D-氨基半乳糖致敏的内毒素休克SD大鼠模型

目的： 建立稳定的D-氨基半乳糖致敏的内毒素休克SD大鼠模型。方法： 采用不同剂量的D-氨基半乳糖（D-GalN）和内毒素（LPS）剂量，分别以腹腔注射10 mg/kg、50 gmg/kg 、100 mg/kg D-GalN,再分别以0.5 mg/kg、1.0 mg/kg、1.5 mg/kg、2.0 mg/kg LPS静脉注射。51只大鼠随机分组，以平均动脉压低于8.0 kPa(60 mmHg)为休克指标，持续6 h以上至实验结束动物不死亡为休克稳定标准，优化与实验要求相符的造模条件。结果： 腹腔分别注射10 mg/kg、50 mg/kg、100 mg/kg D-GalN和同时分别静脉注射LPS 0.5 mg/kg、1.0 mg/kg组无动物死亡，但休克持续时间较短。静脉注射LPS 2.0 mg/kg组动物死亡率较高。静脉注射LPS 1.5 mg/kg和同时腹腔注射D-GalN 100 mg/kg组，尽管有少量动物死亡，但休克持续时间最长(P<0.01)。 结论： 腹腔注射D-GalN 100 mg/kg和静脉注射内毒素1.5mg/kg时可建立稳定的D-GalN致敏的内毒素休克SD大鼠模型。     

枯否细胞在刀豆蛋白A诱导的急性肝损伤中的作用

给小鼠用刀豆蛋白以O，YIAWkg）尾静脉注射，复制实验性急性肝损伤模型，通过检测血浆丙氨酸氨基转移酶（ALT），肿瘤坏死因子．a（’FNF－a）、光镜和电镜观察下肝组织病理学变化评价肝损伤。雄性国出VCjJ’鼠，体重20－3（），6－7周龄，实验前16h禁食，动物由湖北省医科院实验动物中心提供。随机将实验小鼠分为对照组（n＝8）、o）’lrt组（n＝8）和二氧化硅（Stq）＋（ConA组（n＝8）。对照组尾静脉注射无菌磷酸盐缓冲液（PBS）0．3ml/只，ConA组尾静脉注射见onA20mg/kg，SiO2＋ConA组在静脉注射haA20lug／kg前18h分别向尾…     

利福喷丁的毒性研究

(一)急性毒性:小鼠口服4g/kg,腹腔注射1g/kg;大鼠口服2g/kg,观察一周均未见动物死亡。 (二)长期毒性:大鼠、狗连续口服不同剂量的药物6～8月,饮食、活动等均未见异常,肝、肾功能,血象与对照组相比,无明显变化,病理组织检查,无药物性病变。 (三)三致毒性:致畸试验阳性,88 mg/kg与利福平相似出现胚胎毒性。     

黄藤素注射液Beagle犬静脉给药毒性观察

目的：采用Beagle犬一次静脉滴注黄藤素注射液．观察其对试验动物所产生的急性毒性反应和死亡情况．为黄藤素注射液临床用药途径提供参考。方法：用近似致死剂量法(ALD)，选择3只健康6月龄Beagle犬，根据黄藤素注射液小鼠静脉注射给药急性毒性试验结果．按50％剂量递增．计算出剂量递增序列，在剂量序列范围内间隔一个剂最给一只动物。1号动物25．0mg/kg体重．2号动物50．0mg/kg体重．3号动物100．0mg/kg体重，     

萘丁美酮大白鼠连续6个月口服给药的毒性试验

本文报告了大白鼠连续灌服萘丁美酮6个月,在剂量为40mg/kg/d和20mg/kg/d对动物的饮食、生长发育和肝、肾功能均无影响;而90mg/kg/d组动物出现明显毒性反应,并有动物死亡。其病理改变主要是胃肠损伤和肾脏损害。故该药品能在40mg/kg/d连续服用半年是安全的。     

依托咪酯对四氯化碳诱导的大鼠肝损伤的保护作用

目的 研究依托咪酯对四氯化碳（CCl4）诱导的大鼠急性肝损伤的保护作用及相关机制。方法 将48只SPF级Wistar大鼠随机分为对照组、模型组、依托咪酯0.5 mg/kg组、依托咪酯1 mg/kg组、依托咪酯2 mg/kg组、水飞蓟素（SIL）组（200 mg/kg,阳性对照）,每组6只。对照组和模型组静脉注射生理盐水0.2 mL,依托咪酯给药组分别静脉注射0.5 mg/kg、1 mg/kg、2 mg/kg依托咪酯0.2 mL,SIL组静脉注射200 mg/kg SIL 0.2 mL,每天1次,连续给药14 d,然后模型组、依托咪酯给药组和SIL组腹腔注射0.2%CCl4(10 mL/kg),对照组腹腔注射等量橄榄油,24 h后处死大鼠。测定血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平;HE染色评估肝组织病理损伤;ELISA检测肝组织中肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)水平;检测超氧化物歧化酶（SOD）和丙二醛（MDA）水平;TUNEL染色评估肝组织中细胞凋亡情况;免疫组化检测大鼠肝组织中NF-κB p65阳性表达;Western blot检...     

米托蒽醌与肝靶向制剂米托蒽醌毫微球延迟毒性的比较研究

目的 :比较米托蒽醌 (mitoxantrone,DHAQ)及其肝靶向药物米托蒽醌聚氰基丙烯酸正丁酯毫微球(mitoxantrone polybutycyanoacrylate nonosphere ,DHAQ PBCA NS)小鼠一次性静脉注射的延迟毒性。方法 :小鼠分别一次性尾静脉注射不同剂量的米托蒽醌毫微球、米托蒽醌注射液 ,观察给药物后 2 1天内的死亡情况。评价延迟毒性方法为给药后动物平均存活天数 ,累计死亡数及百分率等。结果 :DHAQ和DHAQ PBCA NS均有一定的延迟毒性 ,以Bliss法计算 7、1 4、2 1天的LD50 分别是 1 1 .2 7± 2 .2 1、9.33± 1 .82、8.1 8± 1 .6 0mg/kg和 1 4…     

柔肝方通过抑制纤维化蛋白抗肝纤维化的机制研究

目的:柔肝方是上海市名中医王灵台教授治疗肝纤维化的临床有效验方,本研究旨在探讨柔肝方通过抑制纤维化蛋白(FBRS)抗肝纤维化的分子机制.方法:质谱法鉴定柔肝方的化学成分及其入血成分.BALB/c小鼠随机分对照组、模型组、柔肝方高剂量组、柔肝方中剂量组和柔肝方低剂量组.通过尾静脉注射ConA(12.5 mg/kg),每周...     

红花黄色素对大鼠中毒性肝纤维化血清和肝组织HA和LN及胶原含量的影响

目的本实验以透明质酸(HA)、层粘连蛋白(LN)为指标,观察CCl4诱导大鼠中毒性肝损伤和肝纤维化后肝组织内储脂细胞变化和胶原的沉积及红花黄色素对其变化的影响,以探讨红花黄色素对中毒性肝纤维化防治作用的机制.方法Wistar大鼠随机分为3组①病理模型组接受40%CCl4一橄榄油皮下注射,剂量为1.2mL/kg体重,每周2次,共12周,与治疗组等容量生理盐水灌胃;②红花黄色素治疗组接受40%CCl4一橄榄油注射,方法、剂量同病理模型组,同时红花黄色素550mg/kg体重灌胃,每日1次,共12周;③正常对照组接受橄榄油皮下注射,方法、剂量同上.各组分别于实验开始后,每隔3周随机处死5只大鼠,剩余大鼠于12周末全部处死.断头采血,分离血清,取1g新鲜肝组织匀浆,用放免法测定大鼠血清和肝匀浆中HA、LN含量.肝组织V-G染色,用病理图像分析系统进行胶原定量分析.用透射电镜观察肝组织内储脂细胞变化.结果红花黄色素治疗组大鼠血清和肝匀浆中HA、LN含量及肝组织内胶原含量和储脂细胞变化显著低于病理模型组.结论红花黄色素能抑制肝脏储脂细胞增殖转化及HA、LN的合成,减少胶原沉积,有防治CCl4诱发中毒性肝纤维化的作用.     

国产DHAQ(Mitoxantrone)对兔的长期毒性试验

健康成年日本大耳白兔60只,随机分成DHAQ高剂量组(D高组,0.18mg/kg/d)、低剂量组(D低组,O.09mg/kg/d)和生理盐水组,连续静脉注射给药18天,处死半数动物,余下者停药继续观察25天,比较动物给药前、给药期及停药后的一般状况、各项生理、生化指标并作病理组织学检查。结果发现D高组给药一周后食欲普遍下降、活动减少、消     

不同镉离子浓度诱导饲养对参环毛蚓体腔细胞溶酶体膜的影响

目的 观察不同浓度镉离子诱导饲养对参环毛蚓体腔细胞溶酶体膜的毒性效应.方法 选取健康参环毛蚓70只,按照饲养土壤镉离子浓度的不同随机分为7组,每组10只.各组土壤镉离子浓度分别为0.28(对照组)、3.28、6.28、12.28、18.28、24.28和30.28 mg/kg,采用不同浓度镉离子诱导参环毛蚓染毒并饲养14 d.诱导饲养7 d和14 d时观察参环毛蚓体腔细胞的形态变化,测定其体腔细胞溶酶体中性红保留时间.结果 高浓度镉离子诱导参环毛蚓体腔细胞溶酶体的损害明显.诱导饲养7 d,对照组、3.28、6.28、12.28、18.28、24.28和30.28 mg/kg镉离子浓度组参环毛蚓体腔细胞溶酶体中性红保留时间随着镉离子浓度的增加而逐渐缩短,分别为(71.3±2.4)、(60.5±1.6)、(55.1±2.9)、(51.9±3.6)、(46.0±2.5)、(38.8±1.8)、(34.2±2.0)min.与对照组比较,诱导饲养7 d、14d时各实验组参环毛蚓溶酶体中性红保留时间明显缩短(均P＜0.05).结论 体腔细胞溶酶体中性红保留时间可用于评价土壤中重金属镉对参环毛蚓的毒性效应.     

The Prenatal Toxic Effect of Methylmercury on the Development of the Appendicular Skeleton of Rat Fetuses and the Protective Role of Vitamin E

Methylmercury (MeHg) is an environmental contaminant that is found in many ecosystems. Many studies reported that MeHg toxicity is accompanied by increased lipid peroxidation that may lead to oxidative damage to DNA, RNA, and proteins. Vitamin E is considered as the most effective antioxidant preventing lipid peroxidation. The aim of this study was to evaluate the effects of MeHg exposure during pregnancy on the development of the appendicular skeleton in rat fetuses and whether vitamin E administration could reduce this toxicity. Positively mated adult female Sprague–Dawley rats were used and divided into the following experimental groups: control group, received only deionized water, and four MeHg treated groups received 1 mg of MeHg/kg/d, 2 mg of MeHg/kg/d, 1 mg of MeHg/kg/d plus 150 mg of vitamin E/kg/d, and 2 mg of MeHg/kg/d, plus 150 mg of vitamin E/kg/d starting from Day 0 of gestation. On Day 20 of gestation, the fetuses from the pregnant rats were extracted and the fetal growth parameters were evaluated. Skeletal evaluation of ossification of both fore‐ and hind‐limbs, and coxal bones were undertaken. Results showed that treatment with MeHg caused adverse effects on fetal growth parameters and ossification of the bones. The coadministration of vitamin E with MeHg revealed an improvement in these parameters. These results suggest that vitamin E may ameliorate some aspects of MeHg developmental toxicity. The underlying and human health implications warrant further investigations. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Protection against adriamycin (doxorubicin)-induced toxicity in mice by several clinically used drugs

Protective effects of clinically used drugs against adriamycin (ADM)-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.). The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg), 402.2% for dextran sulfate (MDS, 300 mg/kg), 121.6% for flavin adenine dinucleotide (20 mg/kg), 236.3% for adenosine triphosphate disodium (50 mg/kg), 213.7% for reduced glutathione (100 mg/kg), 121.6% for phytonadione (50 mg/kg), 155.2% for inositol nicotinate (Ino-N, 500 mg/kg), 335.5% for nicomol (1000 mg/kg), 157.5% for nicardipine (10 mg/kg) and 123.3% for dipyridamol (50 mg/kg). Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.     

Friction, wear, and tensile properties of vacuum hot pressing crosslinked UHMWPE/nano-HAP composites

Ultra high molecular weight polyethylene (UHMWPE) is a thermoplastic engineering plastic with excellent mechanical properties. In this study, nonirradiated and irradiated UHMWPE/nano-hydroxyapatite (nano-HAP) composites were prepared by vacuum hot-pressing method, and then friction, wear, and tensile properties were investigated. To explore mechanisms of these properties, differential scanning calorimetry, infrared spectrum, and scanning electron microscopy with energy dispersive spectrometry analysis were carried out on the samples. The results in this study indicated that reduced friction coefficients and wear rate could be obtained when nonirradiated and irradiated UHMWPE were filled with 7% nano-HAP. The irradiated UHMWPE/7% nano-HAP also had a synergistic function of wear reduction as compared with irradiated UHMWPE and nonirradiated UHMWPE/7% nano-HAP. Samples filled with 7% nano-HAP showed a brittle fracture behavior, and a linear relationship between modulus and crystallinity for a nonirradiated and irradiated sample was found in this study.     

Acute and Subchronic Toxicity Study of Tud-Rak-Ka-Sai-Puu Recipe in Rats

Acute and subchronic toxicities of Tud-Rak-Ka-Sai-Puu (TR) recipe were studied in male and female rats. After 14 days of a single oral administration of test substance (5,000 mg/kg body weight), measurement of the body and organs weights, necropsy and health monitoring were performed. No signs and differences in the weights and behavior were observed relative to the control rats, suggesting that TR recipe in the dose of 5,000 mg/kg body weight does not produce acute toxicity. The subchronic toxicity was determined by oral feeding in male and female rats daily with the test substance at 2, 20, 200 and 2,000 mg/kg body weight for 90 days. No defects of animal behavior were observed in the test groups. Both test and control groups (on the 90^th day) as well as the satellite group (on the 118^th day) were analyzed by measuring their final body and organ weights, taking necropsy, and examining hematology, blood clinical chemistry, and microanatomy. These results together with the information of signs, behavior and health monitoring can lead to a conclusion that an oral administration of TR recipe at 2, 20, 200 and 2,000 mg/kg body weight for 90 days did not cause subchronic toxicity.     

Toxicity Studies of the Water Extract from the Calyces of Hibiscus Sabdariffa L. in Rats

Acute and chronic toxicities of the water extract from calyces of Hibiscus sabdariffa were studied in male and female rats. After 14 days of a single oral administration of test substance 5,000 mg/kg body weight, measurement of the body and organ weights, necropsy and health monitoring were performed. No signs and differences of the weights or behaviour compared to the control rats were observed. The results indicated that the single oral administration of H. sabdariffa extract in the amount of 5,000 mg/kg body weight does not produce acute toxicity. The chronic toxicity was determined by oral feeding both male and female rats daily with the extract at the doses of 50, 100, and 200 mg/kg body weight for 270 days. The examinations of signs, animal behaviour and health monitoring showed no defects in the test groups compared to the control groups. Both test and control groups (day 270th) and satellite group (day 298th) were analysed by measuring their final body and organ weights, taking necropsy, and examining haematology, blood clinical chemistry, and microanatomy. Results showed no differences from the control groups. Overall, our study demonstrated that an oral administration of H. sabdariffa extract at the doses of 50, 100 and 200 mg/kg body weight for 270 days does not cause chronic toxicity in rat.     

Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

Background

Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats.

Methods

Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed.

Results

In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment.

Conclusion

Acute study reveals that the LD₅₀ of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions.     

Safety analysis of high dose (>6 mg/kg/day) daptomycin in patients with concomitant statin therapy

There is a paucity of data regarding efficacy and safety of concomitant therapy of daptomycin and statins, so we reviewed patients that concomitantly received daptomycin and statins to identify any potential increase in toxicity in our cohort. This retrospective study included all patients that received >6 mg/kg/day of daptomycin along with statins and had efficacy and safety data. Patients on high dose (>6 mg/kg/day) daptomycin therapy that did not received statins served as controls. One hundred four patients were included. Median daptomycin dose was 7.8 mg/kg/day (range 6.5-10.8 mg/kg/day), for a mean duration of therapy of 17 days (range 10-51 days). Thirty-six patients received daptomycin and statins and 68 received only daptomycin. Muscular toxicity defined as CPK levels>1000 UI/L (2.5 times upper normal limit, range of determination 200-400 UI/L) was equally distributed between both groups (3/36, 8% vs 7/68, 10%; p=0.746). Despite biochemical toxicity, we did not find clinical toxicity and daptomycin treatment was completed in all cases. We did not find predictors of increased CPK during daptomycin therapy. Based on our data, concomitant administration of daptomycin and statins is safe and is not associated with an increased risk of rhabdomyolysis.     

Safety evaluation of recombinant staphylokinase in rhesus monkeys

Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial origin. The objective of this study was to assess the toxicity of rSTAR administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were thickening of the skin in all animals and mild hematoma formation in three dosage groups at the injection sites. There were no effects on body weight, absolute or relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts, hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2. Significant prolongtion of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity were observed in the three treated groups. Increased neutralizing rSTAR activity diminished the phamacologic effects of rSTAR (ie, prolonged APTT, PT, and TT approaching baseline levels at week 2). Histopathological findings included hemorrhage, and perivascular inflammatory cell infiltration at the injection sites, heptocellular degeneration characterized as cytoplasmic eosinophilia, vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma within some Bowman's capsules and hyaline casts within the lumen of some renal tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune deposits in glomeruli in the kidneys from the three treated groups were detected. These changes were reversible following a 4-week recovery period. In the present preclinical evaluation of toxicity in monkeys, rSTAR is well toleratte at doses up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone marrow.     

Prenatal effects of natural calcium supplement on Wistar rats during organogenesis period of pregnancy

The potential of oral exposure to calcium and magnesium citrate, a natural product obtained from dolomite, to initiate teratogenesis was analyzed in Wistar rats. Animals received calcium and magnesium citrate oral doses of 250, 500 and 1000 mg/kg during the period of gestation from day 6 to 17 post conception. Maternal, embryo and fetal toxicity was evaluated. Calcium and magnesium citrate exposure did not produce maternal toxicity assessed by clinical observations, body weight gain, food intake, hematology, biochemical parameters and necropsy finding. Signs of embryo–fetal toxicity were not observed. Skeletal and visceral malformations were seen occasionally in all drug-treated and control groups. Skeletal and visceral variations were similar in control and drug-treated groups except for incomplete ossification rib. These finding was spontaneous and unrelated to the drug. In conclusion, in this study we found that the oral exposure to rats of up to 1000 mg/kg of calcium and magnesium citrate during organogenesis did not induce significant maternal and embryo–fetal toxicity. The experimentally derived NOAEL for developmental toxicity was 1000 mg/kg.