曲美他嗪对庆大霉素致大鼠肾毒性的预防作用研究

目的:探讨曲美他嗪对庆大霉素致大鼠肾毒性的预防作用。方法:将大鼠分为溶媒对照组,曲美他嗪低、高剂量组(5、10mg.kg-1.d-1),庆大霉素组(100 mg.kg-1.d-1)和低、高剂量联用组(曲美他嗪5或10 mg.kg-1.d-1+庆大霉素100 mg.kg-1.d-1),每组6只,曲美他嗪灌胃给予2 d,第3天开始曲美他嗪灌胃30 min后腹腔注射庆大霉素,无对应药物的注射生理盐水,连续给药7 d,末次给药后24 h处死大鼠。采用荧光偏振免疫分析法测定各组大鼠肾组织中庆大霉素的浓度;缺口末端标记(TUNEL)法观察各组肾脏细胞凋亡情况;苏木精-伊红(HE)染色观察肾脏组织病理学改变。结果:与庆大霉素组比较,高剂量联用组大鼠肾组织中庆大霉素浓度明显降低(P<0.05),低、高剂量联用组大鼠肾脏细胞凋亡数目均明显降低(P<0.05或P<0.01);庆大霉素组大鼠肾脏可见炎性细胞浸润等病变形态;低、高剂量联用组肾脏组织病理变化均有好转。结论:曲美他嗪可能通过降低庆大霉素在肾脏中的蓄积来减轻庆大霉素引起的肾毒性。     

注射用灯盏花素Beagle犬和小鼠安全药理学差异性研究

目的观察注射用灯盏花素对Beagle犬呼吸系统、心血管系统以及ICR小鼠协调功能和自发活动的影响,考察药物可能关系到人安全性的非期望药理作用。方法 24只Beagle犬雌雄各半,按体重随机分为10、30、90 mg·kg-1和溶媒对照组,每组6只,平行测定动物给药前和给药后2 min、30 min、1 h、2 h及4 h的心电图、呼吸、血压及肛温;ICR小鼠80只雌雄各半,其中40只按体重随机分为10、100、500mg·kg-1和溶媒对照组,分别尾静脉给予不同剂量注射用灯盏花素后观察动物机体协调能力;另外40只同样分组测定给药后不同时间点的小鼠自发活动次数。结果相同时间点各剂量组与溶媒对照组及给药前自身比较发现,Beagle犬心电指标、体温、收缩压、舒张压和平均动脉压均有一定程度的波动,但差异无统计学意义(P>0.05)。ICR小鼠给药后高剂量组出现闭眼和运动减少等反应,1 h左右恢复正常;与溶媒对照组比较,各组动物协调功能差异没有统计学意义(P>0.05),高剂量组雌雄小鼠给药后2 min和30min自发活动次数均有下降的趋势,雌鼠给药后2 min自发活动次数明显减少(P<0.05)。结论在本实验条件下,单次静脉给予注射用灯盏花素对Beagle犬的呼吸、心血管系统及体温无明显影响。单次给予注射用灯盏花素对小鼠协调功能无明显影响,500 mg·kg-1注射用灯盏花素对雌性小鼠在2 min时会产生一过性的轻度躯体运动障碍或中枢抑制作用。     

类叶升麻苷大鼠安全性评价

目的 通过单次给药和重复给药毒性试验,初步评价类叶升麻苷的安全性,为深入全面开展其安全性评价奠定了基础。方法 单次给药毒性试验,SD大鼠随机分为溶媒对照组和给药组(5 000 mg·kg^-1),经口单次给药,观察并记录14 d内大鼠一般临床症状、死亡情况、体重;对主要脏器进行肉眼观察。重复给药毒性试验,SD大鼠随机分为溶媒对照组,类叶升麻苷低(100 mg·kg^-1)、中(500 mg·kg^-1)、高(2 000 mg·kg^-1)剂量组,每组30只,连续给药28 d,恢复28 d,观察并检测一般临床症状、体重、摄食量、尿常规等相关指标。结果 单次给药毒性试验中各动物无死亡、无异常、与溶媒对照组相比,体重差异无统计学意义(P> 0.05),脏器组织无肉眼可见病变。重复给药毒性试验中,与溶媒对照组相比,大鼠体重、摄食量、凝血指标、脏器湿重及系数差异无统计学意义(P>0.05);对血液学、肝功能和肾功能无毒理学影响,高剂量组脏器组织未见明显给药相关组织病理学改变;高剂量组雌性动物尿常规中出现白...     

地塞米松注射液对大鼠细胞色素P4502D6的影响

目的 观察地塞米松(激素类药物)注射液对大鼠细胞色素P4502D6(CYP2D6)亚型的影响.方法 SD大鼠,雌雄各半,随机分成2组,地塞米松组按50mag·kg-1尾静脉给药,对照组按10 mL·kg-1尾静脉给生理盐水,给药7 d后,每组给予氢溴酸右美沙芬注射液5 mg·kg-1;按时间从大鼠眼静脉取血10次,血样处理后,用HPLC法同时测定大鼠血浆CYP2D6R探针药物右美沙芬及其代谢产物去甲右美沙芬浓度,用DAS2.0软件进行分析,求出其主要药代动力学参数.结果 地塞米松组与对照组比较,对右美沙芬t1/2无显著性差异;而AUC0-1右美沙芬为(63.43±7.71)mg·L-1·min,与对照组(41.07 ±4.63)mg·L-1·min比较有显著性差异(P<0.05).结论 地塞米松注射液对右美沙芬有一定诱导作用,可以促进合用药物的消除,从而加速其代谢.     

羟基脲对雄性大鼠的生殖毒性

目的观察羟基脲(HU)对雄性大鼠的生殖毒性。方法雄性大鼠分别腹腔注射HU×100、200和400mg·kg-1,连续10d。末次给药后分别于d9、d23处死动物。结果停药d9时,200、400mg·kg-1组不活动精子增加明显(P<0.05或P<0.01);停药d23时,各给药组睾丸脏/体比都明显下降(P<0.05或P<0.01);400mg·kg-1组附睾脏/体比下降明显(P<0.05),并且仍然有大量不活动精子(P<0.01);200、400mg·kg-1组精子计数明显减少(P<0.01);随给药浓度增加,各组精子畸形数量增加(P<0.01)。结论雄性大鼠连续10d腹腔注射羟基脲100mg·kg-1以上,对生殖系统产生明显毒性。     

尖吻蝮蛇毒无出血活性纤溶酶对大鼠的长期毒性试验

目的:研究无出血活性纤溶酶(Non-hemorrhagic fibrinolytic enzyme,NHFLE)对大鼠的长期毒性,评价其安全性.方法:健康Wistar大鼠随机分为低、中、高剂量(2.25,4.5,9.0 mg·kg-1·d-1)组及生理氯化钠注射液对照组,每组24只.尾静脉注射给药,每周给药7 d,连续给药4周,给药容积为10 mL·kg-1.停药后24 h每组处死12只动物,余下动物继续观察2周后活杀检查.观察动物一般性状、体重、饮食等,检测血液学、凝血、血液生化、脏器系数及组织病理学改变.结果:NHFLE高剂量组大鼠在4周给药期出现多动、烦躁不安、轻微腹泻以及体重增长缓慢,以上改变在停药后恢复正常,其余动物各项检查未见异常.结论:NHFLE毒性较低.     

水杨酸咪唑的毒理学研究

目的考察水杨酸咪唑对小鼠的急性毒性和对大鼠胃部的刺激作用。方法①取小鼠50只,禁食16h后随机分成5组,每组10只,雌雄各半,按1 300,1 105,939,798,679 mg.kg-1的剂量分别灌胃给予水杨酸咪唑,给药后将小鼠饲喂14 d,观察小鼠中毒反应和死亡情况,计算半数致死量(LD50);②取小鼠50只,禁食16 h后随机分成5组,每组10只,按625,500,400,320,256 mg.kg-1的剂量尾静脉注射水杨酸咪唑,给药后将小鼠饲喂14 d,观察小鼠的毒性反应和死亡情况,计算LD50;③取大鼠70只,禁食24 h后随机分成7组,每组10只,雌雄各半,其中3组按200,400,600mg.kg-1的剂量灌胃给予水杨酸咪唑溶液,另取3组按50,75,100 mg.kg-1的剂量灌胃给予阿司匹林溶液灌胃,另一组为对照组,按20 mL.kg-1的剂量灌胃给予纯化水。5 h后将大鼠处死,观察胃黏膜面溃疡程度,测量溃疡面积,计算半数致溃疡剂量(UD50);④取大鼠70只,分组方法同实验③,其中3组按150,300,450 mg.kg-1的剂量灌胃给予水杨酸咪唑溶液,另取3组按50,100,200 mg.kg-1的剂量给予阿司匹林溶液,另一组灌胃给予纯化水(20 mL.kg-1),连续给药14 d后处死,观察胃黏膜面溃疡程度和溃疡面积,计算UD50。结果小鼠灌胃给予水杨酸咪唑的LD50为1 035.3(904.7~1 184.6)mg.kg-1,小鼠静脉注射给予水杨酸咪唑的LD50为408.7(370.4~451.1)mg.kg-1;大鼠急性UD50为218.7(141.2~336.9)mg.kg-1,是阿司匹林的3.8倍(以毫摩尔数计);大鼠慢性UD50为273.5(165.6~451.5)mg.kg-1,是阿司匹林的4.3倍(以毫摩尔数计)。结论水杨酸咪唑毒性较低,对胃肠道的毒性作用比阿司匹林小。     

阿比朵尔对大鼠的长期毒性

目的:观察阿比朵尔对大鼠的长期毒性反应。方法:96只Wistar大鼠,雌雄各半,随机分成4组,即1200,350和100 mg·kg-1剂量组和对照组,连续灌胃给药4周,按常规方法观察动物一般状况、体重、摄食量、血液学、血液生化、脏器重量系数及组织病理学改变。结果:阿比朵尔未引起动物死亡。给药期:高剂量组雌鼠第1-4周体重明显低于对照组,并有6只动物陆续出现明显掉毛;高剂量组雄鼠第2-4周体重明显低于对照组,并有4只动物陆续出现明显掉毛;其他指标与对照组比较无明显差异。低剂量组和中剂量组各项指标与对照组比较均无明显差异。恢复期:高剂量组雌鼠第1周体重仍明显低于对照组,其他各剂量各项指标与对照组比较均无明显差异。结论:大鼠口服阿比朵尔4周,350 mg·kg-1为安全剂量,1 200 mg·kg-1对大鼠生长有可逆性抑制作用。     

复方冰甲乳膏长期毒性试验研究

目的:观察复方冰甲乳膏对大鼠的长期毒性。方法:将80只SD大鼠,雌雄各半,随机分为4组,分别是空白对照组和受试药高剂量组(3.00 g·kg-1)、中剂量组(1.50 g·kg-1)、低剂量组(0.75 g·kg-1),每组20只,每天皮肤涂抹一次,每周6 d,连续给药13周,停药恢复2周。观察一般状况、体质量及进食量。同时检测大鼠的血常规、血生化、脏器系数和组织病理学改变。结果:各剂量组大鼠外观体征、行为活动等无明显异常,体质量、摄食量增加正常;血常规指标、血生化指标、脏器系数与对照组比较差异均无统计学意义(P>0.05),组织病理学检查未出现任何异常改变。结论:复方冰甲乳膏对SD大鼠皮肤涂抹给药13周,未出现明显的毒性作用。     

对氯苯氧异丁酸甲氧基苯丙烯酸酯的小鼠急性毒性和大鼠长期毒性

目的评价对氯苯氧异丁酸甲氧基苯丙烯酸酯(AZ)的安全性。方法 小鼠分别ig给予AZ3000～1001mg.kg-1或ip给予AZ1600～983mg.kg-1,观察14d,测定小鼠的半数致死量(LD50)。大鼠ig给予AZ500,291.7和166.7mg.kg-1(为临床拟用剂量的60倍、35倍和20倍),连续13周,停药2周后,观察大鼠一般状况、体质量增长、血液学、血液生化学和病理组织学等指标的变化。结果小鼠ig及ip给AZ的LD50分别为2053和1254mg.kg-1。大鼠给药13周后,AZ500mg.kg-1组血清转氨酶、尿素氮和肝系数升高(P<0.05),AZ291.7mg.kg-1组血清天冬氨酸转氨酶(AST)和肝系数升高(P<0.05),其他各组各指标与溶媒对照组相比均无显著性差异。病理组织学检查显示,AZ500mg.kg-1有1例肝组织炎细胞浸润,其余组大鼠未见与药物毒性相关的明显病变。停药2周后各异常指标均恢复正常。结论 AZ在规定剂量下使用应有较好的安全性。     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

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.