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目的探讨噬菌体LH-01在小鼠体内的药代动力学及其影响因素。方法观察LH-01在小鼠体内的代谢过程和LH-01中和抗体产生规律。建立小鼠败血症感染模型,使用高剂量和低剂量LH-01进行治疗,观察小鼠健康评分(0~5),同时检测小鼠外周血和主要脏器内活菌数和噬菌体滴度变化规律。结果噬菌体LH-01在小鼠体内具有较低的清除率,活性噬菌体可在小鼠体内持续存在数天,10d后完全消失。2周时外周血LH-01中和抗体效价为1︰8,5周时最高为1︰1 024。用高剂量组(1010 PFU/ml)和低价量(104 PFU/ml)的噬菌体LH-01尾静脉注射治疗小鼠败血症,两组组小鼠健康评分最终差异无统计学意义(P>0.05),最终生存率均为100%,而对照组为0%。治疗组小鼠外周血和脏器(肝脏、脾脏和肺脏)中的菌落数显著少于对照组菌落数(P<0.01),尤以脾脏中菌落数减少最显著。LH-01治疗中具有自我放大效应,高剂量和低剂量治疗组小鼠外周血、肝脏和肺脏中的噬菌体滴度与噬菌体对照组相比均显著升高(P<0.01),尤以外周血增加最为明显。结论 LH-01具有杀菌效率高、自我增殖能力强、活性维持时间长、中和抗体产生晚等良好的药代动力学特性,可试用于多重耐药肺炎克雷伯菌感染的治疗。
Objective To investigate the pharmacokinetics of phage LH-01 in mice and its influencing factors. Methods The metabolism of LH-01 in mice and the production of LH-01 neutralizing antibody were observed. The mouse model of sepsis infection was established and treated with high dose and low dose of LH-01. The mice health score (0 ~ 5) was observed. The changes of viable cell count and phage titer in peripheral blood and major organs . Results The phage LH-01 had a low clearance rate in mice. The active phage could persist in mice for several days and disappeared completely after 10 days. At 2 weeks, the titer of LH-01 neutralizing antibody in peripheral blood was 1︰8 and the highest value was 1︰1 024 at 5 weeks. Treatment of sepsis in mice by high-dose (1010 PFU / ml) and low-dose (104 PFU / ml) phage LH-01 tail vein injection did not show any significant difference in the final health scores between the two groups ), The final survival rate was 100%, while the control group was 0%. The number of colonies in the peripheral blood and organs (liver, spleen and lung) of the treated mice was significantly less than that of the control mice (P <0.01), especially in the spleen. LH-01 treatment had self-amplification effect. The phage titers in peripheral blood, liver and lung of high-dose and low-dose treatment groups were significantly higher than that of phage control group (P <0.01), especially in peripheral blood The most obvious increase. Conclusions LH-01 has good bactericidal efficiency, self-proliferative ability, long-lasting activity and good neutralization antibody production pharmacokinetic properties, and can be used for the treatment of multi-drug resistant Klebsiella pneumoniae infection.