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。     

上海地区初中生CYP3A酶活性分布

目的了解上海地区初中生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980名受检者CYP3A酶的活性为5.21±2.32,年龄(X)与CYP3A酶的活性(Y)的线性方程为:Y=0.342X 0.900。结论上海地区初中生CYP3A酶活性无性别差异,其正常值范围为1.00~27.16。     

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.     

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.     

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。     

2430名中小学生健康志愿者晨尿中6β-OHFC/FC分布

目的 观察2430名中小学生健康志愿者晨尿中6β-氢化可的松(6β-OHFC)与氢化可的松(FC)比值(6β-OHFC/FC)的分布.方法 采用HPLC法测定尿液中6β-OHFC和FC的含量,用6β-OHFC/FC计算健康儿童个体内CYP3A酶的活性.结果 儿童健康志愿者CYP3A酶活性分布经自然对数转换,呈正态分布,其值为(-0.663±1.573),其中男性为(-0.641±1.563),女(-0.683±1.583).结论 CYP3A酶活性随着年龄进入生理发育期而有所增加,但不同性别间差别无统计学意义.     

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。     

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。     

急性淋巴细胞性白血病患儿化疗前后CYP3A酶活性研究

目的:探索急性淋巴细胞性白血病(ALL)患儿体内CYP3A酶活性与正常儿童群体间的差异及化疗前后患儿对CYP3A酶活性影响。方法:测定尿中6β-羟基氢化可的松与氢化可的松比值,计算体内CYP3A酶活性。结果:ALL患儿化疗前CYP3A酶活性明显高于化疗后酶活性,也显著高于正常儿童酶活性(P<0.05)。结论:ALL患儿化疗前后体内CYP3A酶活性差异极大。     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Polymorphisms in genes involved in neurotransmission in relation to smoking

Smoking behavior is influenced by both genetic and environmental factors. The genetic contribution to smoking behavior is at least as great as its contribution to alcoholism. Much progress has been achieved in genomic research related to cigarette-smoking within recent years. Linkage studies indicate that there are several loci linked to smoking, and candidate genes that are related to neurotransmission have been examined. Possible associated genes include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D₁, D₂, and D₄ receptors, dopamine transporter, and serotonin transporter genes. There are other important candidate genes but studies evaluating the link with smoking have not been reported. These include genes encoding the dopamine D₃ and D₅ receptors, serotonin receptors, tyrosine hydroxylase, trytophan 2,3-dioxygenase, opioid receptors, and cannabinoid receptors. Since smoking-related factors are extremely complex, studies of diverse populations and of many aspects of smoking behavior including initiation, maintenance, cessation, relapse, and influence of environmental factors are needed to identify smoking-associated genes. We now review genetic polymorphisms reported to be involved in neurotransmission in relation to smoking.     

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood–brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.     

Disease control in asthmatic children seen in private practice in Switzerland

ABSTRACT

Background: Asthma is the most common chronic childhood disease in Switzerland with a prevalence of 10%. Asthma has a high economic burden accounting for high medical costs. Assessment of disease control is likely to be of help in the implementation of strategies to improve asthma. Therefore, we aimed to evaluate asthma control and therapy regimens among children in private practice.

Methods: We assessed asthma control as well as therapy regimens in 575 asthmatic children in an experience programme in Switzerland by using an abbreviated questionnaire based on the asthma control questionnaire and the child health questionnaire on Visit 1 and Visit 2.

Results: Good asthma control at Visit 1 was only present in 25.7% of asthmatic children. Occasional asthma symptoms, limitation of physical activity, nocturnal awakening and anxiety of the parent was present in 80.5%, 41.2%, 46.8% and 57% of the children, respectively. After adjustment of therapy regimens at Visit 1, mainly by adding a leukotriene receptor antagonist, asthma control was reported to be much better in 53.4% of the children at Visit 2.

Conclusions: As asthma control is inadequately achieved within a major portion of asthmatic children, it is imperative to find measures to improve asthma control and hence, to reduce the burden of disease.