基于内毒素模型的何首乌特异质肝损伤评价

基于内毒素特异质肝损伤模型,考察何首乌对大鼠肝脏的损伤作用。将何首乌(Polygonum multiflorum Thunb.)50%乙醇提取物单独灌胃或联合无毒剂量的脂多糖(lipopolysaccharide,LPS,尾静脉注射2.8 mg·kg-1)给予SD大鼠,检测血清丙氨酸氨基转氨酶(ALT)、天冬氨酸氨基转氨酶(AST),HE染色观察肝脏病理学改变,对比考察何首乌单用或联合LPS的量-毒关系,探讨LPS对何首乌肝损伤的影响。结果表明,单次灌胃18.9、37.8、75.6 g·kg-1的何首乌对大鼠ALT、AST无显著影响(均P>0.05),肝脏切片未见明显病理学改变;单独尾静脉注射无毒剂量的LPS,对ALT、AST无显著影响(均P>0.05),肝脏切片可见汇管区炎症细胞增多,未见肝细胞有明显病理学改变;而相同剂量的何首乌联合LPS给药后,ALT、AST显著升高(均P<0.01),肝脏切片可见中央静脉扩张、内膜脱落,中央静脉周肝细胞肿胀、坏死,汇管区有大量炎症细胞浸润,中间区部分肝细胞肿胀、坏死。进一步降低何首乌给药剂量,1.08及2.16 g·kg-1(分别相当于生何首乌6 g/日,临床剂量的2倍、4倍等效剂量)联合LPS仍然显著升高大鼠ALT、AST(均P<0.05),而0.54 g·kg-1何首乌对ALT、AST无显著影响(均P>0.05)。研究表明,对于普通正常大鼠,单次灌胃给药超大剂量(75.6 g·kg-1)何首乌无明显肝损伤作用;而在LPS特异质肝损伤模型上,临床2倍等效剂量(1.08 g·kg-1)的何首乌即可造成实验大鼠肝功能损伤,该模型可用于何首乌特异质肝损伤评价。     

姜黄素对二乙胺基亚硝胺诱发小鼠肝癌前病变的预防作用

目的:观察姜黄素对小鼠肝癌前病变的预防作用.方法:每周腹腔注射二乙基亚硝胺(DEN,95 mg·kg-1)建立小鼠肝癌前病变,每天灌胃姜黄素(120 mg·kg-1)或姜黄素与山药(3.03 g·kg-1)联合用药,连续10周(70 d);第71天眼球后静脉丛取血,检测血清肝功指标丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)和谷胱甘肽-S-转移酶(GST),肝脏经灌注固定后用光学显微镜观察病理组织学变化.结果:模型组小鼠肝脏同时存在变质与修复性病变,增生肝细胞具有异型性;血清ALT:(195.57±91.56) U·L-1、AST:(39.68±24.20) U·L-1、GST:(42.31±8.19)U·L-1升高明显(P<0.01).姜黄素组肝损伤较轻,增生肝细胞异型性降低,ALT:(98.54±48.07) U·L-1、AST:(26.89±7.51) U·L-1、GST:(47.47±8.54) U·L-1下降明显(P<0.05),姜黄素联合山药组ALT:(82.75±38.54) U·L-1、AST:(30.32±7.80) U·L-1、GST:(24.61±7.58) U·L-1疗效优于单用(P<0.01).结论:姜黄素对诱导性小鼠肝癌前病变具有防治作用,姜黄素与山药联合用疗效更佳.     

牛磺酸对原代培养大鼠肝细胞的毒性作用

目的用原代培养正常大鼠肝细胞研究牛磺酸(β氨基酸)对肝细胞的毒性作用。方法用2步灌注法分离原代大鼠肝细胞;用MTT法测定细胞活力并计算IC50,观察药物作用后,培养液上清中AST、ALT和LDH活性及培养液中GSH和细胞内GSH的含量。结果细胞生长抑制率与剂量成正相关性,牛磺酸的IC50为24.23g.L-1。高浓度牛磺酸组培养液上清中AST、ALT和LDH活性显著升高,GSH含量显著减少。结论高浓度的牛磺酸对体外培养的肝细胞有一定损伤。     

姜黄素对雷公藤甲素肝损伤的保护作用

目的：探讨姜黄素对雷公藤甲素诱导小鼠慢性肝损伤的保护作用。方法：小鼠32只随机均分4组,每组8只。对照组：每天灌胃生理盐水;姜黄素组：每天灌胃姜黄素100 mg·kg-1;雷公藤甲素模型组：每天灌胃雷公藤甲素400μg·kg-1;姜黄素+雷公藤甲素组：每天灌胃雷公藤甲素400μg·kg-1+姜黄素100 mg·kg-1。每天给药1次,连续28 d。检测血清中丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBIL）、碱性磷酸酶（ALP）和乳酸脱氢酶（LDH）;测定肝组织中超氧化合物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽（GSH）、谷胱甘肽-S-转移酶（GST）和尿苷二磷酸葡萄糖醛酸转移酶1（UGT1）含量。 HE染色观察肝脏病理改变。结果：与雷公藤甲素组相比,联合组的小鼠ALT和ALP有显著的下降（P<0.05）,AST和LDH没有显著性改变,TBIL有明显升高。姜黄素能升高肝组织中GST、GSH、SOD和UGT1含量（P<0.05）,降低肝组织中MDA的含量。病理检查结果也显示联合姜黄素给药改善了雷公藤甲素引起的病理改变。结论：姜黄素能增强雷公藤甲素慢性中毒小鼠体内的抗氧化能力,对小鼠雷公藤甲素慢性肝损伤具有一定的保护作用。     

半夏水提组分对小鼠肝毒性"量-时-毒"关系研究

目的 考察半夏水提组分单次给药小鼠肝毒性"量-时-毒"关系.方法 单次给药"时-毒"关系研究:制备62.5 g·kg-1半夏水提组分,按25 mL·kg-1给小鼠灌胃给药1次,给药后按处理时间点依次为0(即空白对照组),0.5,1,2,4,8,12,24,48,72h,于相应时间点取血,测定血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST),取肝组织,常规染色,光学显微镜下观察其组织形态学变化;单次给药"量-毒"关系研究:设定半夏水提组分82.5 g·kg-1、70.1 g·kg-1、59.6g·kg-1、50.7 g·kg-1、43.1 g·kg-1、36.6g·kg-16个剂量组,小鼠灌胃给药1次,空白组给蒸馏水,于给药后4h按上述方法测定血清ALT、AST及肝组织镜检.结果 半夏肝毒性"时-毒"关系的研究显示小鼠单次灌胃62.5 g·kg-1的半夏水提组分血清ALT、AST值随时间的不同造成的肝损害的程度也不同,毒性高峰出现在给药后4h,持续约48h.肝组织病理形态学检查显示,半夏水提组分在给药后4h对肝组织产生明显损伤.半夏肝毒性"量-毒"关系的研究显示小鼠单次灌胃较高剂量半夏水提组分可使血清ALT、AST值显著升高.肝组织病理形态学检查显示给予较高剂量的半夏水提组分后,肝细胞可出现不同程度的水肿、脂肪变性以及部分点状坏死,而低剂量给小鼠灌胃,肝组织病理形态学未见异常改变.结论 单次给予半夏水提组分可造成小鼠肝毒性损伤,并呈现一定的"量-时-毒"关系.     

半夏酸水渗漉液单次给药对小鼠肝毒性"量-时-毒"关系研究

目的 考察半夏酸水渗漉提取样品单次给药对小鼠肝毒性"量-时-毒"关系.方法 单次给药"时-毒"关系研究:制备1.77 g·kg-1半夏酸水渗漉液,取小鼠按不同时间点分组,25 mL·kg-1给小鼠灌胃给药1次,观察给药后小鼠死亡情况和毒性反应,分别于给药后相应时间点取血,测定血清丙氨酸氨基转移酶(ATL)、天门冬氨酸氨基转移酶(AST)水平,计算肝体比值,另取肝组织,常规染色,光学显微镜下观察其组织形态学变化;单次给药"量-毒"关系研究:取小鼠按不同剂量分组,单次灌胃给予不同剂量的半夏酸水渗漉液2.68g·kg-1、2.14g·kg-1、1.72g·kg-1、1.37g·kg-1、1.10 g·kg-1、0.88 g·kg-1,空白组给同体积蒸馏水,于给药后2h按"时-毒"研究方法对小鼠进行相应处理.结果 半夏肝毒性"时-毒"关系的研究显示小鼠单次灌胃1.77 g·kg-1 的半夏酸水渗漉液,血清ALT、AST.值随时间的不同造成的肝损害的程度也不同,毒性高峰出现在给药后2h,持续时间约达72h.肝组织病理形态学检查显示,半夏酸水渗漉液在给药后2～4h对肝组织产生明显损伤.半夏肝毒性"量-毒"关系的研究显示小鼠单次灌胃较高剂量半夏酸水渗漉液对肝组织产生明显损伤,且随着剂量的增大,可使血清ALT、AST值显著升高.肝组织病理形态学检查显示给予较高剂量的半夏酸水渗漉液后,可致肝细胞部分出现灶状坏死,而低剂量给小鼠灌胃,肝组织病理形态学未见异常改变.结论 单次给予较高剂量的半夏酸水渗漉液可造成小鼠急性肝损伤,毒性出现早、持续时间长,具体表现为血清ALT、AST值升高甚或肝组织病理形态学的改变,且呈明显的时毒、量毒关系.     

脑肠肽通过抗炎抗氧化作用发挥酒精性肝损伤的保护作用

目的研究脑肠肽对小鼠酒精性肝损伤的保护作用。方法采用4周5%酒精饲料喂饲加5 g·kg-1的高剂量酒精灌胃诱导酒精性肝损伤模型,用分光光度法检测血清中ALT、AST和肝匀浆MDA、SOD、GSH-Px含量;Real-time PCR法检测肝脏中炎症细胞因子TNF-α、IL-1β、IFN-γ、IL-6和MCP-1的表达。HE染色检测肝脏病理改变。结果这种慢性酒精喂饲+单剂量大剂量酒精灌胃模式可明显诱导酒精性肝损伤,可导致明显的转氨酶升高、脂肪肝和炎症浸润。给予脑肠肽(5、10、20μg·kg-1)ip后可明显降低酒精性肝损伤小鼠增高的血清ALT、AST活性,改善酒精肝病理改变和炎症浸润;并能减少肝匀浆MDA含量,使降低的肝匀浆SOD活性升高;降低酒精性肝损伤小鼠肝脏的炎症细胞因子TNF-α、IL-1β、IFN-γ、IL-6和MCP-1的mRNA表达。结论脑肠肽对小鼠酒精性肝损伤具保护作用,其机制与抗氧化和抑制炎症作用有关。     

凤尾草对雷公藤甲素致小鼠肝损伤的保护作用研究

目的:研究凤尾草对雷公藤甲素致小鼠肝损伤的保护作用。方法:连续5d给小鼠灌胃凤尾草各提取部位,而后以雷公藤甲素灌胃复制小鼠急性肝损伤模型,检测丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST),并取肝组织作病理检查,筛选凤尾草保肝有效部位。结果:雷公藤甲素造成小鼠急性肝损伤的适合剂量为1.0mg·kg-1,灌胃给药后18h可观察肝损伤指标。凤尾草70%乙醇总提取物、水部位以及大孔树脂95%乙醇洗脱部位均可以显著降低肝损伤小鼠血清ALT、AST水平,能对抗雷公藤甲素所致的小鼠急性肝损伤。结论:凤尾草对雷公藤甲素致小鼠急性肝损伤有保护作用,水部位以及大孔树脂95%乙醇洗脱部位为有效部位。     

河蚬提取物对小鼠急性化学性肝损伤的保护作用

目的 研究河蚬提取物对小鼠急性化学性肝损伤的保护作用.方法 采用灌胃给予乙醇或腹腔注射四氯化碳(CCl4)方法制备小鼠急性化学性肝损伤模型,检测血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)活性、肝脏指数.结果 连续6 d灌胃给予15.0.30.0,60.0mg/(kg·d)的河蚬提取物能明显抑制肝损伤小鼠血清ALT及AST活性的升高(P<0.05),降低增加的肝脏指数.结论 河蚬提取物对四氯化碳及乙醇引起的小鼠急性肝损伤具有保护作用.     

注射用胡黄连总苷对ConA引起小鼠急性免疫性肝损伤的保护作用研究

目的利用Concanavalin A（ConA）引起的免疫性肝损伤模型,对注射用胡黄连总苷的保肝活性和量效关系进行研究。方法注射用胡黄连总苷静脉给予ICR小鼠（0．5—8mg·kg-1×5）,于末次给药后2h,动物尾静脉ConA20mg·kg-1,建立急性免疫性肝损伤模型,16h后处理动物,制备血清,全自动生化分析仪检测血清A1JT,AST及LDH水平,H.E．染色考察肝脏病理状态。结果ConA20mg·kg-1能引起小鼠显著的急性免疫性肝损伤,血清ALT,AST及LDH含量均显著升高,肝组织出现以炎症细胞浸润、肝细胞坏死为主要特征的病理改变。注射用胡黄连总昔0．5～Cmg·kg-1剂量对ConA引起的肝损伤有显著保护作用,明显降低血清转氨酶水平,改善肝脏病理状态,其中1mg·kg-1剂量药效最佳,8mg·kg。剂量药效有所下降,但此剂量未显示明显毒性。结论注射用胡黄连总苷对ConA引起的免疫性肝损伤有明确的保护作用,其起效剂量低,高于8mg·kg-1活性下降,在临床实验时需注意剂量的选择问题。     

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.