多种口服升白药物联合粒细胞集落刺激因子治疗化疗相关白细胞减少症的实验研究

Treatment of Chemotherapy Related Leukocytopenia by Oral Administration of Multiple Leucogenic Drugs Combined with G-CSF: an Experimental Study

目的通过实验研究评价3种常用口服升白细胞药物盐酸小檗胺片、芪胶升白胶囊、利可君片(单药、两药及三药)联合粒细胞集落刺激因子(granulocyte colony-stimulating factor,G-CSF)皮下注射治疗化疗相关白细胞减少症的疗效。方法将156只昆明系雄性小鼠分为正常对照组(简称A组)、模型组(简称B组)、G-CSF组(简称C组),每组24只,及G-CSF加芪胶升白胶囊组(简称D组)、G-CSF加盐酸小檗胺片组(简称E组)、G-CSF加利可君片组(简称F组)、G-CSF加芪胶升白胶囊加盐酸小檗胺片组(简称G组)、G-CSF加芪胶升白胶囊加利可君片组(简称H组)、G-CSF加利可君片加盐酸小檗胺片组(简称I组)及GCSF加利可君片加芪胶升白胶囊加盐酸小檗胺片组(简称J组),每组12只。采用环磷酰胺(cyclophosphamide,CTX)腹腔注射法制备小鼠化疗相关白细胞减少症模型,以G-CSF组作为阳性对照,将芪胶升白胶囊、盐酸小檗胺片、利可君片3种药物采用单药、单药联合G-CSF、两种或3种升白药物联合G-CSF处理模型小鼠,统计小鼠死亡率;采用全血细胞分析仪测定白细胞(WBC)计数及分类、红细胞(RBC)计数、血小板(PLT)及血红蛋白(Hb)水平,解剖小鼠并将其重要脏器称重,计算脏器指数。结果各组小鼠死亡率比较,差异无统计学意义(P>0.05)。与B组比较,其余各组WBC均明显升高(P<0.01),J组升白细胞及PLT的效果最佳,同时可提高Hb及RBC含量(P<0.05,P<0.01)。与B组比较,E、F、G、I、J组RBC均明显升高(P<0.01);C、E、F、H、I、J组Hb均明显升高(P<0.01)。与B组和D组比较,含有盐酸小檗胺片、利可君片的组别均可提升G-CSF对红系造血的刺激能力(P<0.05,P<0.01);C、D及G组可明显提高模型小鼠的脾脏指数(P<0.01);H组可明显提高模型小鼠的胸腺指数(P<0.05)。结论治疗化疗相关小鼠白细胞减少症或全血细胞减少的最佳方案为口服3种常用升白细胞药物联合G-CSF,推测G-CSF、芪胶升白胶囊对CTX引起的免疫抑制可能具有一定的疗效。

Objective To evaluate efficacies of three commonly used oral drugs including Berbamine Hydrochloride Tablet（ B）,Qijiao Shengbai Capsule（ Q）,and Leucogen Tablet（ L）（ by single drug,two drugs or three drugs） combined with granulocyte colony-stimulating factor（ G-CSF） for treatment of chemotherapy related leukocytopenia in mice. Methods Totally 156 Kunming male mice were divided into the normal control group（ A,n = 24）,the model group（ B,n = 24）,the G-CSF group（ C,n = 24）,the G-CSF ＋ Q group（ D,n = 12）,G-CSF ＋ B（ E,n = 12）,the G-CSF ＋ L group（ F,n =12）,the G-CSF ＋ Q ＋ B group（ G,n = 12）,the G-CSF ＋ Q ＋ L group（ H,n = 12）,the G-CSF ＋ L ＋ B group（ I,n = 12）,and the G-CSF ＋ L ＋ Q ＋ B（ J,n = 12）. Mouse models of chemotherapy related leukocytopenia were established byintraperitoneal injection of cyclophosphamide（ CTX）. A G-CSF group was set up as a positive control. Mice were treated by a single oral drug,a single oral drug combined with G-CSF,and two or three drugs combined with G-CSF respectively,and the death rate calculated. Hemocytes [such as white blood cells（ WBC） and its classification,red blood cells（ RBC）,platelet（ PLT）,hemoglobin（ Hb） ] were calculated by hematology analyzer. Mice were anatomized and important organs weighed. Organ indices were calculated. Results There was no statistical difference in the mortality rate among all groups（P〈0. 05）. Compared with Group B,WBC was elevated in all other groups（P〈0. 01）. WBC and PLT were elevated most in Group J,Hb and RBC were also increased at the same time（P〈0. 05,P〈0. 01）. Compared with Group B,RBC increased in Group E,F,G,I,and J（P〈0. 01）; Hb obviously increased in Group C,E,F,H,I,and J（P〈0. 01）.Compared with Group B and D,the promotion of erythroid hematopoiesis by G-CSF could be elevated in any group contained drug B and L（P〈0. 05,P〈0. 01）. The spleen index of model mice could be significantly improved in Group C,D,and G（P〈0. 01）. The thymus index of model mice could be significantly improved in Group H（P〈0. 05）. Conclusions The best scheme to treat mice with chemotherapy related leukopenia or decreased three blood series was to administrate three commonly oral drugs combined with G-CSF. Authors speculated that G-CSF and Q might have a certain effect on CTX induced immune inhibition.