本文選題：重組腺病毒Ad-VT + 急性毒性試驗(yàn)　； 參考：《吉林大學(xué)》2012年碩士論文

【摘要】：重組腺病毒Ad-VT為一種具有特異性殺傷腫瘤細(xì)胞和特異性復(fù)制能力的雙特異性抗腫瘤重組腺病毒。有希望成為一種安全、特異、有效的治療腫瘤的臨床候選藥物，極具有開發(fā)前景。 藥物的安全性、有效性和質(zhì)量可控制性是藥品屬性的三個(gè)基本要素。其中，對(duì)藥物的安全性評(píng)價(jià)是任何新藥在申報(bào)進(jìn)入臨床試驗(yàn)之前必須進(jìn)行的。安全性評(píng)價(jià)一般包括一般毒性試驗(yàn)（急性毒性試驗(yàn)和長(zhǎng)期毒性試驗(yàn)）、特殊毒性試驗(yàn)、藥物依賴性試驗(yàn)及其它如過敏性試驗(yàn)等等。 本研究在小鼠的急性毒性試驗(yàn)中按照重組腺病毒Ad-VT的最高滴度和最高給藥容積給藥，給藥量為5×1010PFU/只。結(jié)果表明，5×1010PFU為小鼠的安全劑量。按照體重計(jì)算，約為重組腺病毒Ad-VT擬臨床用量的650倍。 本試驗(yàn)通過對(duì)Wistar大鼠和Beagle犬長(zhǎng)達(dá)三個(gè)月的長(zhǎng)期毒性試驗(yàn)，對(duì)重組腺病毒Ad-VT的毒性進(jìn)行了考察。劑量大小設(shè)置為小劑量組5×108pfu/kg,為擬臨床用量的3倍；中劑量組2.5×109pfu/kg，為擬臨床用量的15倍；高劑量組1.25×1010pfu/kg，為擬臨床用量的75倍。主要對(duì)動(dòng)物在給藥期和恢復(fù)期的一般行為狀態(tài)、體重、體溫、尿液生化、血液學(xué)、血液生化、抗體水平、病理組織學(xué)及心電影響等幾方面進(jìn)行了觀察記錄。從而了解重組腺病毒Ad-VT的毒性反應(yīng)的靶器官和蓄積毒性，進(jìn)一步確定安全劑量范圍。試驗(yàn)結(jié)果表明，在Wistar大鼠和Beagle犬的長(zhǎng)期毒性試驗(yàn)中，未發(fā)現(xiàn)與正常對(duì)照組的明顯異常，各項(xiàng)指標(biāo)均在正常范圍內(nèi)波動(dòng)，所設(shè)的三個(gè)劑量為安全劑量。 安全性藥理試驗(yàn)的目的在于揭示對(duì)主要生理系統(tǒng)（如心血管、呼吸、腎和中樞神經(jīng)系統(tǒng)）的功能的影響。所有這些研究可解釋某些特定器官毒性的作用機(jī)理，并應(yīng)仔細(xì)考慮這些特定器官毒性與人體應(yīng)用和適應(yīng)證的關(guān)系。本研究通過對(duì)重組腺病毒Ad-VT對(duì)小鼠一般狀態(tài)、自發(fā)性活動(dòng)、神經(jīng)系統(tǒng)興奮性、運(yùn)動(dòng)協(xié)調(diào)性、消化功能等方面的影響，探索了Ad-VT對(duì)動(dòng)物中樞神經(jīng)系統(tǒng)、心血管、消化系統(tǒng)等的影響。結(jié)果表明，對(duì)小鼠一次注射擬臨床用量的重組腺病毒Ad-VT，對(duì)以上指標(biāo)沒有明顯影響。 在全身過敏性試驗(yàn)中，按照豚鼠過敏反應(yīng)級(jí)數(shù)對(duì)激發(fā)給藥后的豚鼠過敏反應(yīng)級(jí)數(shù)做出判斷，判斷結(jié)果為0級(jí)，說明重組腺病毒Ad-VT不會(huì)引發(fā)動(dòng)物或人的全身過敏性反應(yīng)。局部刺激性試驗(yàn)中，依據(jù)皮膚刺激性強(qiáng)度評(píng)價(jià)標(biāo)準(zhǔn)對(duì)家兔股四頭肌進(jìn)行評(píng)價(jià)，結(jié)果表明重組腺病毒Ad-VT對(duì)皮膚有輕微的刺激性，但不會(huì)引起水腫等炎癥反應(yīng)。 本研究依次進(jìn)行了重組腺病毒Ad-VT的急性毒性試驗(yàn)、長(zhǎng)期毒性試驗(yàn)、一般藥理學(xué)試驗(yàn)及過敏、刺激性試驗(yàn)，，對(duì)重組腺病毒Ad-VT的安全性做出了評(píng)價(jià)。該試驗(yàn)結(jié)果對(duì)重組腺病毒Ad-VT用于臨床試驗(yàn)提供參考依據(jù)。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R373.1

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