Figures
Abstract
Background
Huangqi injection is derived from Astragalus membranaceus root. In China, recent reports of Huangqi injection for the treatment of leucopenia have emerged. However, a systematic review of these reports has not been performed. Thus, we conducted a meta-analysis of clinical controlled trials to assess the clinical value of Huangqi injection in the treatment of leucopenia.
Methods
We searched the Chinese Biomedical Literature Database (CBM), Wanfang Database, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), as well as PubMed and EMBASE to collect the data about trials of Huangqi injection for treating leucopenia. A meta-analysis was performed using RevMan 5.2 software.
Results
A total of 13 studies involving 841 patients were included in this study. The overall study quality was lower according to the Jadad scale. The meta-analysis showed that experimentally treated patients experienced greater therapeutic efficacy and lower white blood cell counts than control groups treated with Western medicine (P < 0.05). No publication bias was evident, according to Egger’s test.
Citation: Zhang C, Zhu C, Ling Y, Zhou X, Dong C, Luo J, et al. (2013) The Clinical Value of Huangqi Injection in the Treatment of Leucopenia: A Meta-Analysis of Clinical Controlled Trials. PLoS ONE 8(12): e83123. https://doi.org/10.1371/journal.pone.0083123
Editor: Robert K Hills, Cardiff University, United Kingdom
Received: June 10, 2013; Accepted: October 29, 2013; Published: December 12, 2013
Copyright: © 2013 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This project was supported by the Natural Science Foundation of China (81071799, 81372212), the Science and Technology Bureau of Changzhou Municipality (CJ2012202), the Natural Science Foundation of Jiangsu (BK2011251), Jiangsu Provincial Special Program of Medical Science (BL2013012), the Health Talents Project for Jiangsu (LJ201157; RC2011038; BRA2011038), and the “831” Health Talents Project of Changzho Municipality. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Leucopenia is defined by a lower-than-normal peripheral white blood cell (WBC) count. Leucopenia commonly arises from cancer chemotherapy or radiotherapy, viral infection, drug-induced reactions, and certain immune diseases [1-7]. Recent studies suggest that a single-nucleotide polymorphism may also cause leucopenia [8]. At present, leucogen, shark glycol, vitamin B4, and inosine have been used to treat leucopenia. However, these treatments fail in some cases, and novel approaches for treating leucopenia are needed. Recently, in China, Huangqi injection for the treatment of leucopenia has been reported in many clinical trials. These individual studies suggest that Huangqi injection may be useful for the treatment of leucopenia, but a systematic review has not been performed. Therefore, we conducted a meta-analysis of clinical controlled trials to assess the therapeutic value of Huangqi injection for the treatment of leucopenia.
Materials and Methods
Inclusion criteria
The clinical trials were clinically controlled studies and experimental groups were treated with Huangqi injection. Controls in the studies were treated with Western medicine as described in Table 1. Outcome measures were effectiveness rates and WBC counts. WBC measurements were performed by an independent laboratory and measured in SI units (109/L). When total WBCs were greater than 4.0×109/L or elevated more than 1.0×109/L in the peripheral blood arising from a drug intervention, treatments were considered to be effective. Before treatment, the baseline peripheral WBCs were comparable between the experimental group (Huangqi injection) and the control group (Western medicine) (P>0.05). In this study, we restricted no clinical trials based on patient gender, race, or language of the publication.
Author [Reference] | Published year | Cases E/C | Age (years) Range, mean | Sex Male/female | Etiopathogenesis |
---|---|---|---|---|---|
Zhang MJ[15] | 1999 | 35/32 | E: 18-50, 33 C: 20-56,37 | E: 7/28 C: 19/23 | Radiotherapy, chemotherapy, immunodiseases |
Dai Y[17] | 1999 | 68/27 | 25-76,55.6 | 59/36 | Radiotherapy, chemotherapy |
Feng CL[10] | 2000 | 32/28 | E: 40-79 C: 42-79 | E: 14/18 C: 13/15 | Infection |
Zhang YS[14] | 2000 | 58/54 | E: 16-52,36 C: 15-56,34.6 | E: 30/28 C: 32/22 | Radiotherapy, chemotherapy, drug use, etc |
Gao P[16] | 2000 | 30/25 | E: 15-56,32 C: 18-55,35 | E: 10/20 C: 9/46 | Radiotherapy, chemotherapy, viral infection, immunodiseases, etc |
Qu W[21] | 2000 | 32/28 | E: 16-63,38.2 C: 15-56,34.6 | E: 14/18 C: 12/16 | Graves disease with tapazole |
Yang DS[11] | 2001 | 25/25 | 18-55,33.5 | 21/29 | Radiotherapy, chemotherapy, drug use |
Mo WG[18] | 2005 | 30/30 | E: 0-12,2.44 C: 0-11,2.99 | E: 19/11 C: 17/13 | Viral infection |
Tang JC[13] | 2007 | 23/22 | 13-64,50 | 30/15 | Nasopharyngeal carcinoma patient with radiotherapy |
Wang HJ[20] | 2007 | 40/39 | 16-68,31.5 | 6/73 | Systemic lupus erythematosus |
Xiao AQ[9] | 2007 | 26/25 | 33-73 | E: 14/12 C: 15/10 | Ticlopidine use |
Mo WX[19] | 2009 | 20/20 | E:16-54,28 C:18-52,26 | E: 8/12 C: 9/11 | Schizophrenia with clozapine |
Qin HZ[12] | 2011 | 35/32 | E: 19-51,32 C: 22-55,36 | E: 9/26 C: 10/22 | Radiotherapy, chemotherapy, viral infection, immunodiseases, etc |
Exclusion criteria
Duplicated literature, reviews, non-clinical studies, case observations, and non-injection formulae literature were excluded in this study.
Research strategy and data extraction
“Huangqi” or “huang qi” or “astragalus” or “astragali” or “astragalus miltiorrhiza” or “Chinese traditional medicine herb” AND “leucopenia” or “leucocytopenia” or “leucopenia” or “aleucocytosis” or “hypolekocytosis” or “hypoleucocytosis” or “hypoleukemia” or “hypoleukia” or “hypoleukocytosis leucocytopenia” or “leucopenia” or “oligoleukocythemia” or “oligoleukocytosis” or “white blood count” were selected as the free-text terms or MeSH terms. The Chinese Biomedical Literature Database (CBM), Wanfang Database, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), PubMed, and EMBASE were searched. Data extraction and quality assessment were independently performed by two researchers [CTZ and YL] and any discrepancies were resolved by consensus or in consultation with a third reviewer [CSZ]. The lack of information in any study was supplemented by contact with the authors in charge of the clinical trials. The database retrieval process is shown in Figure 1.
Statistical analysis
Statistical analysis was performed using Cochrane RevMan 5.2 and STATA 11.0 software. Categorical variables were compared using odds ratios (OR), and continuous variables were compared using standard mean differences (SMD). A 95% confidence interval (CI) was calculated and the Chi-square test was used for heterogeneity of inclusion trials. Data of heterogeneity were studied using a random effects model; otherwise a fixed effects model was used. A funnel plot and Egger’s test were employed to judge potential publication bias.
Results
Characteristics of included studies
Thirteen articles [9-21] involving 841 subjects (experimental groups: 454 cases; the control groups: 387 cases) were included in this study. Causes of leucopenia were mainly viral infection, cancer chemotherapy, drug-induced reactions, and immune disorders. The general characteristics of the study are shown in Table 1, and interventions, treatments, and outcomes are depicted in Table 2.
Author | The regimens of intervention | Treatment | |
---|---|---|---|
[reference] | Experimental group | Control group | Time |
Zhang MJ[15] | Huangqi injection (40 ml) were respectively added to a 5% glucose solution (250 ml), intravenously, qd | Oral leucogen, and batyl alcohol; energy mixture, intravenously | 30 d |
Dai Y[17] | Huangqi injection (40 ml) were respectively added to a 5% glucose solution (250 ml), intravenously, qd | Oral batyl alcohol and leucogen | 7-10 d |
Zhang YS[14] | Huangqi injection (40 ml) were respectively added to a 5% glucose solution (500 ml), intravenously, qd | Oral inosine, leucogen and batyl alcohol | 14 d |
Gao P[16] | Huangqi injection (40 ml) were respectively added to a 5% glucose solution (250 ml), intravenously, qd | Oral batyl alcohol, tid | 30 d |
Tang JC[13] | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral inosine | 49 d |
Mo WX[19] | Huangqi injection (20 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral leucogen and vitamin B4 | 45 d |
Qin HZ[12] | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral leucogen and batyl alcohol, energy mixture, intravenously | 30 d |
Feng CL[10]# | Huangqi injection (20-40 ml) were respectively added to a 5‑10% glucose solution (250 ml), intravenously, qd | Anti-infecion and symptomatic treatment | 15–21 d |
Qu W[21]# | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral tapazole | 28 d |
Yang DS[11]# | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral vitamin B4 and leucogen | 30 d |
Mo WG[18]# | Huangqi injection (5-10ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Conventional antiviral and symptomatic treatment | 7 d |
Wang HJ[20]# | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral prednisone and leflunomide | 2–4 w |
Xiao AQ[9]# | Huangqi injection (40 ml) were respectively added to a 5% solution (250 ml), intravenously, qd | Oral leucogen and batyl alcohol | 30 d |
The quality assessment
The Jadad scale was scored by randomization, randomization methodology, double-blinding, withdrawals/dropouts, and allocation concealment [22-24]. The Jadad scores ranged from 0 to 2 (Table 3), suggesting that the overall quality of the literature was lower.
Author[reference] | Randomization | Randomization methodology description | Double-blinding | Withdrawals/dropouts | Allocation concealment | Scores |
---|---|---|---|---|---|---|
Zhang MJ[15] | No | No | No | No | No | 0 |
Dai Y[17] | Yes | No | No | No | No | 1 |
Feng CL[10] | No | No | No | No | No | 0 |
Zhang YS[14] | Yes | No | No | No | No | 1 |
Gao P[16] | Yes | No | No | No | No | 1 |
Qu W[21] | Yes | No | No | No | No | 1 |
Yang DS[11] | Yes | Yes | No | No | No | 2 |
Mo WG[18] | No | No | No | No | No | 0 |
Tang JC[13] | Yes | No | No | No | No | 1 |
Wang HJ[20] | Yes | No | No | No | No | 1 |
Xiao AQ[9] | Yes | No | No | No | No | 1 |
Mo WX[19] | Yes | No | No | No | No | 1 |
Qin HZ[12] | Yes | No | No | No | No | 1 |
Meta-analyses of the effectiveness of Huangqi injection
Ten studies [9-18] described the effectiveness of Huangqi (Figure 2). Meta-analysis revealed an overall effectiveness rate in the experimental group that was higher than that in the control group [OR = 6.69, 95% CI (4.14, 10.81), P < 0.05; fixed effects model] (Figure 2). The combined estimates of WBCs in the experimental group was also higher than that in the control group [SMD=1.94, 95% CI (1.19-2.69), P < 0.05; random effects model] (Figure 3).
Events: the numbers of the effective cases.
Subgroup analyses of Huangqi injection versus Western medicine
The pool effectiveness rate in Huangqi injection treatment group was higher than that in the Western medicine treatment group [OR = 7.06, 95% CI (4.11, 12.15), P < 0.05; fixed effects model] (Figure 2). WBC counts in the Huangqi injection treatment group were higher than those in the control group [SMD=0.82, 95% CI (0.38, 1.25), P < 0.05; random effects model] (Figure 3).
Subgroup analyses of Huangqi injection combined with Western medicine versus Western medicine
There was significant difference in the pool effectiveness rate between the experimental group with Huangqi injection combined with Western medicine and the control group with Western medicine [OR = 5.64, 95% CI (2.04, 15.58), P < 0.05; fixed effects model] (Figure 2). WBCs in the experimental group were significantly higher than those in the control group [SMD=1.88, 95% CI (1.06, 2.71), P<0.05; random effects model] (Figure 3).
Side effects
In this study, five reports [9,12,13,16,19] confirmed that no side effects in clinical trials were observed. The remaining reports did not mention adverse effects. Thus, we could not evaluate adverse effects due to this deficit.
Publication bias
There was no publication bias according to the results of Egger’s test performed by STATA 11.0 (P = 0.264). The funnel plot drawn by Cochrane Revman 5.2 was basically symmetric (Figure 4).
Discussion
Recently, in China, apart from treating leucopenia, Huangqi injection has been widely used to treat chronic hepatitis [25-27], cirrhosis [28], chronic heart failure [29,30], chronic nephritis [31-33], and diabetic nephropathy [34,35].
Huangqi injection is derived from the Radix Astragali Mongolici root using ethanol. Modern pharmacological studies demonstrated that astragalus flavonoids, an effective component of Huangqi, can eliminate radiation toxicity and increase granulocyte colony-stimulating factor to promote stem cell proliferation [36]. In addition, Huangqi can regulate humoral immunity, inhibit proliferation of tumor cells and reduce chemotherapeutic toxicity [37-41].
According to this meta-analysis, Huangqi injection was more efficacious than the Western medicine control group. Subgroup analyses revealed that the overall effectiveness rates in the experimental group receiving Huangqi injection alone or combined with Western medicine was higher compared with Western medicine alone.
We noted that five studies suggested that clinical trial side effects were not observed. Whereas, according to a review of 83 studies [42] regarding adverse reactions in response to Huangqi injection (1995–2008) by the Evidence Based Medicine Centre, Tianjin University of Traditional Chinese Medicine, China, data suggest that only moderate reactions were observed. Most of these were dermal allergenic reactions; no deaths were reported. These findings suggest that Huangqi may be safe and may have a potential clinical value in the treatment and prevention of leucopenia. Considering reports that Huangqi injection could enhance immunity and inhibit tumors, use of Huangqi to treat cancer patients during radiotherapy and chemotherapy may be possible. Interestingly, the previous Cochrane systematic review [43] reported that the proportion of patients with leucopenia was significantly lower in the groups treated with Huangqi injection in addition to chemotherapy and the pooled estimate of absolute rate reduction was 36% (95% CI: 21% to 51%), suggesting that Huangqi injection may be used as a preventative treatment for leucopenia during chemotherapy. However, in this present study, we didn’t conduct a meta-analysis on the preventative treatment.
Although no publication bias was confirmed according to the results of Egger’s test, the meta-analysis did have some limitations. These may decrease the validity of evidence-based medicine within this meta-analysis. The main limitations were poor quality of included studies and in our meta-analysis, no study accounted for withdrawals/dropouts and only one provided a description of randomization methodology. Neither double-blind nor concealed allocation studies were mentioned in the included literature. Moreover, available data about follow-up regarding long-term efficacy and safety were insufficient. Based on these disadvantages, a treatment effect of this size seems quite unlikely. It must be emphasized that such trials should be randomized and ideally placebo controlled.
Fortunately, in the included studies, WBC counts were performed by independent laboratory personnel and the staff was blinded to the treatment drug group/patient group. These data suggest that the outcome evaluation was reliable.
Presently, most clinical trials published in Chinese medical journals were of poor quality with respect to methodological design according to the Jadad scale [41,44]. Future trials to evaluate Huangqi should incorporate clinical trial registration and adoption of the international reporting criteria such as CONSORT, STROBE and PRISMA. These procedures would drastically elevate the validity of the clinical trials.
Conclusions
The validity of this meta-analysis was limited by the overall poor quality of the included studies. Huangqi injection may have potential clinical value in the treatment of leucopenia, but further studies are warranted, especially rigorous and well-designed multi-center trials.
Author Contributions
Conceived and designed the experiments: CTZ YL CSZ XFZ. Performed the experiments: YL CTZ CSZ XFZ CLD JDL YPL. Analyzed the data: CTZ YL CSZ CLD. Contributed reagents/materials/analysis tools: YL CTZ. Wrote the manuscript: CTZ YL CSZ CLD.
References
- 1. Zhou W, Ding Q, Liang X, He Z, Zha X et al. (2012) The risk of amenorrhea is related to chemotherapy-induced leucopenia in breast cancer patients receiving epirubicin and taxane based chemotherapy. PLOS ONE 7: e37249. doi:https://doi.org/10.1371/journal.pone.0037249. PubMed: 22615953.
- 2. Bruserud O (1998) Cellular immune responses in acute leukaemia patients with severe chemotherapy-induced leucopenia; characterization of the cytokine repertoire of clonogenic T cells. Cancer Immunol Immunother 46: 221-228. doi:https://doi.org/10.1007/s002620050481. PubMed: 9671145.
- 3. Aguilar-Ponce JL, Granados-García M, Cruz López JC, Maldonado-Magos F, Alvarez-Avitia MA et al. (2013) Alternating chemotherapy: gemcitabine and cisplatin with concurrent radiotherapy for treatment of advanced head and neck cancer. Oral Oncol 49: 249-254. PubMed: 23043985.
- 4. Huang CS, Liu L, Liu J, Chen Z, Guo J et al. (2012) Association of chemotherapy-induced leucopenia with treatment outcomes in advanced non-small-cell lung cancer cases receiving the NP regimen. Asian Pac J Cancer Prev 13: 4481-4485. doi:https://doi.org/10.7314/APJCP.2012.13.9.4481. PubMed: 23167365.
- 5. Hayashi K, Ohtsu F, Yano R, Sakakibara J, Goto N (2011) Risk factors and subjective symptoms of drug-induced leucopenia. Yakugaku Zasshi 131: 139-152. doi:https://doi.org/10.1248/yakushi.131.139. PubMed: 21212623.
- 6. Hooper C, Slocombe R, Day R, Crawford S (2012) Leucopenia associated with abalone viral ganglioneuritis. Aust Vet J 90: 24-28. doi:https://doi.org/10.1111/j.1751-0813.2011.00877.x. PubMed: 22256981.
- 7. Shafi MS, Sheikh NI, Rizvi F, Afzal M, Manzoor S (2009) Treatment induced leucopenia in hepatitis C and Role of G-CSF in its management. J Coll Physicians Surg Pak 19: 346-349. PubMed: 19486571.
- 8. Wroblova K, Kolorz M, Batovsky M, Zboril V, Suchankova J et al. (2012) Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance, and pancreatitis in azathioprine-treated patients. Dig Dis Sci 57: 2394-2401. doi:https://doi.org/10.1007/s10620-012-2163-y. PubMed: 22535280.
- 9. Xiao AQ, Dong BQ (2007) Huangqi injection for the treatment of ticlopidine-induced leukopenia. Taishan Yi Xue Yuan Xue Bao 28: 706-707.
- 10. Feng CL (2000) Huangqi injection combined antibiotic for the treatment of 32 cases of leukopenia complicated with pulmonary infection. Shi Yong Zhong Yi Nei Ke za Zhi 2: 23 -24.
- 11.
Yang DS, Du SY (2001) The efficacy observation of Huangqi injection for treating 25 cases of leukopenia. Xian Dai Zhong Xi Yi Jie He Za Zhi 10:812.
- 12. Qin HZ, Lu HY (2011) Huangqi injection for the treatment of leukopenia. Yi Xue Xin Xi 24: 151.
- 13. Tang JC, Ou GF (2007) Effect of Huangqi injection on white blood cells in the patients with nasopharyngeal carcinoma during radiotherapy. Shi Yong Yi Xue za Zhi 23: 280-281.
- 14. Zhang YS, Wen HJ, Liu XY (2000) The clinical observation of Huangqi injection for treating 112 cases of leucopenia. Shi Zhen Guo Yi Guo Yao 11: 935.
- 15. Zhang MJ, Hu RQ (1999) Huangqi injection for treating leukopenia. Lin Chuang Xue Ye Xue za Zhi 12: 28.
- 16. Gao P, Fu L, Han M (2000) Huangqi injection for the treatment of leukopenia. Changchun Zhong Yi Xue Yuan Xue Bao 4: 24.
- 17. Dai Y (1999) The clinical observation on Huangqi injection for treating 68 cases of chemotherapy-induced leucopenia. Zhejiang Zhong Yi za Zhi 34: 42.
- 18. Mo GW, Guo XM, Lin YG (2005) Efficacy of Huangqi injectionon for the treatment of leucopenia caused by viral infection. Guangzhou Zhong Yi Yao da Xue Xue Bao 22: 13-15.
- 19. Mo WX (2009) Huangqi injection for the treatment of 40 cases of clozapine -induced leucopenia. NE Ke 4: 64-65.
- 20. Wang HJ, Wang JP, Zhang JH (2007) The clinical observation on combined Huangqi injection for the treatment of systemic lupus erythematosus. Lanzhou da Xue Xue Bao (Medical Sciences) 33: 76-78.
- 21. Qu W, Song WX (2000) Huangqi injection combined methimazole for the treatment of Graves' disease with leukopenia. Tianjin Yao Xue 4: 71-72.
- 22. Jadad AR, McQuay HJ (1996) Meta-analyses to evaluate analgesic interventions: a systematic qualitative review of their methodology. J Clin Epidemiol 49: 235-243. doi:https://doi.org/10.1016/0895-4356(95)00062-3. PubMed: 8606325.
- 23. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ et al. (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17: 1-12. doi:https://doi.org/10.1016/S0197-2456(96)90740-0. PubMed: 8721797.
- 24. Moher D, Jadad AR, Tugwell P (1996) Assessing the quality of randomized controlled trials. Current issues and future directions. Int J Technol Assess Health Care 12: 195-208. doi:https://doi.org/10.1017/S0266462300009570. PubMed: 8707495.
- 25. Li QZ, Huang CJ, Jiao LH, Pan SJ (1997) Experiment and trials of Huangqi injection for the treatment of chronic active hepatitis. Shanghai Yi Yao 18: 21-22.
- 26. Liu BJ, Xia DW, Zheng JH, Yang F (2000) The clinical evaluation of Huangqi injection for the treatment of acute jaundice hepatitis. Liaoning Yao Wu Yu Lin Chuang 3: 13-14.
- 27. Xiao L, Wang JY, Shang HC, Mu W, Zhang L (2012) Huangqi injection for the treatment of chronic hepatitis: a systematic review of randomized controlled trials. Zhongguo Zhi Ye Yao Shi 9: 25-32.
- 28. Fan JH, Deng M (2007) Oxymatrine combined with Huangqi injection on for the treatment of liver fibrosis in chronic hepatitis B patients. Hainan Yi Xue Yuan Xue Bao 13: 233-234.
- 29. Bao XN (1999) Huangqi injection for the treatment of aged patients with congestive heart failure. Zhong Yi Yao Li Yu Lin Chuan 15:39-40.
- 30. Fu S, Zhang J, Menniti-Ippolito F, Gao X, Galeotti F et al. (2011) Huangqi injection (a traditional Chinese patent medicine) for chronic heart failure: a systematic review. PLOS ONE 6: e19604. doi:https://doi.org/10.1371/journal.pone.0019604. PubMed: 21573109.
- 31. Shi JF, Zhu HW, Zhang C, Bian F, Shan JP et al. (2002) Observation on Huangqi injection for the treatment of chronic glomerulonephritis. Shanghai di Er Yi Ke da Xue Xue Bao 22: 245-247.
- 32. Luo WW, Chen Q (2000) Clinical observation on Huangqi injection for the treatment of chronic glomerulonephritis proteinuria. Zhonghua Shen Zang Bing za Zhi 16: 189.
- 33.
Su L, Mao JC, Gu JH (2007) Effect of intravenous drip infusion of cyclophosphamide with high-dose Astragalus injection in treating lupus nephritis. Zhong Xi Yi Jie He Xue Bao 5: 272-275.
- 34. Liu ZQ, Li QZ, Qin GJ (2001) Effect of Astragalus injection on platelet function and plasma endothelin in patients with early stage diabetic nephropathy. Zhongguo. Zhong Xi Yi Jie He Za Zhi 21: 274-276.
- 35. Li M, Wang W, Xue J, Gu Y, Lin S (2011) Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy. J Ethnopharmacol 133: 412-419. PubMed: 20951192.
- 36.
Zhu XL, Zhu BD (2001) Mechanism of the effect of Huangqi injection on the hematopoiesis of granulocytic, monocyte,and erythrocyte series in anemic mice. Zhongguo Zhong Xi. Yi Jie He Ji Jiu Za Zhi 5:284-286.
- 37. Zou YH, Liu XM (2003) Effect of astragalus injection combined with chemotherapy on quality of life in patients with advanced non-small cell lung cancer. Zhongguo. Zhong Xi Yi Jie He Za Zhi 23: 733-735.
- 38. Dong J, Lu HY, Mao JE (2010) Meta-analysis of the attenuated toxicity and synergistic effects of Huangqi injection for cancer chemotherapy. Zhong Yi Yao Dao Bao 16: 87-92.
- 39. Cai XY, Xu YL, Lin XJ, Fu ZZ, Qin SG et al. (2006) Effect of Huangqi injection on apoptosis and immune function of the patients with systemic lupus erythematosus. Zhongguo. Zhong Xi Yi Jie He Za Zhi 26: 443-445.
- 40. Wang HJ, Wang JP, Chen P (2007) Effect of Huangqi injection on peripheral blood and immune function Huangqi injectionon for the patients with systemic lupus erythematosus. Sichuan Zhong Yi 25: 20-21.
- 41. McCulloch M, See C, Shu XJ, Broffman M, Kramer A et al. (2006) Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: meta-analysis of randomized trials. J Clin Oncol 24: 419-430. doi:https://doi.org/10.1200/JCO.2005.03.6392. PubMed: 16421421.
- 42. Fu SF, Zhang JH, Shang HC, Gao XM (2009) Eighty-three case reports on adverse reaction of Huangqi injection. Yao Wu Ping Jia Yan Jiu 32: 54-61.
- 43. Wu T, Munro AJ, Guanjian L, Liu GJ (2005) Chinese medical herbs for chemotherapy side effects in colorectal cancer patients. Cochrane Database Syst Rev 25:CD004540.
- 44. Xu L, Li J, Zhang M, Ai C, Wang L (2008) Chinese authors do need CONSORT: reporting quality assessment for five leading Chinese medical journals. Contemp Clin Trials 29: 727-731. doi:https://doi.org/10.1016/j.cct.2008.05.003. PubMed: 18579449.