整合子与铜绿假单胞菌多重耐药性研究进展

铜绿假单胞菌（PA）多重耐药性是临床抗感染治疗的难点，以往的研究多注重PA的天然耐药机制，如外膜渗透性降低及泵出机制。近年来，在PA中发现了多种β-内酰胺酶，如广谱酶中的PSE-1。SHV-1．超广谱酶中的VEB-1。对碳青霉烯类抗生紊（如亚胺培南）耐受的金属β-内酰胺酶。但上述研究只局限于细菌的单一耐药机制。不能解释为什么没有接触过抗生素的病原菌也会出现对抗生紊的多重耐药。基因盒一整合子系统是细菌基因组中可移动的基因克隆和表达单位，能携带位点特异性重组系统组分，形成多种基因的组合、排列，对细菌及质粒基因组的进化具有重要意义。并且通常涉及到抗生素的耐药基因。与细菌产生多重耐药和耐药基因的水平传播密切相关。目前发现，细菌整合子携带的耐药基因有70余种，整合子作为一个移动遗传元件，通过质粒、转座子在细菌同种或不同种属间进行基因水平转移。使细菌的耐药性在病原菌中广泛传播。整合子结构是国际上研究细菌多重耐药机制、监测细菌耐药性播散趋势的热点。     

质粒介导喹诺酮耐药基因阳性菌株中超广谱β-内酰胺酶的研究进展

质粒介导的喹诺酮耐药(PMQR)基因是近年来新发现的细菌耐药机制,研究发现PMQR阳性菌株也往往对大部分β-内酰胺类抗菌药物耐药而表现为多药耐药,最主要的原因是该类细菌产生了能分解绝大多数β-内酰胺类药物的超广谱β-内酰胺酶(ESBLs).PMQR基因阳性菌株中ESBLs的发生率和主要型别在世界各地的报道各不相同,现就质粒介导喹诺酮耐药基因阳性菌株中超广谱β-内酰胺酶的基本进展进行综述.     

Recent Progress on Treatment of Infections Caused by Bacteria Producing ESBLs

超广谱β-内酰胺酶(extended specturn β-lactamerses,ESBLs)是丝氨酸蛋白酶的衍生物,它能够水解青霉素类、广谱及超广谱头孢菌素类和单环β-内酰胺类抗生素,是革兰阴性细菌对抗生素耐药性产生的重要机制.产ESBLs细菌常具有对氨基糖苷类、喹诺酮类等抗菌药物的多重耐药,给临床抗感染治疗带来严峻挑战.本文就近年来治疗产ESBLs细菌感染的研究进展作一综述,以期为临床有效合理使用抗菌药物提供参考.     

治疗产ESBLs细菌感染的研究进展

超广谱β-内酰胺酶(extended specturn β-lactamerses,ESBLs)是丝氨酸蛋白酶的衍生物,它能够水解青霉素类、广谱及超广谱头孢菌素类和单环β-内酰胺类抗生素,是革兰阴性细菌对抗生素耐药性产生的重要机制。产ESBLs细菌常具有对氨基糖苷类、喹诺酮类等抗菌药物的多重耐药,给临床抗感染治疗带来严峻挑战。本文就近年来治疗产ESBLs细菌感染的研究进展作一综述,以期为临床有效合理使用抗菌药物提供参考。     

抗击超级细菌:耐药酶的起源研究和变异预测

随着抗菌药物在临床和农、林、牧、副、鱼业上广泛应用,细菌的耐药性现象越来越严重,新出现的携带新德里金属β-内酰胺酶-1(new delhi metallo-β-lactamase-1,NDM-1)基因的超级细菌,几乎对临床上所有抗菌药物均具有耐药性,而且这一耐药基因位于质粒上,会在细菌中水平转移,对人类健康具有潜在的极大威胁。更严重的是,目前尚无法预知今后将出现何种新的耐药基因,但抗菌药物选择性压力的结果必然导致新的更为棘手的耐药性出现。国内外已有一些探索性工作试图揭示耐药基因的起源,并着力于预测这些基因今后可能的演变方向,以期在新的耐药性出现前作出应对。该文将以β-内酰胺耐药酶为主,概述国内外在耐药酶起源、自然进化、模拟进化等领域的研究进展,希望能为抗击超级细菌提供新的实验思路。     

细菌体内药物蓄积浓度减少与氟喹诺酮耐药性的研究进展

对氟喹诺酮耐药性细菌体内药物蓄积浓度减少机制--膜通透屏障和主动外排泵激活的研究进展进行了讨论,该机制涉及细菌染色体非特异性基因位点的突变,通过基因间的相互作用,激活多重抗生素耐药操纵子marRAB,导致细菌外膜孔道蛋白异常和主动外排泵功能增强.该机制可由其它药物诱发,可单独或与药物作用靶位改变共同引起细菌发生氟喹诺酮耐药性.     

非发酵革兰阴性杆菌感染及耐药性研究

非发酵革兰阴性杆菌大多产生能水解β-内酰胺类抗菌药物的灭活酶（β-内酰胺酶）,β-内酰胺酶能裂解青霉素族和头孢菌素族抗菌药物的基本结构β-内酰胺环,从而使其丧失抗菌活性,是细菌对β-内酰胺类抗菌药物的主要耐药机制,尤其能产生超广谱β-内酰胺酶（ESBL）的铜绿假单胞菌和鲍曼不动杆菌为代表的多重耐药菌以及对氨基糖苷类及所有β-内酰胺类（替卡西彬克拉维酸除外）天然耐药的嗜麦芽窄食单包菌,是临床住院患者院内感染治疗的重点;洋葱伯克霍尔德菌、木糖氧化无色杆菌、脑膜炎败血金黄杆菌的检出率呈现上升趋势,且多重耐药严重;卡他莫拉菌对利奈唑胺、达托霉素等天然耐药。治疗产ESBL菌引起的感染,应根据药物敏感性试验结果合理使用抗菌药物,延缓细菌耐药性的产生。     

质粒介导的喹诺酮类耐药机制研究进展

质粒介导的喹诺酮类抗菌药物的耐药是近十几年来新发现的一类细菌耐药机制,可在肠杆菌科细菌中水平传播,引起的感染不易控制,导致院内感染大范围流行.本文对质粒介导喹诺酮耐药基因的发现及种类、遗传背景、对喹诺酮类的作用机制及其临床意义等方面进行综述,为研究新型喹诺酮类抗菌药物及抗感染治疗中合理使用氟喹诺酮类抗菌药物提供依据.     

新型抗感染药物外排泵抑制剂研究新动向——对多重耐药性铜绿假单胞菌的致病菌抑制效果的有关研究

近几年,多重耐药性铜绿假单胞菌（MDRP）引起院内耐药菌株的突发性蔓延,而备受人们的关注。综观世界抗菌药物的开发状况,针对这些耐药菌株的新型抗菌药物的研究与开发迫在眉睫。2006年日本抗生素学术研讨会奖励奖的颁奖演讲记录报告了日本长崎大学医学系附属医院对用作新型抗感染药物的外排泵抑制剂的研究开发现状,并就铜绿假单胞菌的临床重要性、金属β-内酰胺酶铜绿假单胞菌和多重耐药性铜绿假单胞菌、铜绿假单胞菌的病原性、长崎大学对耐药性铜绿假单胞菌的对策以及今后的展望等方面进行综述。     

细胞体内药物蓄积浓度减少与氟喹诺酮耐药性的研究进展

对氟喹诺酮耐药性细菌体内药物蓄积浓度养活机制－膜通透屏障和主动外排腺激活的研究进展进行了探讨,该机制涉及细菌染色体非特异性基因位点的突变,通过基因间的相互作用,激活多重抗生素耐药操纵子marRAB,导致细菌外膜孔道蛋白异常和主动外排泵功能增强。该机制可由其它药物诱发,可单独或药物作用靶位改变共同引起细菌发生氟喹诺酮耐药性。     

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.     

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 x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 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.     

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。     

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     

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.     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.