欧前胡素急性毒性和安全药理学研究

目的观察欧前胡素对大、小鼠的急性毒性,以及对小鼠神经系统和犬心血管系统、呼吸系统的影响。方法通过腹腔内注射给药（ip）和灌胃给药（培）研究欧前胡素对小鼠的急性毒性,以及培对大鼠的急性毒性实验。安全药理学实验中以50、100、200mg／kg分别单次培给予小鼠欧前胡素,观察对小鼠神经系统的影响（包括小鼠自发活动、爬杆能力、小鼠阈下剂量戊巴比妥钠催眠协同实验）;以25、50、100mg／kg分别单次口服给药（po）欧前胡素,观察对犬心血管系统和呼吸系统的影响（包括心电图、血压、心率,以及呼吸频率、幅度、节律等指标）。结果欧前胡素培对小鼠的LD50为988．5mg/kg;ip对小鼠的LD50为603．3mg／kg;ig对大鼠的LD50为3188．7mg／kg。欧前胡素单次ig对小鼠神经系统无明显影响;单次po对犬心血管系统指标和呼吸系统指标无明显影响。结论欧前胡素安全范围较大,毒性较容易控制,且对正常动物（包括小鼠、大鼠和犬）的降压作用不显著,因此具有较大的临床应用可能性。     

茶酚硒混合物的小鼠急性毒性试验

目的:观察茶多酚(TP)与亚硒酸钠(sodium selenite)混合物一次给予小鼠的急性毒性反应和死亡情况.方法:一次灌胃(ig)给药,观察14d.结果:测得TP单用一次ig的LD50为2914.45mg/kg;亚硒酸钠单用一次ig的LD50为33.54mg/kg;当TP与亚硒酸钠按7997.3mg∶2.7mg比例做成混合物,测得混合物单次ig的LD50为2510.29mg/kg,其中亚硒酸钠的含量为0.85mg/kg.结论:茶酚硒混合物单次ig的LD50为2510.29mg/kg.     

茶酚硒混合物的小鼠急性毒性试验

目的:观察茶多酚(TP)与亚硒酸钠(sodium selenite)混合物一次给予小鼠的急性毒性反应和死亡情况.方法:一次灌胃(ig)给药,观察14d.结果:测得TP单用一次ig的LD50为2914.45mg/kg;亚硒酸钠单用一次ig的LD50为33.54mg/kg;当TP与亚硒酸钠按7997.3mg∶2.7mg比例做成混合物,测得混合物单次ig的LD50为2510.29mg/kg,其中亚硒酸钠的含量为0.85mg/kg.结论:茶酚硒混合物单次ig的LD50为2510.29mg/kg.     

抗疟化合物三氟乙酰伯氨喹的毒性及诱变性

三氟乙酰伯氨喹(M 8506)对小鼠、大鼠与犬的毒性明显低于伯氨喹(PQ)。小鼠 igM 8506的LD50为 PQ 的3倍。大鼠 igM 8506 30mg/(kg·d)×28d,犬 ig 2mg/(kg·d)×28d 无不良反应。犬 ig量≥5mg/(kg·d)时有消化道反应,肝、肾与心等受损。6只犬 igM 8506 10mg/(kg·d),3只犬完成21d疗程;2只犬 ig 同剂量 PQ 1～2剂后均死亡。M 8506无诱变性。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

盐酸阿米登太的药理、毒理研究

盐酸阿米登太对感染鼠巴西日本圆线虫的大鼠及感染钩蚴的犬可获100%及95%以上的虫体减少,犬治疗后无蛔虫发现。犬单次 iv 本品20mg/kg 以下无异常反应;犬连续 ig15天,每天100mg/kg 以下未见任何异常。大鼠 ig 的急性 LD_(50)为7354 mg/kg,小鼠为1962～2572 mg/kg。亚急性毒性试验中所出现的毒副反应及病理改变,在停药后两周可基本恢复正常。遗传毒理研究表明该药无诱变性及致畸性。     

西洋参茎叶总皂甙的药理、毒理研究

西洋参茎叶中提取的总皂甙,ip25和50mg/kg,可使小鼠自发活动次数由对照组的64.4±18.4减少为16.8±4.4和4.3±2.5(p<0.01);ig425和850mg/kg由73.3±19.7减少为30.8±14.6和18.4±4.8(p<0.01);ig850mg/kg能使阈下剂量的戊巴比妥钠催眠时间持续30.0±0.0min(p<0.01);ip20mg/kg和ig850mg/kg小鼠耐缺氧平均存活时间由对照组的37.6±8.2和37.5±7.7min延长为48.6±8.6和68.3±21.8min(p<0.01);ig30和60mg/kg,可对抗环磷酰胺引起的WBC减少。ip和ig给药,LD_(50)分别为204±SE2.6mg/kg和8511±SE1061mg/kg;长期毒性实验表明,动物体重、脏器重量、WBC、Hcmo各组间无显著差异,GPT、ZTT及TTT均在正常值范围,动物脏器经病理组织学检查属基本正常。     

吡非尼酮灌胃小鼠的急性光毒性

目的:研究一种新的抗纤维化试验药物吡非尼酮(PFD)灌胃(ig)小鼠的急性光毒性反应。方法:设小鼠igPFD100、200、400mg·kg-1·d-13个剂量组;2个溶媒对照组:0.5%羧甲基纤维素钠(CMC-Na)溶液对照组,生理盐水对照组;盐酸氯丙嗪注射液30mg·kg-1·d-1阳性对照组、空白对照组共7个组,每组10只小鼠,连续给药7d后,于第7天给药15min后,用黑光灯(220V,40W,波长320~450nm,峰值360nm,滤去致正常组织红斑的290~340nm波长)连续照射24h,观察小鼠igPFD后两耳有无红斑、水肿、皮肤瘙痒和色素沉着甚至局部坏死、溃烂、表皮脱落等光毒反应,共严密观察7d。结果:阳性对照组小鼠双耳出现中度充血、水肿等反应,3d后症状消失。PFD各剂量组和2个溶媒对照组、空白对照组小鼠在长波紫外线照射后7d内均未出现急性光毒反应。结论:连续7digPFD小鼠未出现急性光毒反应。     

一类创新药苯胺洛芬注射液急性毒性研究

目的研究一类创新药苯胺洛芬的急性毒性,并与日本同类上市产品联苯乙酸乙酯注射液的急性毒性实验结果进行比较,为新药研发提供依据。方法选用NIH小鼠和Beagle犬为研究对象,采用最大耐受量法和近似致死量法考察一类创新药苯胺洛芬的急性毒性情况。结果苯胺洛芬NIH小鼠静脉注射给药最大耐受量为900 mg/kg,Beagle犬静脉滴注给药的近似致死剂量范围为405～608mg/kg(均以联苯乙酸计);联苯乙酸乙酯小鼠LD50分别为雄性337 mg/kg(294.5～347.4),雌性433 mg/kg(392.3～462.9);Beagle犬静脉滴注近似致死量为250～500 mg/kg(均以联苯乙酸计)。结论与联苯乙酸乙酯注射液相比,一类创新药苯胺洛芬注射液的安全性较好,安全范围较大,具有较好的应用前景。     

Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models, and has been evaluated in a phase I study. In order to establish the toxicity profile of this prodrug, acute and repeat-dose toxicity studies were performed with DOXO-EMCH in CD1-mice, Sprague-Dawley rats and Beagle dogs. Although the objective of the acute toxicity studies was not the determination of LD50 values, the LD50 of DOXO-EMCH was >60 mg/kg doxorubicin equivalents in both male and female mice (the LD50 of doxorubicin in CD-1 mice is -12 mg/kg). In Sprague-Dawley rats, the LD50 was 23.4 and 45.9 mg/kg doxorubicin equivalents for males and females, respectively. For comparison, the LD50 of doxorubicin in Sprague-Dawley rats is -10.5 mg/kg. The major clinical sign noted following intravenous administration of DOXO-EMCH in mice and rats was a dose-dependent peripheral neuropathy which, in general, developed as a delayed toxicity 1-3 weeks after application. The observed neurotoxicity has been well documented for Sprague-Dawley rats treated with doxorubicin at a dose of 5 and 10 mg/kg. In Beagle dogs, LD10 was not reached for DOXO-EMCH at 4.5 mg/kg doxorubicin equivalents. A four-cycle intravenous study with DOXO-EMCH at dose levels of 4 x 2.5, 5.0 or 7.5 mg/kg doxorubicin equivalents in rats revealed approximately three-fold less side effects on the hemolymphoreticular system when compared to 4 x 2.5 mg/kg doxorubicin dose, whereas effects on the testes/oligospermia seem to be comparable between both drugs at equitoxic dose. A No Observable Adverse Effect Level (NOAEL) for DOXO-EMCH of 4 x 2.5 mg/kg doxorubicin equivalents was established in this study. This dose is equivalent to the maximum tolerated dose (MTD) of doxorubicin in rats. In a two-cycle study over a period of 6 weeks in Beagle dogs (intravenous administration of DOXO-EMCH at dose levels of 1.5, 3.0 or 4.5 mg/kg doxorubicin equivalents), dose-related systemic histamine-like reactions within the first 3 hours after injection were noted in all treated groups. Only transient and temporary effects on hematology, urinary function, as well as on histopathology in mid- and/or high-dose animals, were observed. The low dose of 2 x 1.5 mg/kg was considered to be the NOAEL in this study, which is equivalent to twice the MTD o f doxorubicin i nBeagle dogs. In summary, the toxicity studies with DOXO-EMCH in mice, rats or dogs have not identified any other special toxicity when compared to the toxicity data for doxorubicin. Preclinical tolerance of DOXO-EMCH was higher in mice, rats and dogs compared to doxorubicin. A dose of 20 mg/m2 doxorubicin equivalents was recommended as the starting dose for a phase I study with DOXO-EMCH.     

白芍总甙的毒性研究

用简化机率法求出iv与ip白芍总甙的LD_(50)分别为159和230mg/kg;给小鼠ig白芍总甙>2500mg/kg,观察一周,未见明显中毒症状,亦无死亡。长期毒性实验采用大鼠(每日ig 50、1000和2000mg/kg,连续给药30与90d)和狗(每日ig 280与560mg/kg连续给药90d)。长期给药后这两种动物除血小板数目增高外,它们的摄食、体重、血尿常规、肝肾功能等均无明显改变,对两种动物的心、肝、肾、脑等18个重要脏器与组织的病理组织学观察亦无明显毒性作用。     

Beagle犬灌胃厄多司坦盐酸氨溴索混合物的急性和亚慢性毒性研究

目的 观察Beagle犬给予厄多司坦盐酸氨溴索混合物后出现的急性和亚慢性毒性反应,为临床安全用药剂量的设计和毒副反应监测提供参考.方法 选用Beagle犬进行急性和13周亚慢性毒性试验.急性试验中,设置厄多司坦盐酸氨溴索混合物剂量组(5.04 g/kg)、厄多司坦组(4.80 g/kg)、盐酸氨溴索组(0.24 g/k...     

Toxicologic evaluation of injectable acemannan in the mouse, rat and dog.

Acemannan, the USAN-accepted name for long-chain polydispersed beta-(1,4)-acetylated polymannose with interspersed 0-acetyl groups with a mannose monomer/acetyl ratio of approximately 1:1 and extracted from Aloe vera (barbadensis Miller), was administered as a 1.0 mg/ml solution to mice, rats and dogs, either as single dose or repeated at 4-d intervals for 8 doses by iv or ip routes. No significant signs of intoxication and no deaths occurred in animals treated with the single injection of acemannan at dosages of 80 mg/kg iv or 200 mg/kg ip in mice, 15 mg/kg iv or 50 mg/kg ip in rats, and 10 mg/kg iv or 50 mg/kg ip in dogs. On repeated injections systemic toxicity was limited to obvious transient discomfort that appeared dose related. There was accumulation of macrophages and monocytes without subsequent inflammatory reaction in lungs of the iv-treated animals, and in liver and spleen and on peritoneal surfaces of ip-treated animals. The effects were not considered adverse, but were consistent with the known immune stimulating activity of acemannan. A few deaths occurred in mice and rats that were suggestive of resulting from improper injection or sequella of necrosis of the injection site. The NOAELs for acemannan determined from these repeated injection studies were 20 mg/kg iv or ip in the mouse, 4.0 mg/kg iv and 50 mg/kg ip in the rat, and 1.0 mg/kg iv in dogs; 5.0 mg acemannan/kg ip in the dog was considered to be LOAEL, based on the emesis and abdominal discomfort induced.     

Preclinical Toxicology Studies with Acyclovir: Acute and Subchronic Tests

Preclinical Toxicology Studies with Acyclovir: Acute and SubchronicTests. Tucker, W.E., Jr., Macklin, A.W., Szot, R.J., Johnston,R.E., Elion, G.B., de Miranda, P. and Szczech, G.M. (1983).Fundam. Appl. Toxicol. 3:573–578. Acyclovir (ACV), a newantiherpes drug, was evaluated for toxicity in a series of acuteand subchronic toxicity tests. Oral LD₅₀ values were greaterthan 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kgin male Long Evans rats. When ACV was given iv, the LD₅₀ was405 mg/kg for male mice and greater than 600 mg/kg for malerats. Additionally, LD₅₀ values for male rats treated sc were1070, 790, 678, and 650 mg/kg in rats that were respectively,3, 10, 28 and 71 days old indicating that very young rats werenot more sensitive to acute toxic effects of ACV. There wereno signs of toxicosis in CD-1 mice given ACV by gavage at doselevels of 50, 150 and 450 mg/kg/day for 1 month. Obstructivenephropathy occurred in rats given 20, 40 and 80 mg/kg/day onceeach day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/daywere no effect dose levels. Renal damage caused by precipitationof drug crystals in renal tubules and collecting ducts in ratsgiven ACV by rapid iv injection was readily reversible within2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogsgiven 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment.At 50 and 100 mg/kg b.i.d. the clinical signs of toxicosis werenumerous and mainly resulted from the underlying morphologicaland functional changes associated with hypoplasia of the esophagealand gastrointestinal mucosa, lymphoid tissue, and bone marrow.At the 20 and 25 mg/kg b.i.d. dose levels the kidney was thetarget organ; the principal indications of altered renal functionwere increased water intake and hyposthenuria. The dose levelof 10 mg/kg b.i.d. was a no effect level for Beagle dogs treatediv. Thus, in subchronic experiments, the rapid iv injectionof acyclovir caused precipitation of crystals in the renal tubules,resulting in obstructive nephropathy in rats and dogs. Primarytoxicity occurred only in the dog where high doses of acyclovircaused hypoplasia of certain tissues with rapid cell turnover.     

毛萼乙素纳米混悬剂.Ⅱ.对小鼠肝癌H22移植瘤的生长抑制作用

采用小鼠肝癌H22移植性肿瘤模型,考察不同给药途径和剂量下,毛萼乙素纳米混悬剂的抗肿瘤作用及毒性.在适宜的给药剂量下,毛萼乙素纳米混悬剂经静脉注射、腹腔注射和灌胃3种途径给药均可抑制小鼠肝癌H22移植瘤的生长,并呈现明确的量效关系,但其毒性也随着剂量的增加而明显增大.在10 mg/kg的剂量下,腹腔注射的抑瘤作用优于静脉注射;但该途径给药产生的毒性也比静脉注射大.灌胃给药的抑瘤作用最弱,且高剂量时会产生严重的胃肠道不良反应.     

Disposition of (5H-dibenzo [a,d]cyclohepten-5-ylidene)acetic acid in laboratory animals

The disposition of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (Wy-41,770), an anti-inflammatory agent, was investigated in rats, mice, rhesus monkeys, and dogs following single 12.5-mg/kg doses of 14C-labeled or unlabeled drug and in rodents receiving single 225-mg/kg doses of 14C-Wy-41,770. The drug was rapidly and well absorbed in all four animal species. Following an iv dose, plasma elimination half-lives of Wy-41,770 in monkeys and dogs were, respectively, 5.0 +/- 1.8 and 0.24 +/- 0.01 hr. Total body clearances (CL) of 1.8 +/- 0.2 ml/min/kg in monkeys and 7.7 +/- 1.1 ml/min/kg in dogs are low, indicating that, after an ig dose, little Wy-41,770 would be eliminated on first passage through the liver. The steady state volumes of distribution of 0.37 +/- 0.1 and 0.14 +/- 0.01 liters/kg, respectively, in monkeys and dogs are low, indicating limited extravascular distribution of Wy-41,770. Plasma half-lives of Wy-41,770 in rats and mice were, respectively, 10.8 and 8.4 hr. The longer half-life in rats compared to other animals is due to the extensive enterohepatic recycling of the drug in rats. The extensive cycling of the drug in rats may explain why ileocecal inflammation occurred in this species but not in mice and dogs following prolonged oral administration of high doses of Wy-41,770. Following a 12.5 mg/kg, ig dose, the rates of urinary excretion of radioactivity in monkeys, mice, and rats were, respectively, 73.4 +/- 10.7, 52.6 and 15.2% of the dose, whereas the fecal excretion was 9.1 +/- 3.7% in monkeys and 74.7% in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

HR0905安全药理学研究

目的观察HR0905对小鼠神经系统、犬心血管系统及呼吸系统的影响。方法实验均分HR0905高、中、低剂量组及溶媒对照共4个组,小鼠实验给药组分别单次灌胃（ig）HR0905 30,100和300 mg/kg,观察药物对小鼠自发活动和爬杆能力的影响;犬实验给药组分别单次igHR0905 2、6、20 mg/kg,观察药物对犬血压、ECG、呼吸频率及节律的影响。结果与溶媒对照组相比,HR0905单次ig后高剂量组爬杆能力显著下降;给药后1.5 h开始动物自发活动有下降趋势,且3.5 h下降最多;HR0905单次ig后犬心率明显减慢。给药后2.0 h中剂量组及高剂量组Beagle犬收缩压、舒张压及平均动脉压有下降趋势,且4.0 h下降幅度最大。HR0905对Beagle犬ECG之P波电压、T波电压、QRS时间、PR间期、QT间期、ST段无明显影响;HR0905对呼吸频率、幅度和节律无明显影响。结论 HR0905对心血管和神经系统有一定的影响,可使犬心率减慢,犬收缩压、舒张压及平均动脉压有下降趋势,小鼠爬杆能力显著下降,自发活动有下降趋势。     

皖南蝮蛇毒蛋白C激活物的急性毒性作用的研究

目的:探讨蛇毒蛋白C激活物(protein Cactivator,PCA)对大、小鼠的急性毒理反应。方法:大鼠采用上下剂量增减法,小鼠采用半数致死量法,观察实验动物症状、体征、死亡时间和累积死亡率。结果:PCA尾静脉注射大鼠(剂量17.5～175mg/kg)、小鼠(剂量为6.25～11mg/kg)的中毒表现为不同程度的口鼻泡沫状出血、呼吸困难、心率加快、走路不稳、蜷缩、昏厥性抽搐;大、小鼠尾静脉注射PCA的LD50及其95%可信限分别为29.57(17.5～55)mg/kg和8.05(7.55～8.54)mg/kg;大体解剖可见双肺有片块状出血,病理镜检显示出血主要累及肺泡、支气管等。其他器官未见明显异常。结论:皖南蝮蛇毒PCA的毒性主要是抗凝过度导致的出血,肺出血引起的急性呼吸衰竭是实验动物死亡主要原因。