拉米夫定與原兒茶酸藥物組合體內(nèi)抗鴨乙肝病毒研究
發(fā)布時間：2018-07-16 13:35
【摘要】：乙型肝炎病毒(HBV)感染成為世界性難題,據(jù)WHO報道,全球受到乙肝病毒(HBV)感染的群體已近20億人,它不僅會引發(fā)急性肝炎和慢性肝炎,而且會導(dǎo)致肝癌和肝硬化。全世界約有3.5億HBV慢性感染者,每年因肝衰竭、肝硬化和原發(fā)性肝細胞癌(HCC)死亡人數(shù)約為100萬。據(jù)資料顯示,目前我國大概有乙型肝炎患者1200萬,攜帶HBsAg有1.2億人,占全球乙肝病毒攜帶者人數(shù)的1/3。 拉米夫定(lamivudine,3TC)是目前治療乙型肝炎的主打藥物,可顯著抑制乙肝患者HBV-DNA,但由于藥物長期療效差、反跳率高、副作用多、易引起病毒突變等各種問題從而限制了其臨床應(yīng)用。我們的前期研究表明,與3TC單用時相比,PA與3TC合用不僅對HepG2.2.15細胞分泌HBV DNA和抗原、HBVX蛋白入核,以及DHBV吸附、進入與感染鴨原代肝細胞[8]有協(xié)同抑制作用,而且還具有明顯保肝護肝作用。同時,PA與3TC二者合用時產(chǎn)生了顯著的藥動學(xué)相互作用：聯(lián)用使拉米夫定的吸收速度減慢,吸收總量增加；使原兒茶酸的吸收速度與消除減慢,延長了其在體內(nèi)作用的時間。本文以感染鴨乙型肝炎病毒(DHBV)的櫻桃谷鴨雛鴨為實驗動物,在前期優(yōu)化了PA與3TC合用劑量比例的基礎(chǔ)上,進一步考察該藥物組合在鴨體內(nèi)抗DHBV和保肝護肝的量效與時效關(guān)系,為開發(fā)抗HBV新藥組合——3TC/PA打下實驗基礎(chǔ)。 方法：(1)量-效關(guān)系實驗：5個劑量3TC/PA(12.5/12.5mg/kg,25/25mg/kg,50/50mg/kg,100/100mg/kg,150/150mg/kg)每天分別灌胃給藥一次,連續(xù)給藥14天。分別于給藥前、給藥第7天、第14天及停藥后第3天取血,檢測血清中DHBV DNA、白蛋白(ALB)和總膽紅素(Tbil)含量,以及谷草轉(zhuǎn)氨酶(GOT)、谷丙轉(zhuǎn)氨酶(GPT)和堿性磷酸酶(AKP)活性。(2)時-效關(guān)系實驗：3TC/PA (50/50mg/kg)每天灌胃給藥一次,連續(xù)給藥28天。分別于給藥前、給藥第7天、第14天、第21天、第28天及停藥后第5天取血,檢測血清中DHBV DNA、DHBsAg、DHBcAb含量,及GOT、GPT活性。 結(jié)果：(1)量-效研究表明,3TC/PA對血清DHBV DNA的抑制作用隨給藥劑量(12.5-150mg/kg)的增大而加強,但高劑量(100-150mg/kg)停藥3天后病毒DNA水平有較明顯的反跳趨勢。5Omg/kg3TC/PA劑量組在給藥期間及停藥3天時病毒DNA含量顯著低于100mg/kg阿昔洛韋對照組,GOT、GPT(?)Tbil值亦顯著低于5g/kg門鳥組。(2)時-效研究表明,在0-28d給藥周期內(nèi),50/50mg/kg3TC/PA對血清DHBV DNA、DHBsAg、GPT和GOT的抑制作用不僅隨給藥周期的延長而加強,而且在給藥期間及停藥5天時血清病毒DNA、DHBsAg水平均顯著低于100mg/kg阿昔洛韋對照組,血清GPT和GOT水平顯著低于5g/kg門鳥對照組。 結(jié)論：在感染DHBV雛鴨體內(nèi),50/50mg/kg3TC/PA是比較合適的體內(nèi)抗DHBV給藥劑量,且其抗病毒效果要好于100mg/kg P可昔洛韋,保肝護肝效果要好于5g/kg門鳥。
[Abstract]:Hepatitis B virus (HBV) infection has become a worldwide problem. According to the WHO report, nearly 2 billion people have been infected with hepatitis B virus (HBV) in the world. It will not only cause acute hepatitis and chronic hepatitis, but also lead to liver cancer and cirrhosis. There are about 350 million chronic HBV infections in the world, and the annual death toll from liver failure, liver cirrhosis and primary hepatocellular carcinoma (HCC) is about 1 million. According to the data, there are about 12 million hepatitis B patients and 120 million HBsAg carriers in China, accounting for one-third of the global hepatitis B virus carriers. Lamivudine 3TC (lamivudine 3TC) is the main drug in the treatment of hepatitis B at present, which can significantly inhibit HBV-DNA in patients with hepatitis B. however, its clinical application is limited because of the long term curative effect, high rebound rate, many side effects, easy to cause virus mutation and other problems. Our previous study showed that compared with 3TC alone, combined with 3TC could not only inhibit the secretion of HBV DNA and antigenic HBV X protein into the nucleus of HepG2.2.15 cells, but also the adsorption of DHBV, and synergistic inhibition with infected duck primary hepatocytes [8]. And also has the obvious function of protecting liver and protecting liver. At the same time, a significant pharmacokinetic interaction was produced by the combination of PA and 3TC: the absorption rate of lamivudine decreased and the total absorption increased, and the absorption rate and elimination of protocatechuic acid slowed down and prolonged the time of its action in vivo. Cherry Valley duck infected with duck hepatitis B virus (DHBV) was used as experimental animal. On the basis of optimizing the dosage ratio of PA and 3TC in earlier stage, the dose-effect and time-effect of the combination of DHBV and liver protection in duck were further investigated. For the development of anti-HBV drug combination-3 TC / PA to lay the experimental foundation. Methods: (1) dose-effect relationship experiment: five doses of 3TC / PA (12.5 / 12.5 mg / kg) were administered once a day for 14 days, respectively, with 50 / 50 mg / kg / 100 mg / kg / 150 mg / kg / kg. The serum levels of DHBV DNA, albumin (ALB) and total bilirubin (Tbil) were measured before, on the 7th day, on the 14th day after administration and on the third day after the withdrawal of the drug, and the serum levels of DHBV DNA, albumin (ALB) and total bilirubin (Tbil) were measured. And the activities of glutamic oxalacetic transaminase (got), alanine aminotransferase (GPT) and alkaline phosphatase (AKP). (2) the time-effect relationship experiment: 3Tc / PA (50/50mg/kg) was administered orally once a day for 28 days. The blood samples were collected before, on the 7th, 14th, 21st, 28th and 5th day after administration, respectively. The serum DHBDNA, DHBcAb and GOTGPT activity were measured. Results: (1) the dose-effect study showed that the inhibitory effect of 3Tc / PA on serum DHBV DNA was enhanced with the increase of dosage (12.5-150mg/kg). However, the level of virus DNA in the high dose (100-150mg/kg) group was significantly lower than that in the 100mg/kg acyclovir control group during administration and 3 days after withdrawal. (2) the time-effect study showed that: (2) the level of virus DNA was significantly lower than that in the control group of 100mg/kg acyclovir. (2) Time-effect study showed that: (2) the concentration of virus DNA in the dose group was significantly lower than that in the control group of 100mg/kg acyclovir. The inhibitory effects of 50 / 50 mg / kg ~ (-3) Tc / PA on serum DHBV-DNA / DHBs _ (GPT) and got were not only increased with the prolongation of administration period, but also were significantly lower than those of 100mg/kg acyclovir control group during the administration period and 5 days after the withdrawal of the drug, and the inhibitory effects of 50 / 50 mg / kg ~ (-3) Tc / PA on serum DHBV-DNA were significantly lower than those of the control group. Serum GPT and got levels were significantly lower than those in 5g/kg control group. Conclusion: in DHBV-infected ducklings, 50 / 50 mg / kg ~ (-3) Tc / PA is an appropriate dose of anti-DHBV in vivo, and its antiviral effect is better than that of 100mg/kg P Cociclovir, and the effect of protecting liver and protecting liver is better than that of 5g/kg.
【學(xué)位授予單位】：湖北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R96;R-332
本文編號：2126552
[Abstract]:Hepatitis B virus (HBV) infection has become a worldwide problem. According to the WHO report, nearly 2 billion people have been infected with hepatitis B virus (HBV) in the world. It will not only cause acute hepatitis and chronic hepatitis, but also lead to liver cancer and cirrhosis. There are about 350 million chronic HBV infections in the world, and the annual death toll from liver failure, liver cirrhosis and primary hepatocellular carcinoma (HCC) is about 1 million. According to the data, there are about 12 million hepatitis B patients and 120 million HBsAg carriers in China, accounting for one-third of the global hepatitis B virus carriers. Lamivudine 3TC (lamivudine 3TC) is the main drug in the treatment of hepatitis B at present, which can significantly inhibit HBV-DNA in patients with hepatitis B. however, its clinical application is limited because of the long term curative effect, high rebound rate, many side effects, easy to cause virus mutation and other problems. Our previous study showed that compared with 3TC alone, combined with 3TC could not only inhibit the secretion of HBV DNA and antigenic HBV X protein into the nucleus of HepG2.2.15 cells, but also the adsorption of DHBV, and synergistic inhibition with infected duck primary hepatocytes [8]. And also has the obvious function of protecting liver and protecting liver. At the same time, a significant pharmacokinetic interaction was produced by the combination of PA and 3TC: the absorption rate of lamivudine decreased and the total absorption increased, and the absorption rate and elimination of protocatechuic acid slowed down and prolonged the time of its action in vivo. Cherry Valley duck infected with duck hepatitis B virus (DHBV) was used as experimental animal. On the basis of optimizing the dosage ratio of PA and 3TC in earlier stage, the dose-effect and time-effect of the combination of DHBV and liver protection in duck were further investigated. For the development of anti-HBV drug combination-3 TC / PA to lay the experimental foundation. Methods: (1) dose-effect relationship experiment: five doses of 3TC / PA (12.5 / 12.5 mg / kg) were administered once a day for 14 days, respectively, with 50 / 50 mg / kg / 100 mg / kg / 150 mg / kg / kg. The serum levels of DHBV DNA, albumin (ALB) and total bilirubin (Tbil) were measured before, on the 7th day, on the 14th day after administration and on the third day after the withdrawal of the drug, and the serum levels of DHBV DNA, albumin (ALB) and total bilirubin (Tbil) were measured. And the activities of glutamic oxalacetic transaminase (got), alanine aminotransferase (GPT) and alkaline phosphatase (AKP). (2) the time-effect relationship experiment: 3Tc / PA (50/50mg/kg) was administered orally once a day for 28 days. The blood samples were collected before, on the 7th, 14th, 21st, 28th and 5th day after administration, respectively. The serum DHBDNA, DHBcAb and GOTGPT activity were measured. Results: (1) the dose-effect study showed that the inhibitory effect of 3Tc / PA on serum DHBV DNA was enhanced with the increase of dosage (12.5-150mg/kg). However, the level of virus DNA in the high dose (100-150mg/kg) group was significantly lower than that in the 100mg/kg acyclovir control group during administration and 3 days after withdrawal. (2) the time-effect study showed that: (2) the level of virus DNA was significantly lower than that in the control group of 100mg/kg acyclovir. (2) Time-effect study showed that: (2) the concentration of virus DNA in the dose group was significantly lower than that in the control group of 100mg/kg acyclovir. The inhibitory effects of 50 / 50 mg / kg ~ (-3) Tc / PA on serum DHBV-DNA / DHBs _ (GPT) and got were not only increased with the prolongation of administration period, but also were significantly lower than those of 100mg/kg acyclovir control group during the administration period and 5 days after the withdrawal of the drug, and the inhibitory effects of 50 / 50 mg / kg ~ (-3) Tc / PA on serum DHBV-DNA were significantly lower than those of the control group. Serum GPT and got levels were significantly lower than those in 5g/kg control group. Conclusion: in DHBV-infected ducklings, 50 / 50 mg / kg ~ (-3) Tc / PA is an appropriate dose of anti-DHBV in vivo, and its antiviral effect is better than that of 100mg/kg P Cociclovir, and the effect of protecting liver and protecting liver is better than that of 5g/kg.
【學(xué)位授予單位】：湖北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R96;R-332
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