| ObjectiveLeucopenia after chemotherapy is important factor affecting the chemotherapy plan execution,this subject adopts the multicenter,randomized,double blind,double modeling,positive drug parallel controlled clinical research design,with qi deficiency syndrome of lung cancer,breast cancer patients as the research object,by Qijiaoshengbai capsule,Anduolin capsule,chemotherapy for intervention measures,monitoring after chemotherapy complete blood count,blood deficiency syndrome two integral change,the evaluation of Qijiaoshengbai capsule prevention and treatment the curative effect of chemotherapy leukopenia related;Further in leukopenia model mice induced by cyclophosphamide as the research object,by Qijiaoshengbai capsule for the intervention measures,through the cell biology and molecular biology techniques,observation of white blood cell count,the spleen index and thymus index in mice,changes in the expression of cytokines,explore the Qijiaoshengbai capsule increase the white blood cells after chemotherapy after often mechanism,to promote proprietary Chinese medicine clinical and experimental foundation for the auxiliary treatment of tumor diseases.Methods1.Clinical research:a multicenter,randomized,double blind and double simulation.positive drug parallel controlled clinical study design,into eight center,260 cases of lung cancer,breast cancer with qi deficiency syndrome and fitting line chemotherapy patients,according to the loss rate of no more than 20%,proposed in 312 cases,the central random according to the proportion of 2:1 into observation group(Qijiaoshengbai capsule group)and control group(Anduolin capsule group).Patients with lung cancer were treated with cisplatin/carboplatin regimen and breast cancer with docetaxel/paclitaxel regimen.The observation group took Qijiaoshengbai capsule orally,while the control group took Anduolin Capsule orally.Patients in both groups took 4 capsules each time for packaging blind drugs,3 times a day,and the course of treatment in both groups was 1 chemotherapy cycle(20 days).3 days before the enrollment,general data were filled in to collect blood routine and evaluate the score and safety index of qi and blood deficiency syndrome.Blood routine was collected on the 5±1 day,10±1 day,15± 1 day and 20±1 day after chemotherapy,and the score and safety of qi and blood deficiency syndrome were evaluated on the 20±1 day.The primary efficacy indicators were analyzed using FAS and PPS,while the secondary efficacy indicators were analyzed using PPSThe main efficacy indicators were grade 4,grade 3/4 and grade 1-4 neutrophils(NE).Secondary efficacy indexes included the lowest values of white blood cell(WBC)and NE,utilization rate of granulocyte colony stimulating factor(G-CSF),delay rate of subsequent chemotherapy,changes of WBC,NE and recovery rate at each visiting point.Stratified statistics were conducted according to the number of courses of chemotherapy,baseline WBC count and patient age,and logistic regression analysis was conducted on the factors affecting the occurrence of grade 1-4 NE decline.The integral quantity of qi and blood deficiency syndrome was quantified,and the total integral improvement rate of qi and blood deficiency syndrome,the improvement rate of individual symptoms and the difference value of each symptom integral were compared between and within groups.2.Experimental research:(1)Modeling:ICR mice were used to prepare the leukopenia model.ICR mice aged 5-6 weeks were given cyclophosphamide 100mg/kg by tail vein for 3 consecutive days.(2)Group administration:The leucopenia model mice were taken as the study object,and Qijiaoshengbai Capsule was taken as the intervention measure.ICR mice were randomly divided into 6 groups:model group,low dose group,medium dose group,high dose group,normal blank group and normal dose group.Groups with low,medium and high doses of Traditional Chinese medicine were given Qijiaoshengbai Capsule 0.5,1.0 and 2.0g/Kg,respectively.In the normal Chinese medicine group,normal mice were given Qijiaoshengbai capsule 1.0g/Kg,and the model group and the normal blank group were given equal volume distilled water for 17 consecutive days.Each Chinese medicine group was given Qijiaoshengbai capsule 3 days before the modeling.Except the normal blank group and the normal Chinese medicine group,cyclophosphamide was injected on the 4th day to make the modeling.(3)Observation indicators:Blood routine collection was conducted on the 7th day after administration;on the 17th day after administration,the animals were sacrificed,blood was collected from the orbit,bone marrow smears were prepared,spleen index and thymus index were weighed and calculated,and the degree of bone marrow hyperplasia was observed.The contents of IL-2,IL-4,IL-6,GM-CSF and serum GM-CSF were detected by ELISA,and the protein expression of GM-CSF in the spleen was detected by Western Blot.Results1.Clinical study:A total of 309 patients with lung cancer and breast cancer with qi and blood deficiency syndrome were included.There was no significant difference in baseline data between the observation group and control group(P>0.05).(1)Main efficacy indicators:complete data set(FAS)287 cases(192 cases in the observation group,95 cases in the control group),in accordance with the protocol set(PPS)252 cases(175 cases in the observation group,77 cases in the control group).The decrease rate of NE in grade 4,3/4 and 1-4 was 14.6%vs 15.5%,31.2%vs 31.7%,73.2%vs 73.5%respectively in the observation group and the control group.In PPS,13.4%vs15.5%,29.4%vs 30.5%,71.9%vs 72.7%,respectively.There was no significant difference between FAS and PPS groups(P>0.05).(2)Secondary efficacy indicators:the lowest value of WBC and NE,the utilization rate of g-csf,and the delayed rate of follow-up chemotherapy were not significantly different between the observation group and the control group(P>0.05);(2)Among the patients in the second cycle of chemotherapy,the WBC and NE counts(×109/L)of the observation group on the 5±1 day of chemotherapy were(6.29±1.87)and(4.79±1.92),which were significantly higher than those of the control group(3.75±1.08)and(2.26±0.75),respectively(P<0.01).Dizziness symptom was an independent risk factor for grade 1-4 NE decrease after chemotherapy.(3)Single disease analysis of lung cancer:168 patients with lung cancer(114 cases in the observation group,54 cases in the control group),161 cases in FAS(109 cases in the observation group,52 cases in the control group),138 cases in PPS(98 cases in the observation group,40 cases in the control group).The decrease rates of NE in grade 4,3/4 and 1-4 were 6.6%vs6.1%,28.8%vs25.7%and 65.5%vs68.3%respectively in FAS in the observation group and the control group,with no statistically significant difference(P>0.05).WBC of the observation group was significantly higher than that of the control group on day 5±1 of chemotherapy.The independent influencing factors of NE decline were KPS score and dizziness symptom.(4)Analysis of single disease of breast cancer:141 cases of breast cancer(96 cases in the observation group,45 cases in the control group),126 cases in FAS(83 cases in the observation group,43 cases in the control group),114 cases in PPS(77 cases in the observation group,37 cases in the control group).The decline rates of NE in grade 4,3/4 and 1-4 were 24.6%vs28.0%,34.4%vs40.0%and 83.3%vs81.5%,respectively,in FAS in the observation group and the control group,with no significant difference(P>0.05).The amplitude of NE recovery was significantly higher in the observation group than in the control group,and it was more prominent in patients receiving chemotherapy in cycle 3 or above.For patients aged>60 years,the reduction of WBC in the observation group was significantly lower than that in the control group,and elderly patients benefited more.2.Experimental study:The mouse model of leukopenia was successfully established.Sixty SPF ICR mice were randomly divided into 6 groups with 10 mice in each group,namely model group,low-dose GROUP,medium-dose group,high-dose group,normal blank group,and normal Chinese medicine group.White blood cell count:On the 7th day after TCM administration,the white blood cells(×109/L)of the model group,the low,medium and high dose TCM group,the normal blank group and the normal TCM group were 4.03±0.92,3.48±1.71,3.60±1.34,3.91±1.52,9.96±1.94 and 11.41±3.63,respectively,and the difference between each group and the normal blank group(P<0.05).On day 15,the white blood cell count of the high-dose group was higher than that of the model group;on day 17,the white blood cell count of the middle-dose and high-dose groups was higher than that of the model group(P<0.05).(2)Degree of myelodysplasia:with the normal blank group as the reference,the degree of hyperplasia in the model group was significantly reduced,while the degree of hyperplasia in the high-dose group was close to normal.(3)Spleen index and thymus index the spleen index and thymus index in the low,medium and high dose groups were all higher than those in the model group(P<0.05).(4)I1-2 and IL-4 in the spleen:the levels of IL-2 and IL-4 in the model group were all lower than those in the blank group and the normal Chinese medicine group(P<0.05).The content of IL-2 and IL-4 in the high-dose group was higher than that in the model group(P<0.05).(5)Content of GM-CSF in spleen tissues:the content of GM-CSF in model group was significantly lower than that in normal blank group and normal Chinese medicine group(P<0.05).The contents of GM-CSF(NG/L)in the medium and high dose groups were 0.99±0.14 and 0.81±0.11,respectively,which were significantly higher than that in the model group(0.33±0.05,P<0.01).The expression level of GM-CSF protein was significantly increased by Western blot in the medium and high dose groups.(6)Serum GM-CSF content:the content of GM-CSF in model group was significantly lower than that in blank group and normal Chinese medicine group(P<0.01).The levels of GM-CSF(NG/L)in the low,medium and high dose groups were 358.75±20.02,350.19±28.28 and 323.60±34.44,respectively,which were higher than those in the model group(290.02±43.74,P<0.05).ConclusionsQijiaoshengbai capsule can effectively prevent and cure chemotherapy-related leukopenia,improve qi and blood deficiency syndrome,improve hematopoietic function by regulating granulocyte-macrophage colony stimulating factor,and promote the recovery of leukocytes and neutrophils after chemotherapy. |
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