阿苯达唑壳聚糖微球抗小鼠泡球蚴药效实验研究

发布时间：2018-11-17 07:56

【摘要】：目的:通过比较阿苯达唑壳聚糖微球(Albendazole Chitosan Mi c r o s p h e r e s,A B Z-C S-M P s)与阿苯达唑脂质体(Liposome-Albendazole,L-ABZ)、阿苯达唑片剂(Albendazole Tablet,ABZ-T)经口灌注治疗继发性感染多房棘球蚴小鼠的效果,评价阿苯达唑壳聚糖微球抗小鼠泡球蚴病的药效,为提高泡球蚴病药物治疗提供实验依据。方法:雄性昆明小鼠2 2 0只,通过腹腔接种建立继发性感染多房棘球蚴小鼠模型,接种1 2周后,将小鼠随机分为4组:ABZ-CS-MPs治疗组、L-ABZ治疗组、ABZ-T治疗组及模型对照组(另设空白对照组2 0只),其前三治疗组按口服A B Z剂量分别为3 7.5 m g/k g、7 5.0 m g/k g、1 5 0.0 m g/k g为标准,又分成三个剂量组,每个剂量组2 0只小鼠,模型对照组给予0.2 m L生理盐水。所有小鼠饲养1 2周后开始灌胃给药,每周三次(每隔一天),连续治疗1 2周后剖检。用药治疗后评价药效的指标如下:(1)观察小鼠肝脏大体形态;(2)称量囊湿重并计算抑囊率;(3)病理组织学观察;(4)电镜观察泡球蚴组织的超微结构变化;(5)高效液相色谱法(H P L C)测定小鼠血浆及肝脏匀浆中阿苯达唑主要代谢产物阿苯达唑亚砜(a b l e n d a z o l e s u l f o x i d e,A B Z-S X)的浓度。结果:经剖检发现,所有治疗组泡球蚴组织跟模型对照组比较囊肿明显缩小,其中A B ZC S-M P s治疗组及L-ABZ治疗组小鼠泡球蚴组织较ABZ-T治疗组明显萎缩及塌陷,大多数泡球蚴组织外观呈黄色或乳白色、质地变硬,实变或钙化程度明显。各治疗组3 7.5 m g/k g,7 5 m g/k g,1 5 0 m g/k g剂量组泡球蚴囊湿重分别为:A B Z-C S-M P s:(0.1 7 6±0.0 3 3,0.1 2 3±0.0 1 6,0.0 8 5±0.0 2 9)g;L-A B Z:(0.1 5 6±0.0 2 0,0.1 4 7±0.0 2 6,0.1 3 7±0.0 2 6)g;A B Z-T:(0.4 9 6±0.0 9 5,0.4 3 3±0.0 6 9,0.3 3 7±0.0 6 3)g;与模型对照组(1.5 6 5±0.0 2 0)g比较差异均有统计学意义(P0.0 5)。各治疗组7 5 m g/k g和1 5 0 m g/k g剂量组中A B Z-C SM P s组抑囊率分别达到9 2.1 3%,9 4.5 6%,其明显高于L-A B Z(9 0.5 8%,9 1.2 3%)和A B ZT(7 2.3 2%,7 8.4 6%)。组织学观察发现,经A B Z-C S-M P s或L-A B Z治疗后泡球蚴组织有不同程度变形坏死,生发层和角质层严重损害,典型泡球蚴结构消失。同时,通过A B ZC S-M P s或L-A B Z治疗后,血浆中A B Z-S X浓度达到较高水平,各用药组3 7.5 m g/k g,7 5 m g/k g,1 5 0 m g/k g剂量组血浆A B Z-S X浓度分别为:A B Z-C S-M P s:(0.6 7 8 5,1.1 0 1 1,1.4 0 3 5)μg/m l;L-A B Z:(1.0 4 1 0,0.8 5 8 7,1.0 2 7 5)μg/m l;A B Z-T:(0.3 1 4 1,0.4 3 0 7,0.5 4 0 9)μg/m l;A B Z-C S-M P s治疗组血浆A B Z-S X浓度在7 5 m g/k g以及1 5 0 m g/k g剂量组在各治疗组中最高,与A B Z-T组比较差异有统计学意义(P0.0 1)。结论:三种ABZ剂型对小鼠泡球蚴生长均有不同程度的抑制作用,尤其是A B Z-C S-M P s有效地促进A B Z的经肠吸收,可明显提高阿苯达唑主要代谢产物阿苯达唑亚砜在血浆中的浓度,有望成为治疗包虫病的一种新的剂型。
[Abstract]:Objective: to compare albendazole chitosan microspheres (Albendazole Chitosan Mi c r o s p h e r e SSA B Z-C S-M P s) with albendazole liposome (Liposome-Albendazole,L-ABZ), albendazole tablet (Albendazole Tablet,) To evaluate the efficacy of albendazole chitosan microspheres in the treatment of alveolar echinococcosis in mice, and to provide experimental evidence for improving drug treatment of alveolar echinococcosis. Methods: 220 male Kunming mice were inoculated intraperitoneally to establish the mice model of secondary infection of echinococcus multilocularis. After 12 weeks of inoculation, mice were randomly divided into four groups: ABZ-CS-MPs group and L-ABZ group. ABZ-T treatment group and model control group (20 blank control group), the first three treatment groups according to the oral A B Z dose of 75.0 mg / kg of 150.0 mg / kg, as the standard. The mice were divided into three dose groups, 20 mice in each dose group, and 0.2 mL normal saline was given to the model control group. After 12 weeks of feeding, all mice were given intragastric administration, three times a week (every other day), after 12 weeks of continuous treatment. The indexes to evaluate the efficacy after treatment were as follows: (1) observing the gross morphology of the liver; (2) weighing the wet weight of the capsule and calculating the inhibition rate; (3) observing the histopathology; (4) observing the ultrastructural changes of the hydatid tissues by electron microscope; (5) the concentration of albendazole in plasma and liver homogenate of mice was determined by (H P L C). The main metabolite of albendazole sulfoxide (a b l e n d a z o l e s u l f o x i d B Z-S X was albendazole sulfoxide. Results: the results showed that the alveolar hydatid tissues in all treatment groups were significantly smaller than those in the model control group, and the alveolar hydatid tissues in the A B ZC S-M P s treatment group and the L-ABZ treatment group were significantly smaller and collapsed than those in the ABZ-T treatment group. The appearance of most alveolar hydatid tissues was yellow or milky white, the texture became hard, and the degree of consolidation or calcification was obvious. In each treatment group, 37.5 mg / k g / k g = 7.5 mg / k g / k g, 7 5 mg / k g / g, The wet weight of hydatid cyst in 150 mg / kg dose group was: A B Z-C S-M P s: (0.1 7 6 卤0.033 卤0.23 卤0.016 卤0.08 5 卤0.029 g, respectively. L-A B Z: (was 0.41 卤0.026 卤0.026 卤0.37 卤0.026) GB Z-T: (0.49 6 卤0.09 5) 0.43 卤0.069 0.37 卤0.063 g; There was significant difference between the model control group and the model control group (1.55 卤0.20) g (P 0.05). The inhibitory rate of A B Z-C SM P s in the groups of 7.5 mg / kg and 150 mg / kg in each treatment group reached 9.2.1% 34.56%, which was significantly higher than that of L-A B Z (9.0.58%. A B ZT (7,2.32% and 7.8.46%). Histological observation showed that after treatment with A B Z-C S-M P s or L A B Z, alveolar hydatid tissues were deformed and necrotized to varying degrees, germinal layer and cuticle were seriously damaged, and typical alveolar hydatid structure disappeared. At the same time, after treatment with A B ZC S-M P s or L-A B Z, the plasma A B Z S X concentration reached a higher level. The concentration of plasma A B Z S X reached a higher level after treatment with A B ZC S-M P s or L A B Z. In 150 mg / kg group, the plasma A B Z S X concentration was: A B Z-C S-M P s: (0.6 7 8 5 1 01 1 1 1 0 3 5) 渭 g / ml; L-A B Z: (1.041 0 0 0 0.8 58 7 + 1.027 5) 渭 g / mL A Z T: (0 31 1 0. 4 3 0 7 0 7 0 5 0 09) 渭 g / m 1; The concentration of plasma A B Z S X in the A B Z C S M P s treatment group was the highest in each treatment group at the dose of 7.5 mg / kg and 150 mg / kg respectively, which was significantly different from that in the A B Z T group (P 0.01). Conclusion: all of the three ABZ formulations can inhibit the growth of mouse alveolar echinococci to varying degrees, especially A B Z-C S-M P s can effectively promote the intestinal absorption of A B Z. Albendazole sulfoxide, the main metabolite of albendazole, can significantly increase the concentration of albendazole sulfoxide in plasma and may become a new dosage form for the treatment of hydatid disease.
【学位授予单位】：石河子大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R532.32

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