吊白块急性毒性作用研究

背景与目的:确定吊白块半数致死剂量LD50.材料与方法:采用改进寇氏法测定吊白块LD50.结果:吊白块对MH小鼠经口灌胃LD50为8 711 mg/kg.结论:根据国家标准评价,吊白块毒性分级属实际无毒级.     

小剂量rh-TNFαD3a协同阿霉素对人肺癌细胞株抑瘤率的影响

目的研究小剂量重组人肿瘤坏死因子α衍生物3a(rh-TNFαD3a)对人肺癌低转移表型(AGZY)和高转移表型(Anip973)细胞株的毒性作用及其与阿霉素(ADM)联合的协同效应.方法采用MTT比色法检测小剂量rh-TNtα D3a及与ADM联合后对AGZY和Anip973细胞株的毒性作用.结果ADM加TNF后,在两细胞株中均可明显降低ADM的半数致死浓度.在Anip973细胞株中,ADM各浓度组加TNF后,其抑制率均明显增加(P＜0.05).而在AGZY细胞株中只有ADM浓度在2.00μg/ml时其抑制率明显增加(P＜0.05),其它浓度组变化不大.结论小剂量rh-TNFαD3a可降低ADM的半数致死浓度,增加ADM对人肺癌细胞株的抑瘤率.     

吉西他滨缓释微球急性毒性实验研究

目的 了解乳酸-乙醇酸共聚物(PLGA)-吉西他滨缓释微球和吉西他滨小鼠皮下给药的急性毒性.方法 采用上下增减剂量法(UDP)分别测定PLGA-吉西他滨缓释微球和吉西他滨小鼠皮下给药对动物的半数致死量(LD50).结果 PLGA-吉西他滨缓释微球皮下给药的小鼠LD50为256.30 mg/kg,吉西他滨小鼠皮下给药时为8.91 mg/kg,相差达28.8倍.结论 PLGA-吉西他滨缓释微球能够显著降低化疗药物对动物的急性毒性.     

磷酸三(1,3-二氯异丙基)酯对大鼠的急性和亚慢性毒性作用

目的：研究磷酸三(1,3-二氯异丙基)酯(TDCIPP)对大鼠的急性和亚慢性毒性作用。方法：急性毒性试验中,将50只SPF级SD大鼠随机分为5组,每组10只,雌雄各半,按照TDCIPP剂量464、1 000、2 150、4 640和10 000 mg/kg分别进行单次经口灌胃染毒,观察14 d。在亚慢性毒性试验中,将80只SPF级SD大鼠随机分为4组,每组20只,雌雄各半,TDCIPP按照0、13.3、40、120 mg/(kg·d)的剂量,每天1次,连续灌胃112 d。于试验结束当天分别称取大鼠体质量;腹主静脉取血进行血常规、血液生化指标的检测;处死大鼠后收集脑、心、肝、脾、肺、肾并称取质量,计算脏器系数,并对这些组织进行HE染色分析组织病理变化。选择具有代表性的指标为毒性效应,使用基准剂量法(BMD)评估在特定风险水平下的暴露水平,与无可见有害作用法(NOAEL)参考值进行比较,分析相对更具体和敏感的剂量限值。结果：在急性经口毒性试验中,TDCIPP对SD大鼠的半数致死剂量(LD50)为2 000～2 300 mg/kg,属低毒物质。在亚慢性经口毒性试验中,与对照组比较,120 m...     

抛射剂四氟乙烷中杂质CFC115和HFC1243zf的吸入毒理安全性评价

目的：对抛射剂四氟乙烷中杂质五氟氯乙烷(CFC115)和3,3,3-三氟丙烯(HFC1243zf)进行吸入毒性和安全性评价。方法：用CFC115和HFC1243zf混合气体(体积比为7∶3)作为受试样品进行体外空气暴露的小鼠成纤维细胞(L929)细胞毒性及Ames试验,SD大鼠口鼻暴露4 h的急性吸入毒性、7 d重复吸入局部刺激性、21 d重复吸入亚慢毒性试验和Hartley豚鼠全身主动过敏性试验,为控制四氟乙烷中CFC115和HFC1243zf杂质限度提供依据。结果：大鼠急性吸入毒性半数致死浓度(LC₅₀) CFC115>3 115 g/m³,HFC1243zf >832 g/m³;未见重复吸入局部刺激性;未见豚鼠全身致敏反应;无细胞毒性作用;Ames试验未见致突变作用。大鼠21 d重复吸入CFC115(3 205 g/m³)和HFC1243zf (856 g/m³)混合气体后,与对照组相比,摄食量减少(P<0.05或P<0.01)、体质量增长缓慢(P<0.05),血液白细胞分类嗜碱性粒细胞(Bas)、单核细胞(Mon)百分数升高,血生化丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、尿素氮(UREA)、碱性磷酸酶(ALP)、总胆红素(TBil)平均值升高(P<0.05或P<0.01),尿液亚硝酸盐(NIT)、酮体(KET)、个别尿蛋白(PRO)和白细胞(LEU)平均值升高(P<0.05或P<0.01),脑系数升高和卵巢湿质量降低(P<0.05或P<0.01),组织病理学发现心内膜灶性或多灶性坏死、单核细胞浸润的改变,另外雄性大鼠肺脏湿质量和肺系数降低(P<0.01)。结论：CFC115和HFC1243zf混合气体的体外试验或短期动物试验在高浓度接触或吸入未见明显毒性,较长期反复高浓度吸入对大鼠存在多器官损伤,但产生毒性的浓度远高于临床最大暴露量。     

毒死蜱对果蝇生长发育的影响

目的：研究毒死蜱（CPF）对果蝇生长发育的影响。方法：设定0.5、1.0、1.5、2.0、2.5、3.0和4.0 mg/L共7个CPF浓度梯度对果蝇进行急性染毒,统计每组果蝇96 h死亡数,Probit法计算毒死蜱染毒96 h对果蝇的半数致死浓度（LC₅₀）,依据LC₅₀分别设置含毒死蜱0.04、0.08、0.16、0.32 mg/L的培养基,用其染毒果蝇后,检测雌、雄果蝇体质量变化,各浓度组随染毒时间延长雌雄果蝇体质量日增减量及各染毒时间段随浓度增加雌雄果蝇体质量变化。结果：CPF对雌果蝇的毒性（LC₅₀为0.447 mg/L）大于雄果蝇（LC₅₀为0.858 mg/L）。CPF各浓度在染毒不同时间对雌果蝇的体质量无显著影响（P>0.05）。0.04~0.32 mg/L CPF使雄果蝇体质量平均日减轻0.01 mg/d,与对照组比较差异有统计学意义（P<0.05或P<0.01）,存在明显时间-效应关系。雄果蝇对低浓度0.04 mg/L（LC₅₀的1/20）CPF极为敏感,体质量显著下降（0.04～0.08 mg）,雄果蝇在0.16 mg/L浓度染毒时体质量增加（0.02 mg）,染毒72或96 h时各浓度组体质量差异有统计学意义（P<0.05）,存在明显剂量-效应关系。结论：CPF使雄性果蝇体质量发生变化,反映CPF可对雄性果蝇生长发育生理生化指标产生相应的影响。     

龙神注射液抑瘤和急性毒性实验研究

目的了解抗癌中药龙神注射液的抑瘤作用和毒性反应。方法在小白鼠体内进行龙神注射液抑制艾氏腹水瘤作用研究和急性毒性试验。结果龙神注射液试验组小鼠平均生存天数为（２０．１７±３．６）ｄ,与生理盐水对照组相比,ｔ＝６．３５２４,Ｐ＜０．０１;ＬＤ５０＝３５６．５３ｍｇ／ｋｇ。结论龙神注射液对小鼠艾氏腹水瘤有明显抑制作用,临床使用较为安全     

水蛭素冻干粉急性毒性和致突变性研究

目的：检测水蛭素冻干粉的急性经口毒性和致突变性。方法：以水蛭素冻干粉（50AT_U/g）给小鼠灌胃检测急性经口毒性,用Ames试验、小鼠骨髓细胞微核试验和精子畸形试验检测其遗传毒性。结果：水蛭素冻干粉对小鼠经口LD50〉10.0g/kg;Ames试验显示在加与不加S9混合液的各剂量组回变菌落数与自发回变对照组无明显差别;小鼠骨髓细胞微核试验和精子畸形试验结果显示,各剂量组的微核率和精子畸形率与阴性对照组比较差别无统计学意义。结论：在本实验条件下,水蛭素冻干粉的经口LD50〉10.0g/kg,属实际无毒级,未见有致突变作用。     

印加果油急性毒性和致突变性研究

目的：研究印加果油的急性经口毒性和致突变性。方法：采用小鼠急性毒性试验（最大给药量法,24 h内3次给药,合计剂量54 g/kg）、Ames试验（分别为每皿5 000、1 000、200、40、8μg）、骨髓嗜多染红细胞微核试验和精子畸形试验（均分别为10、5、2.5 g/kg）,检测印加果油的急性毒性与致突变性。结果：印加果油对小鼠的LD_（50）〉54 g/kg,Ames试验各剂量组的回变菌落数与自发回变菌落数的比值与对照组比较,差异无统计学意义（P〉0.05）,各剂量组的微核率和精子畸形率与阴性对照组间的差异均无统计学意义（P〉0.05）。结论：在本实验条件下,印加果油的急性经口毒性属于无毒级,亦未显示致突变性。     

奇亚籽急性毒性及遗传毒性研究

目的： 了解奇亚籽的毒理学安全性。方法：采用小鼠急性毒性试验和遗传毒性试验(Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验)对奇亚籽进行研究,小鼠急性经口毒性试验剂量为22.5 g/kg,观察经口给予受试物后14 d内动物的死亡情况;Ames试验设5个剂量,分别为每皿0.008、0.04、0.20、1.0和5.0 mg (每皿给受试物体积为0.1mL),同时设自发回变、溶剂对照(丙酮)和阳性对照(9-芴酮、2-AF、NaN3、MMC、1.8-二羟蒽锟),接种后,在37 ℃下培养48 h,计数每皿回变菌落数;小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验均设3个剂量组,分别为1.875、3.750和7.500 g/kg,同时设溶剂对照组(玉米油)和阳性对照组(环磷酰胺,50 mg/kg),分别观察骨髓涂片中嗜多染红细胞中的微核发生率和精子标本中精子畸形的类型和相应的数量。结果：奇亚籽的小鼠经口最大耐受剂量(maximum tolerated dose,MTD)>22.5 g/kg,为无毒级物质;在Ames试验、小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验中结果均呈阴性;结论：奇亚籽属于无毒级物质,亦不具有遗传毒性。     

甲氧化三丁基锡的急性毒性和遗传毒性研究

目的:研究甲氧化三丁基锡(tributyltin methoxide,TBTMO)对小鼠的急性毒性和遗传毒性。方法:选取昆明种小鼠110只,随机分为11组(TBTMO 420、286、194、180、132、90、73、61、41.5、28 mg/kg及阴性对照组),一次性灌胃给药进行急性毒性测试;另取昆明种小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),各剂量组和阴性对照组均连续给药2 d,阳性对照组连续给药5 d,均连续观察35d,处死小鼠取双侧附睾制片进行精子畸形试验;并取昆明种小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),灌胃给药30 h后处死小鼠取胸骨骨髓进行微核试验;取GFP转基因小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),收集每只小鼠的脾淋巴细胞进行hprt基因突变试验。然后用不同浓度TBTMO(69.4、48.6、34.0、23.8、16.6、0μg/ml)分别处理中国仓鼠肺成纤维细胞(Chinesehamster lung,CHL)进行染色体畸变试验;用不同浓度TBTMO(每皿5×10~5、5×10~4、5×10~3、5×10~2、50、5、0.5、0.05、5×10~-3、5×10~-4μg)分别处理TA97、TA98、TA100、TA102 4种菌株进行Ames试验。结果:TBTMO对小鼠的半数致死量(LD_(50))为98 mg/kg。与阴性对照组比较,TBTMO可致小鼠精子畸形(P0.05或P0.01),且有剂量依赖趋势,其余4项遗传毒性试验结果均为阴性。结论:在本实验条件下,TBTMO对小鼠的急性经口毒性属于中等毒性,可能具有一定的遗传毒性。     

Acute mucocutaneous toxicity following high-dose hydroxyurea

Three patients with advanced acute myeloid leukemia were treated with oral high-dose hydroxyurea at a dose of 10 g daily for 8–10 days. Severe acute stomatitis developed in all three patients. In addition, two of the patients developed a peculiar acute cutaneous type of toxicity associated with soreness, violet erythema, and edema of the palms and foot soles followed by intense universal hyperpigmentation of the skin. Apparently, the pronounced acute mucocutaneous toxicity was caused by the sustained high daily dose of hydroxyurea, indicating that myelosuppression may not be the dose-limiting toxicity of this drug.     

Acute encephalopathy: a new toxicity associated with high-dose paclitaxel.

The purpose of this study was to describe acute encephalopathy as a new toxicity associated with paclitaxel, when it is delivered at high doses (> or =600 mg/m2) with stem cell support. A total of 129 patients, included in clinical trials of paclitaxel-containing high-dose chemotherapy, were analyzed. A total of 114 patients received paclitaxel at a dose of > or =600 mg/m2. Six patients presented acute encephalopathy starting between 7 and 23 days after paclitaxel treatment; two of them had received prior whole-brain irradiation. Paclitaxel was given alone (one patient), with cyclophosphamide and cisplatin (two patients), and with cyclophosphamide and cisplatin plus 1,3-bis(2-chloroethyl)-1-nitrosourea (three patients). Central nervous system toxicity consisted of rapid obtundation and coma (five patients) and severe confusional picture with paranoid ideations (one patient). Brain magnetic resonance imaging showed diffuse white matter atrophy (one patient) or multiple small infarcts (one patient), or it was normal (four patients). Other complementary tests, including cerebrospinal fluid analysis and electroencephalography, were nondiagnostic. An effect from concomitant psychotropic medications or from other organ toxicities was excluded in all patients. Three patients recovered after 8-15 days, either spontaneously (two patients) or after high-dose steroids (one patient). Three patients died of irreversible coma. Necropsy, performed in two patients, showed generalized white matter atrophy and multiple brain parenchymal infarcts, respectively. No pharmacodynamic correlation between the occurrence of encephalopathy and a pharmacokinetic parameter of paclitaxel could be identified. Paclitaxel-containing high-dose chemotherapy can cause severe acute encephalopathy. An aggravating effect from prior brain irradiation or concurrent 1,3-bis(2-chloroethyl)-1-nitrosourea seems possible.     

Anthracyclines - a review of general and special toxicity studies

Preclinical safety assessment data on doxorubicin (DOXO), epirubicin (EPI), idarubicin (IDA) and methoxymorpholinodoxorubicin (MORPHO), from mouse, rat and dog studies are reviewed. These data are put into perspective allowing for extrapolations across species, doses and dose regimens with recommendations for proper human use. The compounds were administered intravenously or intraperitoneally in studies ranging from single dose to multiple dose studies of different durations. The compounds were given once, daily, weekly or cyclically. In the cyclic administration studies, DOXO, EPI, and IDA were given for 3 consecutive days a week for 6 or 13 weeks; MORPHO was given for 3 consecutive days a week every three weeks for a total of 9 cycles. The duration of the cyclic studies was from 6-26 weeks. Daily dose studies lasted from 4-26 weeks. In the single dose studies the recovery ranged from 4 weeks to one year; in the multiple dose studies from 4 to 8 weeks. A few special studies were also considered. In all studies reviewed, 2 different types of toxicity were observed. These toxicities occur also in man. The first is the acute toxicity, which is the consequence of cytotoxicity and expresses the exaggerated pharmacological activity of the compounds. The target sites in all 3 species and in man include the hemolymphopoietic system (HLPS), the gastrointestinal (GI) tract, skin and testes; all renewing cell types. The second type of toxicity is the chronic progressive toxicity. This toxicity is the expression and result of sustained disruption of cytoplasmic homeostasis and occurs in non-renewing cell types. The target sites include the heart (both animals and man), kidneys (rodents) and peripheral nervous system (PNS) (rodents). From single administration animal data, chronicity, site and magnitude of toxicities can be predicted in man. Despite strong mitogenic stimuli in the rat, there is no evidence that there is a potential for hemolympho- or hepatocarcinogenicity with these compounds.     

Acute neurological toxicity of intrathecal cytosine arabinoside

Summary A patient developed severe neurological toxicity, with peripheral and cerebral components and hyponatraemia following one intrathecal injection of 80 mg cytosine arabinoside. The severity of his symptoms may reflect heavy prior neurotoxic chemotherapy.     

High-dose 7-hydroxymethotrexate: Acute toxicity and lethality in a rat model

To elucidate mechanisms for methotrexate (MTX)-induced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0.4 g/kg 7-hydroxymethotrexate (7-OH-MTX) in the rat. We demonstrate for the first time in any species the occurrence of acute lethal toxicity within a few hours after 7-OH-MTX administration. Serum concentrations of 7-OH-MTX measured at the time of death were 1.4 mM (mean), about one-half of those achieved in some patients after infusion of high-dose MTX (HD-MTX) in the clinic. The data suggest an approximate LD50 (the dose lethal to 50% of the study population) of 0.3 g/kg and a steep dose/ lethality curve for 7-OH-MTX. Moreover, acute renal and hepatic toxicity occurred as evidenced by severe morphological findings and increased serum levels of creatinine and liver transaminases. In all rats subjected to continuous infusion of 7-OH-MTX, yellow microscopic precipitations were apparent in the kidney tubules. Crystallization was also seen in bile ducts of the liver in some of the rats. These results further support that the formation of 7-OH-MTX is disadvantageous and that reported attempts to prevent its formation during MTX treatment are warranted.     

Acute toxicity and mutagenicity of Sacha lnchi oil

目的:研究印加果油的急性经口毒性和致突变性.方法:采用小鼠急性毒性试验(最大给药量法,24h内3次给药,合计剂量54 g/kg)、Ames试验(分别为每皿5 000、1 000、200、40、8 μg)、骨髓嗜多染红细胞微核试验和精子畸形试验(均分别为10、5、2.5 g/kg),检测印加果油的急性毒性与致突变性.结果:印加果油对小鼠的LD50＞ 54 g/kg,Ames试验各剂量组的回变菌落数与自发回变菌落数的比值与对照组比较,差异无统计学意义(P＞0.05),各剂量组的微核率和精子畸形率与阴性对照组间的差异均无统计学意义(P＞0.05).结论:在本实验条件下,印加果油的急性经口毒性属于无毒级,亦未显示致突变性.