抗癌药顺铂对小鼠的耳、肾和肝毒性及其机制的研究

目的　以小鼠为实验对象建立抗癌药顺铂毒性研究的实验动物模型 ,并探讨其毒性作用产生的可能机制 ,为进一步对顺铂毒性作用的防治研究提供科学参考资料。方法　选择♂昆明种小鼠 ,经腹腔连续注射顺铂 5d ,观察不同剂量顺铂对小鼠的听力、肾脏和肝脏的毒性作用及肝和肾组织抗氧化系统各指标的变化。结果　顺铂可引起小鼠体重明显下降、全频率的听力阈值升高 ,肝和肾的脏器系数、血清尿素氮 (BUN)含量和丙氨酸氨基转换酶 (ALT)活性等指标的异常 ,并呈剂量依赖关系。此外 ,顺铂还可引起肝和肾抗氧化及氧化损伤指标的异常。结论　 3 0～ 4 0mg·kg-1b w的顺铂可引起小鼠出现明显的听力、肾和肝组织的损伤。氧化损伤是抗癌药顺铂产生其毒性作用的可能机制之一 ,但对于不同的脏器和在不同的给药时期 ,其发挥的作用不同     

顺铂肾毒性机制及防护方法的研究进展

肾毒性是顺铂（Cisplatin,DDP）较常见且影响较大的不良作用之一,其发生率和损伤程度与顺铂的剂量成正比。顺铂肾毒性的表现形式多种多样,包括从可逆的急性肾功能损伤到伴有显著肾组织学改变的不可逆慢性肾功能衰竭。顺铂肾毒性的病理机制有两种：一是顺铂可引起血管收缩,使肾血流量和肾小球率过滤下降;二是顺铂可引起近端小管上皮细胞缺血、缺氧,甚至坏死。但顺铂引起肾小管细胞损害的机制仍未完全清楚,本文对近几年的有关研究进行了综述。     

顺铂的肾毒性及其预防

<正> 本文就顺铂致肾损伤病理特征、肾毒性检测及其预防措施作一综述。 顺铂致肾损伤的病理特征 Schaeppi等先后报告顺铂可引起肾毒性,并证明其剂量依赖关系。小鼠、大鼠、狗和猴接受顺铂后可表现出肾毒性。顺铂治疗的癌症病人也发现有肾脏损伤。按其病理类型可分为增生性损伤和肾小管坏死性损伤,以后者研究得最广泛。     

大鼠静注双环铂、卡铂与顺铂后铂的肾排泄与肾分布比较研究

目的比较顺铂、卡铂和双环铂3种铂制剂的肾排泄速度和肾组织中浓度,探讨铂类抗癌药的肾毒性机制,为临床用药提供参考。方法大鼠按铂元素10mg·kg-1剂量静脉注射3种铂制剂后,采用原子吸收法测定大鼠尿液中3种铂的排泄量,计算4h尿药累积排泄百分率。结果顺铂组4h的累积排泄量平均为(33.7±5.7)%;卡铂组为(89.1±8.5)%;双环铂组为(70.1±9.8)%,由此结果可见顺铂排泄最少,双环铂和卡铂则较多;静注顺铂、卡铂和双环铂后4h测定肾组织中铂的浓度分别为(70.6±31.6),(217.7±97.6)和(278.8±112.0)μg·g-1。结论与顺铂相比,双环铂与卡铂肾排泄较快,肾组织中的铂浓度相对较高,肾组织中铂浓度与肾毒性间可能无直接关系。     

大鼠静脉注射3种铂制剂后铂的肾排泄与肾分布比较研究

目的:探讨铂类抗癌药的肾毒性机制。方法:12只大鼠均分为3组,分别按铂元素10mg·kg-1剂量静脉注射顺铂、卡铂和双环铂,采用原子吸收法测定并计算4h尿药累积排泄率及肾组织中浓度。结果:4h累积排泄率顺铂、卡铂、双环铂分别平均为(33.7±5.7)%、(89.1±8.5)%、(70.1±9.8)%,肾组织中铂的浓度分别为(70.6±31.6)、(217.7±97.6)、(278.8±112.0)μg.g-1。结论:与顺铂相比,双环铂与卡铂肾排泄较快,肾组织中的铂浓度相对较高;肾组织中铂浓度高低与肾毒性大小之间可能无直接关系。     

三七皂苷对抗顺铂导致的肾毒性(英文)

目的:研究三七皂苷(PnS)对顺铂肾毒性的防护作用。方法:采用小鼠和原代兔肾近端小管细胞培养(FTC)建立体内外顺铂肾毒性模型。用双乙酰、苦味酸、溴乙锭、台酚蓝、~(125)碘标记和Fura 2-AM方法分别测血尿素氮、血清肌酐、细胞存活率、DNA链间交联、DNA-蛋白交联和细胞内游离钙离子。结果:预先2d给PnS(100,200mg·kg~(-1)·d~(-1))使顺铂导致的小鼠血尿素氮下降到83％和31％,血清肌酐下降到86％和42％(P<0.01)。提前24h PnS(10,100mg/L)与PTC孵育,细胞存活率从顺铂组的78％提高到81％和89％,DNA链间交联下降到47％和40％,DNA-蛋白交联下降到77％和42％,细胞内游离钙下降到70％和63％(P<0.01)。结论:PnS可预防顺铂的肾毒性,其机制是降低顺铂导致的DNA链间交联、DNA-蛋白交联和钙离子超载。     

中医药抗顺铂肾毒性的研究进展

顺铂（DDP）是一种有效的临床抗肿瘤药物,其疗效与用药剂量成正比,但其严重肾毒性是临床应用受限的主要因素。近年国内许多中医学者在顺铂肾毒性的防治方面进行了临床与实验研究,可为临床更好地运用顺铂提供参考。     

两种药物对顺铂所致肾毒性的影响

目的 :研究顺铂所致肾毒性及茶多酚、硫代硫酸钠两种药物对其毒性的影响。方法 :小鼠随机分为对照组、顺铂组、顺铂 +硫代硫酸钠组、顺铂 +茶多酚组。处死小鼠 ,观察血清中的尿素氮 (BUN)和肌酐 (Cr)的变化 ,肾脏病理的变化。结果 :顺铂组小鼠血清尿素氮、肌酐较对照组高且差异有显著性 ;顺铂 +茶多酚组、顺铂 +硫代硫酸钠组的尿素氮较顺铂组低 (P <0 .0 5 ) ;顺铂 +硫代硫酸钠组较顺铂 +茶多酚组尿素氮、肌酐高。肾脏病理组织学显示 :顺铂致小鼠肾损伤主要表现为肾曲管上皮细胞重度浊肿 ,顺铂 +硫代硫酸钠组均表现为近曲小管上皮细胞中度浊肿 ,顺铂 +茶多酚组肾小球结构较顺铂组完整且清楚 ,近曲小管上皮细胞轻度浊肿。结论 :茶多酚对肾脏有一定的保护作用且效果优于硫代硫酸钠     

硝酸铋预处理对顺铂肾毒性的防护作用

大鼠预先sc硝酸铋(30μmol·kg~(-1)·d~(-1))连续3d,可显著降低肾毒性剂量顺铂(5mg·kg~(-1))引起的尿蛋白含量,尿NAG活性和BUN水平的升高;并可有效地防护顺铂造成的肾脏髓层外带近端小管坏死,铋对肾脏MT合成有诱导作用,这可能与其防护顺铂的急性肾毒性有关。     

奈达铂与顺铂在局部晚期宫颈癌联合化疗中的疗效比较

目的:研究奈达铂和顺铂在局部晚期宫颈癌新辅助化疗中的疗效和安全性。方法:58例巨块型局部晚期宫颈癌患者行新辅助化疗,奈达铂化疗组32例与顺铂化疗组26例均行2～3疗程静脉化疗,观察两组疗效及不良反应。结果:奈达铂组和顺铂组有效率分别为65.63%和61.54%,差异无统计学意义(P>0.05)。奈达铂组胃肠道毒性、肾毒性明显低于顺铂组(P<0.05),两组肺毒性、神经毒性、过敏反应及血液毒性(包括白细胞减少、贫血、血小板减少)无明显差异(P>0.05)。结论:奈达铂可应用于局部晚期宫颈癌新辅助治疗,值得进一步研究其临床价值。     

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.     

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.