上海市2671名儿童细胞色素P450 3A酶活性分布

目的 了解上海地区6～15岁学龄儿童细胞色素P450 3A酶活性(CA)的分布.方法 采用固相萃取-反相高效液相色谱测定尿液中氢化可的松和6β-羟基氢化可的松的浓度,以6β-羟基氢化可的松与氢化可的松的浓度比来表示CYP3A酶的活性.结果 2671名受检者CYP3A酶的活性为(2.75±2.75),各年龄间CYP3A活性(CA)的差异有统计学意义,年龄(X)与lgCA(Y)呈线性相关,线性回归方程为Y=0.052×X-0.096,r=0.963.结论 上海地区6～15岁学龄儿童CYP3A酶活性分布与年龄相关.     

上海地区210名12周岁儿童CYP3A活性分布

目的:了解上海地区12岁儿童CYP3A酶活性的分布。方法:采用HPLC法测定尿液中氢化可的松和6β-羟基氢化可的松的浓度,以6β-羟基氢化可的松/氢化可的松的浓度比来表示CYP3A酶的活性。结果:210名受检者CYP3A酶的活性为(5.0±2.3),其中男性为(4.7±2.3),女性为(5.4±2.4)。结论:12岁儿童CYP3A酶活性无性别差异,正常值范围为0.96~26.55。     

上海地区208名儿童CYP3A活性分布

目的:了解上海地区3岁儿童CYP3A酶活性的分布。方法:采用高效液相色谱法(HPLC)测定尿液中氢化可的松和6β-羟基氢化可的松的浓度,以6β-羟基氢化可的松/氢化可的松的浓度比来表示CYP3A酶的活性。结果:208名受检者CYP3A酶的活性为4.0±1.9,其中男性为4.2±1.9,女性为3.7±1.8。结论:3岁儿童CYP3A酶活性无性别差异,正常值范围为1.13~13.77。     

内源性氢化可的松为探针的体内CYP3A活性测定

目的建立测定精神病患者体内CYP3A酶活性的方法。方法直接收集20例精神病住院患者晨尿液,测定尿液中内源性氢化可的松与6β-羟基氢化可的松的含量,以6β-羟基氢化可的松/氢化可的松来评估CYP3A酶的活性。结果患者尿液中6β-羟基氢化可的松与氢化可的松的比值为(8.12±4.36)。结论CYP3A酶的活性可以通过测定6β-羟基氢化可的松与氢化可的松的比值进行预测。     

上海市6～12岁儿童CYP3A酶活性分布

目的了解上海地区6～12岁儿童CYP3A酶活性分布情况。方法采用高效液相色谱法［固定相：HP Hypersil ODS分析柱(250 mm×4 mm，5 μm)；流动相：CH3CN(A相)和7.56 mmol·L^-1 (NH4)2SO4(B相)，梯度洗脱，柱温：30 ℃；流速：1.0 mL·min^-1；紫外检测波长：240 nm；取处理完毕的样品20 μL进样］测定入选志愿者尿液中氢化可的松和6β-羟基氢化可的松的浓度，以6β-羟基氢化可的松与氢化可的松的浓度比值来表示CYP3A酶的活性。结果450例受检者CYP3A酶的活性均值为(3.75±2.82)，均值95%可信区间为3.41～4.12。结论6～12岁儿童CYP3A酶活性无性别差异，正常值范围为0.49～28.71。     

温州地区180名10周岁儿童细胞色素P450 3A酶活性分布

目的:调查温州地区180名10周岁儿童细胞色素P450 3A酶活性(cytochrome P450 3A activity,CA)的分布情况及正常值范围.方法:采用HPLC梯度洗脱法测定尿液中氢化可的松和6β-羟基氢化可的松浓度,以6β-羟基氢化可的松与氢化可的松的浓度之比来表示CYP3A酶的活性.结果:180名10周岁儿童CA分布不呈正态分布,变异系数为2.96,变异系数的标准误为0.13,偏度系数＞l.受检者CYP3A酶的平均活性为4.8±1.9,其中男孩为4.4±1.6,女孩为5.1±1.9.温州地区10周岁儿童CYP3A酶的活性无性别差别,正常范围值是0.85～21.52.结论:通过对180名10周岁儿童CYP3A酶活性的测定,推断出该年龄正常值范围,可为制定儿童个体化给药方案提供科学依据.     

性别与青春期发育对CYP3A酶活性的影响

目的研究性别及青春期发育对人体CYP3A酶活性的影响。方法采用高效液相色谱梯度洗脱法测定并计算569例中小学生尿液中6β-羟基氢化可的松和氢化可的松的含量，以两者的浓度比值表示CYP3A酶的活性，分析青春期发育前后CYP3A酶活性的变化及性别对CYP3A酶活性的影响。结果性别间的F值为0.734 271，青春期发育前后的F值为22.620 83。不同性别间CYP3A酶的活性差异无显著性，青春期发育后CYP3A酶的活性较发育前明显降低(P＜0.01)。结论性别对CYP3A酶的活性无影响，青春期发育对CYP3A酶的活性有较大影响。学龄期儿童CYP3A酶的活性比青春期学生高。     

上海市中小学女生CYP3A酶活性分析

目的:分析女中小学生CYP3A酶活性及其变化趋势。方法:用HPLC梯度洗脱法测定573名女中小学生尿液中6β-羟基氢化可的松和氢化可的松的含量,并通过计算其比值分析CYP3A的活性。结果:在青春期开始发育时CYP3A酶的活性降低,且发育后酶活性个体差异变大。结论:中小学女生年龄跨越大,临床使用经CYP3A酶代谢的药物时应根据身体发育情况适当调整。     

高效液相色谱法测定分析中小学男生CYP3A活性

目的通过高效液相色谱法测定CYP3A酶活性,研究中小学男生CYP3A酶活性变化及其趋势。方法用高效液相色谱法梯度洗脱法测定并计算515名中小学男生尿液中6β-羟基氢化可的松和氢化可的松的比值,以反映CYP3A的活性。通过统计分析,研究CYP3A的活性的变化及其趋势。结果酶的活性在青春期前后都较平稳,但在开始发育时出现酶活性降低,有统计学意义,且发育后酶活性个体差异变大。结论中小学男生年龄跨越大,临床用经CYP3A酶代谢药物时,应根据身体发育情况适当调整。     

人细胞色素P450 3A活性测定

目的:建立测定人细胞色素P4503A酶活性的方法。方法:收集24h尿液,以HPLC法测定尿液中氢化可的松(HC)与6β-羟基氢化可的松(6β-OHC)的含量,以6β-OHC/HC来评估细胞色素P4503A酶的活性。结果:健康志愿者尿中6β-羟基氢化可的松和氢化可的松的比值为(8.5±3.0),肿瘤患者为(6.2±4.5)。结论:细胞色素P4503A酶的活性可以通过测定6β-OHC与HC的比值进行预测。     

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.