阿苯达唑脂质体治疗小鼠继发性肝、腹腔泡状棘球蚴病的动物实验研究

Experimental study on therapeutic efficacy of liposomal albendazole against Echinococcus multilocularis infection in liver and abdominal cavity

目的 :通过使用新的载体药物阿苯达唑脂质体 (L ipsomal abendazole,L- ABZ)经口服和腹腔注射治疗感染泡状棘球蚴 (Echinococcus multiloculais,E.m.)的小鼠 ,并与口服阿苯达唑片剂粉末对照 ,观察阿苯达唑脂质体对动物体内的泡状棘球蚴的治疗作用。感染泡状棘球蚴的小鼠经一定时间阿苯达唑脂质体治疗后 ,将其泡状棘球蚴组织再种植于健康小鼠体内 ,观察 E.m.的生长情况 ,以了解 L- ABZ对 E.m.组织及原头蚴活力的影响。同时观察阿苯达唑脂质体对实验动物体内泡状棘球蚴原头蚴感染的预防作用。 方法 :本实验分 3部分。实验(一 ) :将人工腹腔感染泡状棘球蚴的模型动物 2 5 0只 ,采用随机分组方法分为治疗组和对照组。治疗组 (2 2 5只 )分为口服阿苯达唑片剂粉末 (Po- ABZ)、口服阿苯达唑脂质体 (Po- L - ABZ)和腹腔注射阿苯达唑脂质体 (IP- L - ABZ) 3个组 ,每个治疗组再分为 3个亚组 (各 2 5只 ) ,给药剂量每次分别为 37.5 m g/ kg、75 m g/ kg和 15 0 m g/ kg。每周给药3次 ,连续用药 10周。对照组 2 5只健康小鼠给予腹腔注射同体积生理盐水。药物疗效观察指标 :(1)泡状棘球蚴囊肿总湿重和减重率 ;(2 )病理和组织学改变 ;(3)超微结构的改变 ;(4 )血药、肝药、囊药浓度的测定。实验 (二 ) :将 6 0只 NIH小?

Objective: Effect of Albendazole(ABZ) with different formulations has been investigated in NIH mice with Echinococcus multilocularis (E.m.) infection. Inhibition effect was observed in E.m. biomass by using liposomal albendazole (L ABZ). Methods: Animal experiments were divided into three parts. In first part, mice with E.m. infection were treated by L ABZ and free ABZ. A total of 250 mice with E.m. infection were randomly divided into 3 groups as follows: (1) Po ABZ group: mice were given ABZ powder orally; (2) Po L ABZ group: mice were orally administered by L ABZ; (3) IP L ABZ: mice were intraperitoneally injected by L ABZ. Each treated group was then divided into three subgroups by using the dose of 37.5 mg/kg, 75 mg/kg and 150 mg/kg three times per week; and (4) control group was intraperitoneally injected by physiological saline. All animals were treated for 10 weeks. Four criteria for drug efficacy were employed: (1) E.m.. tissues wet weight and reduction rate, (2) Histopathological changes, (3) Ultrastructural changes, and (4) concentrations of ABZ and its main metabolites, albendazole sulfoxide (ABZSX) and albendazole sulphone (ABZSN). In the second part, 60 healthy mice were divided into two groups. The mice in group Ⅰ were transferred the E.m. tissues that had been treated by L ABZ for 10 weeks. While, the mice in group Ⅱ were transferred the E.m. tissues only. After 8 weeks, all mice were killed, and the evaluating targets, and the E.m. infection rates were performed in the lab. In the third part, 45 mice were intraperitoneally injected by E.m. tissues and randomly divided into three groups : (1) Po L ABZ group , (2) IP L ABZ group, and (3) control group injected by physiological saline. At the same day, the mice in group (1) were orally administered L ABZ at 75 mg/kg three times per week, in group (2) were intraperitoneally given L ABZ at 75 mg/kg three times per week, in group (3) injected by physiological saline for 8 weeks. Results: 1. In part one, L ABZ both oral and injecting administered had more effect than free ABZ. The E.m.. tissue wet weight was 1 039.6mg in the control group. The wet weight and the reduction rates were 690.0 mg (33.63%), 592.1 mg (43.05%) and 622.9 mg (40.08%) in the Po ABZ groups; 545.4 mg (47.54%),548.7 mg (47.22%) and 351.7 mg (66.17%) in Po L ABZ groups ; 276.7 mg (73.38%), 256.5 mg (75.32%) and 220.4 mg (78.80%) in IP L ABZ groups respectively. The histopathological and ultrastructural changes of E.m.. tissues showed some changes in both Po L ABZ group and IP L ABZ group. The effect of L ABZ against E.m. in mice by injecting in abdominal cavity had more effect than that by oral administration. The drug distribution in mice of both ABZ and L ABZ were measured by HPLC. The results showed that the drug concentrations in plasma, liver and E.m.. tissues in the Po L ABZ group and the IP L ABZ group were higher than that in the Po ABZ group. 2. In part two, the E.m. infection rates were much lower in group Ⅰ(42.11%), compared to group Ⅱ(92.31%). 3. In part three, the E.m.. infection rates in IP L ABZ and Po L ABZ groups were 57.14% and 53.85%, while there was 93.33% in control group. The histopathological changes of E.m.. tissues showed degeneration and necrosis in Po L ABZ group and IP L ABZ group. Conclusion: 1. The L ABZ had more effect than free ABZ, especially through absorption from abdominal cavity. The effect of L ABZ against E.m. in mice by injection intraperitoneally had more effect than by oral administration. 2. The liposomes can help the drugs to accumulate in the liver and penetrate E.m. tissues. 3. The liposomal albendazole can reduce E.m.. biomass. 4. liposomal albendazole has prevertive effect for E.m.. infection in mice.