摘要
第一部分原藜芦碱A的毒性及其与人参总皂苷的配伍研究
目的:对原藜芦碱A进行毒性及配伍研究,明确原藜芦碱A的毒性靶器官,探索与人参皂苷的配伍关系。方法:(1)急性毒性:32只wistar大鼠,设20.0 mg/kg、10.0 mg/kg、5.0 mg/kg、2.5 mg/kg共4个剂量组,观察给药后动物的毒性反应症状及24 h内死亡情况,根据死亡情况用Bliss法计算LD50。Beagle犬,8只,每组2只,分别给原藜芦碱A ig 0.5 mg/kg,ig 0.25 mg/kg,iv 0.2 mg/kg,iv 0.002 mg/kg,给药后观察毒性反应症状;(2)重复给药毒性试验:Wistar大鼠36只,分成空白对照组,1 mg/kg组,0.5 mg/kg组共3组,入代谢笼单笼饲养。每天ig给药,连续14天。每周称体重,隔天测尿量。14天后处死,采血测生化、血象指标。解剖取心、肝、脾、肺、肾、脑、胃等主要脏器进行病理组织学观察;(3)心血管系统、呼吸系统毒性观察:40只wistar大鼠分为空白对照组(溶媒)、原藜芦碱A 4 mg/kg组、原藜芦碱A 2 mg/kg组、原藜芦碱A 1mg/kg组共4组,每组10只,观察记录动物给药后3h内的心电、血压、呼吸变化;(4)降压机制研究:取健康Wistar大鼠,分别侧脑室给药2.5μg/kg,尾静脉给药0.05 mg/kg,观察其降压作用。用酚妥拉明、阿托品行α受体、M受体阻断,再给原藜芦碱A,观察其降压情况;(5)人参总皂苷与原藜芦碱A配伍毒性:50只wistar大鼠分为5组,每组10只,组别为空白对照组(溶媒)、人参皂苷组(TG 10 mg/kg)、原藜芦碱A组(PA 2 mg/kg)、TG与PA 5:1配伍组(TG 10 mg/kg,PA 2 mg/kg)、TG与PA 5:2配伍组(TG 5 mg/kg,PA 2 mg/kg),麻醉后行颈动脉插管术,记录给药后3h心电、血压、呼吸情况。结果:大鼠ig原藜芦碱A的LD50为5.1 mg/kg;Beagle犬ig 0.5 mg/kg原藜芦碱A即可出现持续性呕吐、排稀便、全身瘫痪等严重毒性反应症状,Beagle犬iv 0.02 mg/kg 30 s即出现站立不稳.约1 min出现呕吐,肌强直,约5 min死亡。iv 0.002 mg/kg后约30 s动物出现站立不稳,呼吸深快,频繁舔舌,10 min后能正常站立;大鼠重复给药原藜芦碱A后体重减轻、尿量增多,血液学指标HCT下降、中性粒细胞增多、淋巴细胞减少,血液生化指标AST、ALP、CPK、LDH、BUN增高,肝、肾组织出现病理性改变;原藜芦碱A单次给药能显著降低大鼠血压、减慢心率、减缓呼吸、严重时导致心律失常;微量原藜芦碱A侧脑室注射能引起大鼠血压下降,且最低点出现在3 min左右,延后于静脉给药(给药后1-2 min出现最低点);TG与PA 5:2配比后对血压、心率、呼吸频率的影响小于单用原藜芦碱A组(P<0.05),而TG与PA 5:1配比后对血压、心率、呼吸频率的影响大于单用原藜芦碱A组(P<0.05)。结论:原藜芦碱A小剂量能使动物出现较大的毒性反应症状。Beagle犬ig原藜芦碱A后严重中毒剂量为0.5 mg/kg,iv致死剂量为0.02 mg/kg,中毒剂量为0.002 mg/kg;原藜芦碱A重复给药大鼠,对动物有一定的利尿作用,对心、肝、肾等组织有毒性作用;原藜芦碱A能降低血压、减缓心率、减慢呼吸、致心律失常,降压机制为中枢系统和外周共同参与;藜芦人参配伍毒性大小与配伍比例有关。
第二部分奈西立肽猴比较长期毒性实验研究
目的:观察化学合成的奈西立肽连续静滴(vd)食蟹猴14天的长期毒性,并与已上市同类生物技术药冻干重组人脑利钠肽(新活素)的毒性进行比较。方法:30只健康食蟹猴分别按体质量随机分为5组:空白对照组、阳性对照组、低剂量组、中剂量组、高剂量组。每组6条,雌雄各半。低、中、高剂量组给药量分别为432、1440、4320μg/kg,给药体积18 ml/kg,相应给药浓度分别为24、80、240μg /ml,阳性对照组为市售新活素,给药剂量和中剂量组相当,滴注速度约为18 ml/kg/hr。连续给药14天。末次给药后24 h处死一半动物做病理解剖,另一半停药后继续观察14天后,进行病理解剖。观察症状和检测指标包括体重、食量等一般症状及指标,血压,心电图,红细胞等血液学指标、乳酸脱氢酶(LDH)等血液生化指标、补体C3等免疫学指标、尿量等尿液指标、骨髓检查、病理组织学检查。结果:高剂量组、中剂量组和阳性对照组的LDH值d7和d14时高于d0的数值,同时高于空白对照组和低剂量组,恢复期差异消失;高剂量组的磷酸肌酸激酶(CPK)值d7时高于空白对照组,阳性对照组d7时高于d0、空白对照组、低剂量组、中剂量组和高剂量组,恢复期差异消失;个别高剂量动物肾素和醛固酮指标有一定程度的降低,但无统计学差异,恢复期时指标恢复到给药前水平。给药后d1、d7、d14,与空白对照组或与给药前相比,给药组平均动脉压在给药后有不同程度的下降,一般在120 ~ 150 min内恢复正常。其余一般症状、心电图、血液学指标、免疫学指标、尿液指标、骨髓检查、病理检查、病理组织学检查未见异常改变。结论:奈西立肽vd食蟹猴14天,奈西立肽组高剂量组、中剂量组和阳性对照组动物在给药后出现血压下降、乳酸脱氢酶和肌酸磷酸激酶升高等反应,这些作用均为可逆。奈西立肽vd对食蟹猴的安全剂量为432μg/kg,毒性剂量为1440μg/kg,主要毒性靶器官为心血管系统。阳性对照药物(新活素)与受试药具有较为相近的药理毒理作用。说明合成产品与重组产品并无明显毒理学差异。
Part One: Toxicity and Compatibility with Total Ginsenoside Study of Protoveratrine A
Objective: To conduct the toxicity and compatibility study on protoveratrine A, to determine the toxic target organ of protoveratrine A and to explore its compatible relationship with ginsenoside.
Methods: 1. Acute toxicity study: Thirty-two Wister rats were involved in this test, and 20.0 mg/kg(all found killed)、10.0 mg/kg、5.0 mg/kg、2.5 mg/kg (no single killed) four dosage groups were set to observe the toxic reaction symptoms and the mortalities after the administration, and calculate the LD50 by Bliss method according to the mortalities. Eight Beagles were separated into four groups, each group was given the dosage of Protoveratrine A by 0.5 mg/kg (ig), 0.25 mg/kg (ig), 0.2 mg/kg (iv), 0.002 mg/kg (iv) respectively to observe the toxic reaction symptoms.
2. Repeat dose toxicity study: 36 Wister rats were divided into three groups which were blank control group, 1 mg/kg group,0.5 mg/kg group. Each rat was bred in the metabolism cage. Each one is treated with drug by intragastric injection for consecutive fourteen days. Each rat was weighed every week and the urinary volume was also measured every other day. The rats were executed fourteen days later, the blood sample was collected to analyze biochemical and blood indexes. The rats were then dissected to obtain the heart, liver, spleen, lung, kidney, brain, stomach and other organs, which are then fixed for pathological observation.
3. The toxicity observation of cardiovascular and respiratory system: Forty wister rats were divided into four groups, which are blank control group (vehicle), 4 mg/kg Protoveratrine A group, 2 mg/kg Protoveratrine A group, and 1mg/kg Protoveratrine A group, the rats were anesthetized later and the carotid artery catheterization was performed, and the ECG, blood pressure, respiratory change were recorded in the duration of three hours after the administration.
4. The study on the antihypertensive mechanism: Lateral ventricle administration of 2.5μg/kg and tail vein administration of 0.05 mg/kg drug were applied on healthy Wistar rats, to observe its hypotensive effect. The phentolamine, atropine were given initially to block the typeαreceptors and the type M receptors, then the Protoveratrine A was given to observe the antihypertension effect.
5. The compatibility toxicity between Protoveratrine A and total ginsenoside: Fifty Wister rats were divided into five groups (ten for each group) which were blank control group (vehicle) , ginsenoside group (TG10mg/kg), Protoveratrine A group (PA 2 mg/kg), the ratio of compatibility group was TG:PA=5:1 (TG 10 mg/kg: PA 2 mg/kg) and TG:PA=5:2 (TG 5 mg/kg: PA 2 mg/kg), respectively. The rats were anesthetized later and the carotid artery catheterization was conducted and the ECG, blood pressure, respiratory change were recorded after the drug administration for three hours.
Results: The LD50 of Protoveratrine A for rats by intragastric injection was 5.1 mg/kg. Repeat dose administration of Protoveratrine A could lead to body weight lose,hydrouria,the desent of HCT and %LYMPH, neutrophilic leukocytosis ,etc.And then increase the AST,ALP,CPK,LDH. The single dose administration of Protoveratrine A could significantly reduce blood pressure, slower the heart rate and breathing, and even lead to arrhythmia. The minor dose administration of Protoveratrine A by lateral ventricle injection could cause the decrease of rat blood pressure; the nadir appears in approximately three minutes which was delayed compared with intravenous administration (the nadir usually appears in one to two minutes after intravenous administration). The influences on the blood pressure, heart rate, and breathe frequency of the total ginsenoside and Protoveratrine A group which has the compatibility ratio of 5:2 is less than the one of single Protoveratrine A administration group (P<0.05), while the influences on the blood pressure, heart rate, and breathe frequency of the total ginsenoside and Protoveratrine A group which has the compatibility ratio of 5:1 is greater than the one of single Protoveratrine A administration group (P<0.05).
Conclusion: The small dose of Protoveratrine A can cause relatively severe toxic reaction symptoms on animals. On rats,some toxic reactions could be observed about 10 min after the administration such as decrease of spontaneous movements, horripilation, loose stools,etc. As Beagle, Persistent vomiting, loose stools, weakness and limp could be observed. Repeat dose on rats,protoveratrine A could do something on diuresis, do harm on heart, liver, kidney by some extent. The single dose administration of Protoveratrine A could significantly reduce blood pressure, slower the heart rate and breathing, and even lead to arrhythmia. There is dose-effect relationship on the influence of blood pressure. The central nerve system and peripheral nerve system are all involved in the antihypertensive mechanism. The compatibility toxicity of Protoveratrine A and ginsenoside is related to their compatibility ratio.
Part Two: Comparative long-term toxicity study of Nesiritide with Recombinant human B-type natriuretic peptide on Cynomolgus monkey
Objective: To observe the long-term toxicity on Cynomolgus monkey administrated with chemical synthetic Nesiritide by intravenous dripping for fourteen days, to compare its toxicity with the same earlier marked biotechnology drug Recombinant human B-type natriuretic peptide(rhBNP).
Methods: Thirty healthy Cynomolgus monkey were divided into five groups by weight which were blank control group, positive control group, low-dosage group, medial-dosage group and high-dosage group, respectively. Each group had six Cynomolgus monkeys, half are male and the other half are female. The dosage given to low-dosage, medial-dosage group and high-dosage group was 432, 1440, 4320μg/kg, respectively. The dosage volume was 18 ml/kg and the dosage concentration was 24, 80, 240μg /ml respectively. The launched Natriuretic Peptides was employed here as positive control whose dose was equivalent to the one of medial-dosage group, the dripping velocity was 18 ml/kg/hr. The Cynomolgus monkey was treated with drug for consecutively fourteen days and half of the monkeys were then executed right after the last drug administration to perform the pathological anatomy. The drug administration of the rest of the monkeys was stopped and they were observed for another fourteen days. Then the pathological anatomy was conducted. The observation symptoms and examining indexes include body weight, appetite and other routine symptoms and indexes such as blood pressure, electrocardiogram, hematology indexes e.g. red blood cells, lactate dehydrogenase (LDH) and other blood biochemical parameters, such as complement C3, urine indexes such as urine volume, bone marrow check, pathological examination, histological examination.
Results:The LDH value of both d7 and d 14 were higher than the one of d0 in high-dosage, medial-dosage and positive control group, respectively, in the meantime they were also higher than the ones in low-dosage group and control group. The differences were not found in their recovery phase. The value of creatine phosphokinase (CPK) in the high-dosage group of d 7 was higher than the one in the blank control group. The d7 value was higher than d0 value in positive control group, also higher than the d0 values in blank control group, low-dosage group, medial-dosage group and high-dosage group, still, the differences were not found in their recovery phase. The renin and aldosterone indexes of individual animal in high-dose group decreased to a certain degree, but it had no statistical significance, these indexes rose to the same levels previous to drug administration. At d1, d7, d14 after drug administration, compared with the arterial pressure measured in blank control group or pre-administration, the average arterial pressure of dosage group after drug administration decline at different levels, the average arterial pressure would generally go back to the normal level in 120 to150 minutes. And no abnormally changes were observed in the rest of the general symptoms, electrocardiogram, hematology indexes, immunology indexes, urine indexes, bone marrow examination, pathological examination and histological examination.
Conclusion: after administration of Nesiritide to Cynomolgus monkey by intravenous dripping for fourteen days, decrease in blood pressure, rise in lactate dehydrogenase and creatine phosphokinase etc reactions in animals after administration were observed in high-dose group, moderate-dose group and positive control group, and all these reaction were reversible. For Cynomolgus monkey, the safe dose of v.d. Nesiritide is 432μg/kg, the toxic dose is 1440μg/kg and the main toxicity target organ lie in cardiovascular system. The positive control drug (rhBNP) has relatively similar pharmacological and toxicological effects with those of the test drug, suggesting there is no significant toxicological difference between synthetic products and recombination products.
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