地塞米松的诱导效应对异烟肼大鼠肝毒性的影响

目的观察大鼠孕烷X受体(pregnane X receptor,PXR)激活剂地塞米松(dexamethasone,DEX)对异烟肼(isoniazid,INH)肝毒性的影响,探讨其发生机制,为临床上抗结核药物所致肝损伤的防治策略提供理论依据。方法 SD♂大鼠随机分成4组(n=6):对照组、INH给药组、DEX给药组和INH-DEX合并给药组,分别给予含DEX 20 mg.kg-1的饲料和含1 000 mg.L-1INH的水喂养28 d后,测定肝脏指数(liver index))和药物代谢酶CYP3A活性,并制备肝组织切片观察各组大鼠肝毒性的程度,同时分析血清中酶学指标ALT、AST、ALP和血脂水平。结果使用DEX组的大鼠肝脏指数与对照组相比明显上升(P<0.01),INH合用DEX后肝细胞CYP3A活性与对照组相比增加了近3.0倍(P<0.01),其肝组织损伤程度加剧,肝细胞脂肪变性并伴有大片梗死,血清中ALT、AST、ALP、血脂水平均较单用INH组明显升高。结论大鼠PXR激活剂DEX能增强INH导致的大鼠肝毒性,其机制可能与DEX上调CYP3A的活性有关。     

地塞米松对大鼠肝脏微粒体细胞色素P-450的诱导效应

目的:观察地塞米松(dexamethasone,DEX)对细胞色素P-450(cytochrome P450,CYP450)的诱导效应,并探讨其诱导机制.方法:雄性Wistar大鼠分别以DEX 0,25,50和100mg·kg-1·d-1诱导处理(ip)4d后,测定大鼠肝脏总CYP450含量,CYP3A1,CYP3A2和CYP2B 1/2的mRNA及蛋白的表达水平,肝脏ERD(CYP3A活性),PROD(CYP2B活性)和BROD(总CYP450活性).结果:CYP450含量、ERD、PROD和BROD活性在DEX多次诱导后都有升高.CYP3A1 mRNA表达水平、蛋白含量和酶活性有明显的升高,剂量效应关系明显;CYP3A2蛋白明显升高,但mRNA表达水平却无明显变化.PROD和CYP2B1/2的mRNA表达水平以及总CYP450含量均在50mg·kg-1·d-1剂量组达到最高值.结论:DEX对雄性大鼠主要诱导CYP3A1和CYP3A2两个CYP450成员表达上调,对CYP2B1/2也有一定的诱导作用,其诱导作用主要表现在酶活性、酶蛋白含量和mRNA表达水平的升高.CYP3A1和CYP3A2的诱导方式可能不同.     

地尔硫抑制大鼠肝脏药物代谢的机制

目的:研究地尔硫(艹卓)(DZ)抑制大鼠肝脏药物代谢的机制.方法:(1)SD大鼠未诱导或经地塞米松(DEX)、苯巴比妥(PB)、β萘黄酮(BNF)诱导,制备肝微粒体,于DZ体外37℃温孵25min,检测细胞色素P450-Fe(Ⅱ)-代谢物(MI)复合物.(2)未诱导大鼠ip DZ 100mg/kg 3d,或经DEX诱导再给予单剂量DZ 100mg/kg,制备肝微粒体并检测MI复合物.结果:DEX、PB诱导组在体外分别有30.62%和10.30%MI复合物形成.未诱导大鼠ip DZ 3d,体内检测到7.9%MI复合物;经DEX诱导再给予单剂量DZ的大鼠,体内有17.57%MI复合物形成.结论:DZ在大鼠肝脏中经细胞色素P450 3A催化,发生N-去甲基化,生成的活性代谢物可与P450 3A络合而形成MI复合物,使P450 3A丧失部分活性.     

Z24对大鼠肝脏CYP450酶系的影响

目的:观察Z24对大鼠肝脏CYP450酶系的影响.方法:雌性Wistar大鼠,灌胃(ig)给予Z24(0,50,100,200 mg·kg-1·d-1),连续5 d,以0.9%氯化钠溶液作对照,末次给药后次日,处死大鼠,测定肝微粒体中CYP450总含量、细胞色素b5(Cyt-b5)含量、NADPH-CYP450还原酶活性以及1A2,181,2E1,3A4亚型活性.结果:与对照组相比,各剂量组CYP450总含量、NADPH-CYP450还原酶活性及CYPlB1、2El亚型活性均明显升高(P＜0.05);100和200 mg·kg-1组Cyt-b5含量升高(P＜0.05);200 mg·kg-1组CYPlA2和3A亚型活性升高(P＜0.05).结论:Z24对CYP450、NADPH-CYP450还原酶及CYPlB1、2El亚型有诱导作用,剂量达100和200 mg·kg-1时分别对cyt-b5和CYPlA2、3A亚型产生诱导作用.     

天天胶囊的安全性评价

目的:对天天胶囊作安全性研究.方法:本实验选取5周龄SD大鼠100只并将其随机分为空白组、芦荟低、高剂量组(27、108 mg·kg-1)、天天胶囊低、高剂量组(108、432 mg·kg-1).连续给药13周和26周后,行血液学检查,同时通过X射线检测大鼠的胃肠传输功能,并对肝、肾、盲肠、结肠进行组织病理学观察.结果:在给药13周和26周,天天胶囊明显增强大鼠胃肠传输和结肠转运的能力,且结肠组织无黑变和炎性病变,天天胶囊高剂量组促进了大鼠结肠杯状细胞数目和肠黏膜厚度的增加.此外,天天胶囊组谷草转氨酶、谷丙转氨酶的活性以及肌酐、尿素氮的含量均无明显变化,肝脏和肾脏无病理改变,但给药26周后芦荟高剂量组肾脏脏器指数和肌酐显著性升高.结论:天天胶囊未引起大鼠结肠黑变和肝肾毒性等副作用,芦荟可能造成肾损伤.     

联苯双酯对大鼠黄曲霉毒素B1代谢及肝毒性的影响

目的研究抗肝炎药联苯双酯对大鼠黄曲霉毒素B1代谢和肝毒性的影响.方法大鼠po联苯双酯300 mg*kg-1*d-1, 连服3 d后ip黄曲霉毒素B1 1.5 mg*kg-1.给黄曲霉毒素B1 16 h后测定血清ALT和AST水平,观察联苯双酯对黄曲霉毒素B1引起肝损伤的保护作用以及对体外代谢的影响.结果联苯双酯(300 mg*kg-1*d-1,连服3 d)可明显降低黄曲霉毒素B1引起的大鼠血清转氨酶升高,增加低毒代谢产物AFM1的生成.联苯双酯还可增加大鼠肝脏细胞色素P450总量和胞浆GSH含量,诱导P450 2B1介导的PROD和GST的活性.此外,联苯双酯对P450 3A介导的红霉素脱甲基酶和P450 1A介导的EROD也有一定的诱导作用.结论联苯双酯可通过增加大鼠肝脏对AFB1代谢的解毒功能起到肝保护作用.     

家独行菜子石油醚提取物对雌性大鼠的毒性作用研究

目的 研究家独行菜子石油醚提取物(SLSPEE)对大鼠的毒性作用.方法 48只♀SD大鼠,用5种浓度的SLSPEE灌胃给药,以脏器系数、组织病理、血液生化为指标检测其毒性.结果 SLSPEE各剂量对大鼠脏器系数无显著影响(P>0.05);45.0g·kg-1组大鼠的血小板数增加(P<0.05),肌酐、尿素、胆固醇、三酰甘油、丙氨酸氨基转移酶、碱性磷酸酶、磷酸肌酸激酶的水平升高(P<0.05或P<0.01),血糖浓度降低(P<0.05),5.4 g·kg-1剂量组大鼠的心脏、肾脏、肝脏有轻微病变;10.8、45.0g·kg-1组大鼠的心脏、肾脏、肝脏、肺部病变较明显.各剂量组的胃、胰腺、卵巢、肾上腺、脾脏未见明显病变.结论 较高剂量的家独行菜子石油醚提取物对大鼠的肝脏、肾脏及心肌有一定的毒副作用.     

环磷酰胺与异环磷酰胺致肝毒性机制的比较

目的　为阐明环磷酰胺 (CP)和异环磷酰胺 (IFO)肝脏毒作用机制。方法　给大鼠腹腔注射CP或IFO 40mg·kg-1·d-1连续 5d ,观察停药后 1、4、7、10d血清生化指标、肝组织中丙二醛含量、巯基状态和细胞色素P45 0含量的变化。结果　两组动物血浆生化指标和肝组织丙二醛含量没有显著变化 ,而肝组织总巯基、非蛋白巯基、蛋白结合巯基和细胞色素P45 0含量下降 ,蛋白巯基的消耗与总巯基含量下降相关。但两药引起上述变化的程度不同。肝微粒体总P45 0含量的变化趋势与巯基相似 ,CP组细胞色素P45 0含量给药结束后 1、4、7、10d分别下降了 19 2 %、2 6 8%、6 1 1%、15 2 % ,IFO组细胞色素P45 0仅在 1、7d分别下降 2 0 7%和 40 2 %。结论　CP引起肝脏巯基和细胞色素P45 0含量下降程度明显强于 1FO ,表明这两种药物的差异可能与其毒性不同有关。     

盐酸小檗碱及其与环孢素A合用对大鼠肝脏和小肠CYP3A1的影响

目的 :阐明盐酸小檗碱 (berberinechloride ,Ber)及其与环孢素A (cyclosporin ,CsA)合用对大鼠肝脏和小肠CYP3A1的影响。方法 :实验分 7组 :溶媒对照组、15 0mg·kg-1酮康唑组、10 0mg·kg-1Ber组、2 0 0mg·kg-1Ber组、4 5mg·kg-1CsA组、10 0mg·kg-1Ber 45mg·kg-1CsA组、2 0 0mg·kg-1Ber 45mg·kg-1CsA组 ,采用RT PCR和Westernblot等方法测定大鼠肝脏和小肠CYP3A1的表达水平。结果 :RT PCR结果显示 :灌胃给药 12d后 ,除了 10 0mg·kg-1Ber组外 ,其余各用药组对大鼠肝脏CYP3A1基因表达均有明显的抑制作用。Westernblot结果显示 :给药 6d后 ,2 0 0mg·kg-1Ber 45mg·kg-1CsA组对大鼠肝脏CYP3A1的表达有明显抑制作用 ;给药 12d后 ,10 0mg·kg-1Ber 45mg·kg-1CsA ,2 0 0mg·kg-1Ber 45mg·kg-1CsA组对大鼠肝脏和小肠CYP3A1的表达均有明显抑制作用。结论 :通过增强CsA对肝脏和小肠CYP3A1基因表达的抑制作用 ,从而减少CsA在肝脏和小肠的代谢及消除 ,可能是Ber增加CsA血浓度的重要机制。     

双环醇对大鼠黄曲霉毒素B1代谢和肝毒性的影响

目的:研究抗肝炎新药双环醇对大鼠黄曲霉毒素B_1(AFB_1)代谢和肝毒性的影响.方法:大鼠灌胃双环醇300 mg·kg~(-1)·d~(-1),连服三日后腹腔注射黄曲霉毒素B_1 1.5 mg·kg~(-1).给黄曲霉毒素B_1 16小时后观察双环醇对黄曲霉毒素B_1引起肝损伤的防护作用以及对体外代谢的影响.结果:双环醇(300 mg·kg~(-1)·d~(-1),连服三日)可明显降低黄曲霉毒素B_1引起的大鼠血清转氨酶和肝脏MDA的升高,增加低毒代谢产物AFQ_1的生成.双环醇还可增加大鼠肝脏细胞色素P450总量和胞浆谷胱甘肽含量,诱导P450 CYP2B1介导的7-戊氧基香豆素脱烃酶和谷胱甘肽疏基转移酶的活性.此外,双环醇对P450 CYP3A介导的红霉素脱甲基酶和 P450 CYP1A介导的7-乙氧基香豆素脱烃酶也有诱导作用.结论:双环醇可通过增加大鼠肝脏对AFB_1代谢的解毒功能起到肝保护作用.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.