重组腺病毒Ad-VT的安全性评价

发布时间：2018-06-21 08:04

本文选题：重组腺病毒Ad-VT + 急性毒性试验　；参考：《吉林大学》2012年硕士论文

【摘要】：重组腺病毒Ad-VT为一种具有特异性杀伤肿瘤细胞和特异性复制能力的双特异性抗肿瘤重组腺病毒。有希望成为一种安全、特异、有效的治疗肿瘤的临床候选药物，极具有开发前景。药物的安全性、有效性和质量可控制性是药品属性的三个基本要素。其中，对药物的安全性评价是任何新药在申报进入临床试验之前必须进行的。安全性评价一般包括一般毒性试验（急性毒性试验和长期毒性试验）、特殊毒性试验、药物依赖性试验及其它如过敏性试验等等。本研究在小鼠的急性毒性试验中按照重组腺病毒Ad-VT的最高滴度和最高给药容积给药，给药量为5×1010PFU/只。结果表明，5×1010PFU为小鼠的安全剂量。按照体重计算，约为重组腺病毒Ad-VT拟临床用量的650倍。本试验通过对Wistar大鼠和Beagle犬长达三个月的长期毒性试验，对重组腺病毒Ad-VT的毒性进行了考察。剂量大小设置为小剂量组5×108pfu/kg,为拟临床用量的3倍；中剂量组2.5×109pfu/kg，为拟临床用量的15倍；高剂量组1.25×1010pfu/kg，为拟临床用量的75倍。主要对动物在给药期和恢复期的一般行为状态、体重、体温、尿液生化、血液学、血液生化、抗体水平、病理组织学及心电影响等几方面进行了观察记录。从而了解重组腺病毒Ad-VT的毒性反应的靶器官和蓄积毒性，进一步确定安全剂量范围。试验结果表明，在Wistar大鼠和Beagle犬的长期毒性试验中，未发现与正常对照组的明显异常，各项指标均在正常范围内波动，所设的三个剂量为安全剂量。安全性药理试验的目的在于揭示对主要生理系统（如心血管、呼吸、肾和中枢神经系统）的功能的影响。所有这些研究可解释某些特定器官毒性的作用机理，并应仔细考虑这些特定器官毒性与人体应用和适应证的关系。本研究通过对重组腺病毒Ad-VT对小鼠一般状态、自发性活动、神经系统兴奋性、运动协调性、消化功能等方面的影响，探索了Ad-VT对动物中枢神经系统、心血管、消化系统等的影响。结果表明，对小鼠一次注射拟临床用量的重组腺病毒Ad-VT，对以上指标没有明显影响。在全身过敏性试验中，按照豚鼠过敏反应级数对激发给药后的豚鼠过敏反应级数做出判断，判断结果为0级，说明重组腺病毒Ad-VT不会引发动物或人的全身过敏性反应。局部刺激性试验中，依据皮肤刺激性强度评价标准对家兔股四头肌进行评价，结果表明重组腺病毒Ad-VT对皮肤有轻微的刺激性，但不会引起水肿等炎症反应。本研究依次进行了重组腺病毒Ad-VT的急性毒性试验、长期毒性试验、一般药理学试验及过敏、刺激性试验，，对重组腺病毒Ad-VT的安全性做出了评价。该试验结果对重组腺病毒Ad-VT用于临床试验提供参考依据。
[Abstract]:Recombinant adenovirus Ad-VT is a kind of double specific anti-tumor recombinant adenovirus which has the ability of killing tumor cells and replicating specifically. It is promising to be a safe, specific and effective clinical candidate for the treatment of cancer. The safety, effectiveness and quality controllability of drugs are the three basic factors of drug properties. The safety evaluation of drugs is required before any new drug is declared for clinical trial. Safety evaluation generally includes general toxicity tests (acute toxicity test and long term toxicity test), special toxicity test, drug dependence test, and others such as allergic test, etc. In the acute toxicity test of mice, according to the maximum titer and volume of recombinant adenovirus Ad-VT, the dosage was 5 脳 10 10 PFU per mouse. The results showed that 5 脳 10 10 PFU was a safe dose for mice. According to body weight, it was about 650 times as much as the recombinant adenovirus Ad-VT. The toxicity of recombinant adenovirus Ad-VT in Wistar rats and Beagle dogs for three months was studied. The dosage of low dose group was 5 脳 10 8 pfur / kg, which was 3 times of the pseudo clinical dosage, the middle dose group was 2.5 脳 10 9 pfur / kg, and the high dose group was 1.25 脳 10 10 pfup / kg, which was 75 times of the clinical dose. The general behavior, body weight, body temperature, urine biochemistry, hematology, blood biochemistry, antibody level, histopathology and electrocardiogram were observed and recorded. The target organs and accumulative toxicity of the toxic reaction of recombinant adenovirus Ad-VT were studied, and the safe dose range was determined. The results showed that in the long-term toxicity test of Wistar rats and Beagle dogs, there was no obvious abnormality compared with the normal control group, and all the indexes fluctuated within the normal range, and the three doses were safety doses. The purpose of the safety pharmacological test is to reveal the effects on the functions of major physiological systems such as cardiovascular, respiratory, renal and central nervous systems. All these studies can explain the mechanism of toxicity of certain specific organs and should carefully consider the relationship between the toxicity of these specific organs and the application and indication of human body. In this study, the effects of Ad-VT on the general state, spontaneous activity, nervous system excitability, motor coordination and digestive function of mice were studied, and the effects of Ad-VT on the central nervous system and cardiovascular system of animals were investigated. The influence of the digestive system, etc. The results showed that the recombinant adenovirus Ad-VT, which was injected into mice in a single dose, had no significant effect on the above indexes. In the whole body anaphylactic test, according to the grade of allergic reaction in guinea pig, the grade of allergic reaction of guinea pig after stimulation was judged, and the result was 0, which indicated that the recombinant adenovirus Ad-VT could not induce the allergic reaction in animals or people. In the local irritation test, the rabbit quadriceps femoris muscle was evaluated according to the criteria of skin irritation intensity. The results showed that the recombinant adenovirus Ad-VT had slight irritation to the skin, but could not cause inflammatory reaction such as edema. In order to evaluate the safety of recombinant adenovirus Ad-VT, acute toxicity test, long-term toxicity test, general pharmacological test, allergy test and irritation test were carried out in this study. The results provide a reference for the clinical trial of recombinant adenovirus Ad-VT.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R373.1

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