拉米夫定与原儿茶酸药物组合体内抗鸭乙肝病毒研究
发布时间：2018-07-16 13:35
【摘要】：乙型肝炎病毒(HBV)感染成为世界性难题,据WHO报道,全球受到乙肝病毒(HBV)感染的群体已近20亿人,它不仅会引发急性肝炎和慢性肝炎,而且会导致肝癌和肝硬化。全世界约有3.5亿HBV慢性感染者,每年因肝衰竭、肝硬化和原发性肝细胞癌(HCC)死亡人数约为100万。据资料显示,目前我国大概有乙型肝炎患者1200万,携带HBsAg有1.2亿人,占全球乙肝病毒携带者人数的1/3。 拉米夫定(lamivudine,3TC)是目前治疗乙型肝炎的主打药物,可显著抑制乙肝患者HBV-DNA,但由于药物长期疗效差、反跳率高、副作用多、易引起病毒突变等各种问题从而限制了其临床应用。我们的前期研究表明,与3TC单用时相比,PA与3TC合用不仅对HepG2.2.15细胞分泌HBV DNA和抗原、HBVX蛋白入核,以及DHBV吸附、进入与感染鸭原代肝细胞[8]有协同抑制作用,而且还具有明显保肝护肝作用。同时,PA与3TC二者合用时产生了显著的药动学相互作用：联用使拉米夫定的吸收速度减慢,吸收总量增加；使原儿茶酸的吸收速度与消除减慢,延长了其在体内作用的时间。本文以感染鸭乙型肝炎病毒(DHBV)的樱桃谷鸭雏鸭为实验动物,在前期优化了PA与3TC合用剂量比例的基础上,进一步考察该药物组合在鸭体内抗DHBV和保肝护肝的量效与时效关系,为开发抗HBV新药组合——3TC/PA打下实验基础。 方法：(1)量-效关系实验：5个剂量3TC/PA(12.5/12.5mg/kg,25/25mg/kg,50/50mg/kg,100/100mg/kg,150/150mg/kg)每天分别灌胃给药一次,连续给药14天。分别于给药前、给药第7天、第14天及停药后第3天取血,检测血清中DHBV DNA、白蛋白(ALB)和总胆红素(Tbil)含量,以及谷草转氨酶(GOT)、谷丙转氨酶(GPT)和碱性磷酸酶(AKP)活性。(2)时-效关系实验：3TC/PA (50/50mg/kg)每天灌胃给药一次,连续给药28天。分别于给药前、给药第7天、第14天、第21天、第28天及停药后第5天取血,检测血清中DHBV DNA、DHBsAg、DHBcAb含量,及GOT、GPT活性。 结果：(1)量-效研究表明,3TC/PA对血清DHBV DNA的抑制作用随给药剂量(12.5-150mg/kg)的增大而加强,但高剂量(100-150mg/kg)停药3天后病毒DNA水平有较明显的反跳趋势。5Omg/kg3TC/PA剂量组在给药期间及停药3天时病毒DNA含量显著低于100mg/kg阿昔洛韦对照组,GOT、GPT(?)Tbil值亦显著低于5g/kg门鸟组。(2)时-效研究表明,在0-28d给药周期内,50/50mg/kg3TC/PA对血清DHBV DNA、DHBsAg、GPT和GOT的抑制作用不仅随给药周期的延长而加强,而且在给药期间及停药5天时血清病毒DNA、DHBsAg水平均显著低于100mg/kg阿昔洛韦对照组,血清GPT和GOT水平显著低于5g/kg门鸟对照组。 结论：在感染DHBV雏鸭体内,50/50mg/kg3TC/PA是比较合适的体内抗DHBV给药剂量,且其抗病毒效果要好于100mg/kg P可昔洛韦,保肝护肝效果要好于5g/kg门鸟。
[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.
【学位授予单位】：湖北大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R96;R-332
本文编号：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.
【学位授予单位】：湖北大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R96;R-332
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