄素的吸收为主动转运.但姜黄素的浓度对其吸收的量影响不大;同时,姜黄素存在明显的肝肠循环;且在全肠道吸收较完全,无特定吸收窗也无明显吸收部位.     

Role of glutathione in reduction of arsenate and of gamma-glutamyltranspeptidase in disposition of arsenite in rats

Arsenate (AsV), the environmentally prevalent form of arsenic, is converted sequentially in the body to arsenite (AsIII), monomethylarsonic acid (MMAsV), monomethylarsonous acid (MMAsIII), and dimethylarsinic acid (DMAsV) and some trimethylated metabolites. Although the biliary excretion of arsenic in rats is known to be glutathione (GSH)-dependent, involving transport of arsenic-GSH conjugates, the role of GSH in the reduction of AsV to the more toxic AsIII in vivo has not been defined. Therefore, we studied how the fate of AsV is influenced by buthionine sulfoximine (BSO), which depletes GSH in tissues. Control and BSO-treated rats were given AsV (50 micromol/kg, i.v.) and arsenic metabolites in bile, urine, blood and tissues were analysed by HPLC-HG-AFS. BSO increased retention of AsV in blood and tissues and decreased appearance of AsIII in blood, bile (by 96%) and urine (by 63%). The biliary excretion of MMAsIII was also nearly abolished, the appearance of MMAsIII and MMAsV in the blood was delayed and the renal concentrations of these monomethylated arsenicals were decreased by BSO. Interestingly, appearance of DMAsV in blood and urine remained unchanged and the concentrations of this metabolite in the kidneys and muscle were even increased in response to BSO. To test the role of gamma-glutamyltranspeptidase (GGT) in arsenic disposition, the effect of the of the GGT inhibitor acivicin was investigated in rats injected with AsIII (50 micromol/kg, i.v.). Acivicin lowered the hepatic and renal GGT activities and increased the biliary as well as urinary excretion of GSH, but failed to alter the disposition (i.e. blood and tissue concentrations, biliary and urinary excretion) of AsIII and its metabolites. In conclusion, shortage of GSH decreases not only the hepatobiliary transport of arsenic, but also reduction of AsV and the formation of monomethylated arsenic, while not hindering the production of dimethylated arsenic. While GSH plays an important role in the disposition and toxicity of arsenic, GGT, which hydrolyses GSH and GSH conjugates, apparently does not influence the fate of the GSH-reactive trivalent arsenicals in rats.     

微透析取样技术在中药体内分析中的应用研究进展

本文综述了微透析取样技术在中药体内分析中的应用,介绍微透析取样技术的原理、组成、探针类型、特点,重点阐述了微透析取样技术在测定脑、血液、皮肤等组织器官中中药有效成分浓度的应用实例。表明微透析取样技术在中药药效研究中具有广阔的前景。     

应用PASS系统分析我院2010年住院医嘱

目的:了解我院2010年住院患者的合理用药情况,探讨如何利用合理用药监测系统( PASS)提高合理用药水平.方法:利用PASS对我院2010年15 966例住院患者的1 184 997条用药医嘱进行监测,以黑色警示医嘱为依据,收集不合理用药信息,并对监测结果进行统计、分析.结果:不合理用药医嘱50 261条,发生率为4.24％.绝对禁止黑色医嘱5441条,主要为药物相互作用(66.54％)、注射液体外配伍(17.86％)、用法用量(15.46％)、儿童警告(1.14％).结论:应用PASS系统能有效监测医嘱中的不合理用药情况,有利于提高临床合理用药水平,但PASS系统尚存在局限性,有待进一步完善.     

Changes in levels of dependency and predictors of mortality in elderly people in institutional care in Dunedin

The 1983 study of dependency of subjects in institutional care in Dunedin was repeated two years later. A significant increase in levels of dependency in residential homes, particularly in the Religious and Welfare sector was found. In 1983 there were 29 high dependency residents and 73 medium dependency residents in residential homes. In 1985 these numbers had increased to 55 and 86 respectively. There was no change in the number of low dependency residents. In 1983, 6 high dependency residents had been admitted to residential home care in the year prior to the study. In 1985 the number of high dependency residents recently admitted had increased to 23. There had also been a significant increase in the dependency of patients in Religious and Welfare continuing care hospitals. Of the 933 subjects in institutional care in 1983 who were able to be followed, 354 (37.9%) died in the following 2 years. Mortality rate was higher for those in hospital care (48.1%) than for those in residential home care (29.6%). Mortality rates were higher in more dependent subjects and this was evident for each measure of dependency.     

应用PASS系统对我院2008年住院医嘱的分析

目的监测分析2008年我院住院患者用药情况。方法将PASS系统嵌入医生工作站、临床药学工作站等子系统,构建合理用药计算机网络系统,对住院医嘱进行及时监测,将监测结果向医生反馈,并对其进行统计、分析。结果2008年共监测医嘱3 620 241条,不合理医嘱908条,占0.02%。不合理医嘱中,配伍禁忌(381条)占41.96%,用法用量(381条)占41.96%,药物相互作用(108条)占11.89%,儿童用药(38条)占4.19%。经与医生沟通后,更改不合理医嘱856条,占94.27%。结论PASS系统可有效监测医嘱中的不合理用药,通过与医生交流,大大减少药物不良事件的发生,值得临床推广应用,也为临床药师开展工作带来了极大的便利。但PASS系统尚存在局限性,有待进一步完善。     

Role of desacetylation in the detoxification of cephalothin in renal cells in culture

The toxicity of three cephalosporin antibiotics to rabbit kidney cells in culture was compared to their known nephrotoxic potential in vivo (cephaloridine greater than cefazolin greater than cephalothin). While cephalothin is considered to be a relatively nonnephrotoxic cephalosporin when administered to many species including humans and rabbits, in several in vitro systems involving rabbit renal tissue, cephalothin was comparatively more toxic than anticipated based on in vivo data. Cephalothin is extensively desacetylated in rabbits to a less microbiologically active metabolite, desacetylcephalothin. When a microsomal S9 fraction from rabbit kidney was added to the in vitro assay in cultured rabbit renal cells, cephalothin was desacetylated and its toxicity to kidney cells was reduced. The addition of S9 in vitro provided a toxicity ranking of the cephalosporins that correlated with their known in vivo nephrotoxic potentials (cephaloridine greater than cefazolin greater than cephalothin). The in vitro detoxification of cephalothin by S9 was blocked by the coadministration of the esterase inhibitor, aminocarb. Desacetylcephalothin was relatively nontoxic to rabbit renal tissue in vitro. These results suggest that the desacetylation of cephalothin in vivo represents a previously unrecognized mechanism of detoxification of this cephalosporin antibiotic. Furthermore, this mechanism of detoxification may be applicable to other acetylated cephalosporins.     

2009年某院住院患者抗真菌药用药调查

目的:分析讨论某院抗真菌药使用的合理性,为临床安全有效地使用抗真菌药提供参考。方法:回顾性统计分析某院2009年住院患者抗真菌药用药信息。结果:2009年某院住院患者抗真菌药DDDs排名前3名分别为:氟康唑、制霉菌素和伊曲康唑;使用金额排名前3名分别为:氟康唑、米卡芬净及卡泊芬净;更换一种抗真菌药进行治疗的患者数为176人,在全部患者中占13.4%。结论:应进一步强化用药指征的意识,提高标本送检率,同时改善某些抗真菌用药不合理更换的现象,以避免耐药性发生,从而更好更长远地体现抗真菌药的治疗价值。     

Kinetics of in vitro metabolism of methoxyphenamine in rats

1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.     

Comparison of in vitro cell models in predicting in vivo brain entry of drugs

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.99, Caco-2 r=0.91 and MDCKII-MDR1 r=0.85). Despite of the substantial differences in the absolute in vitro P(app) values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood-brain barrier passage of new drug candidates.