“Buyi Ganshen”, A Traditional Chinese Medicine Treatment, Combined With Dopa Preparation For Parkinson’s Disease Therapy: A Meta-analysis Of Randomized Controlled Trials

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Xiao-Qian Hao, Wen-Wen Si, Ye Tian, Jie Liu, Yi-Chun Ji, Xin-Rong Li, Zi-Feng Huang, Yu Zhu, Dong-Feng Chen, Wei-Hong Kuang, Mei-Ling Zhu

1 Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen 510800, China

2 Traditional Chinese Medicine Innovation Center, Shenzhen Baoan Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518000, China

3 Department of Anatomy, The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

4 The Second Clinical Medical College, Guangdong Medical University, Dongguan 523808, China

Highlights

Traditional Chinese medicine Buyi Ganshen therapy combined with dopa preparation in the therapy of Parkinson’s disease could enhance the clinical safety and efficacy compared with dopa preparation alone. The exact mechanism of how Buyi Ganshen works combined with dopa preparation is still unknown and the quality of the enrolled articles was relatively inadequate, yet it could provide the reference in the clinical application and further studies.

Abstract

Background: To research the influence of “Buyi Ganshen”, a traditional Chinese medicine that is commonly used in “Tonifying the Liver and the Kidney”, added dopa preparation for the therapy of Parkinson’s disease. Methods: This meta-analysis examined existing literature by searching 7 electronic databases (CNKI, WanFang, EMBASE, PubMed, Medline, the Cochrane Library, and the VIP database) from inception to December 2019. Randomized controlled trials evaluating the influence of “Buyi Ganshen” combined with dopa preparation for Parkinson’s disease were identified. The main results were clinical efficacy, UPDRS I (mental score), total unified Parkinson’s disease rating scale score, UPDRS III (motor score), UPDRS II (activities of daily life), and UPDRS IV (complications of treatment). The subordinate results were the SPOCA-AUT scores, traditional Chinese medicine syndromes, and other adverse reactions. The Review Manager 5.3 software was used to calculate the pooled estimate effect. The outcomes were shown as the relative ratio with a 95% confidence interval. The fixed or random model was elected based on the level of homogeneity among researchers. The I2 was used to detect heterogeneity. The quality of the research was also assessed. Results: The meta-analysis includes 2,241 individuals from a total of 30 studies. These data suggested that the therapy of Parkinson’s disease with the combination of “Buyi Ganshen” and dopa preparation was more effective compared to dopa preparation alone. Conclusion: “Buyi Ganshen” combined with dopa preparation exists, to some degree, to enhance clinical safety and effectiveness in the cure of Parkinson’s disease, compared with dopa preparation alone. As most of the studies included were of low quality, this conclusion must be considered with caution. Thus, more multi-center, high-quality, prospective randomized controlled trials with large enough sample sizes are required to further illuminate the influence of “Buyi Ganshen” combined with dopa preparation for Parkinson’s disease.

Keywords: Parkinson’s disease, Buyi Ganshen, Dopa preparation, Meta-analysis

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Background

Parkinson’s disease (PD), the second most common neurodegenerative disease in the world, is a gradual neurodegenerative disease connected with non-motor and motor deficits that seriously influence the quality of life [1]. Growing research has revealed that the occurrence of PD ranged from 3.5% to 42.8% and keeps elevated over the last several years [2], and the global incidence of PD is expected to reach around 13 million by 2040 [3].

Dopamine preparation has been the principal drug for treating PD since 1975 [4]. While, long-term therapy of dopa preparation is constantly connected with insurmountable movement complications such as dyskinesia choreoathetosis, and movement fluctuations in motor function [5]. With the development of PD, non-motor symptoms such as cognitive dysfunction, sensory abnormalities, autonomic dysfunction, mental behavior abnormalities, and sleep disorders are becoming more and more obvious, which seriously affects the quality of life of patients and increases their mortality [6].

The therapy of traditional Chinese medicine (TCM) for PD is particularly familiar. TCM could be retrospect to the earliest existing in classic Chinese herbal medicine Huangdi Neijing (Inner Canon of Yellow Emperor, 221 B.C.E.–220 C.E.) in China [7]. Until now, TCM remains popular in the remedy of PD particularly in Asian countries [8]. “Buyi Ganshen” (BYGS) is a variety of compounds of Chinese medicine mixture aimed at “Tonifying Liver and Regulating Kidney” (that’s what it means “Buyi Ganshen”). BYGS is often used for the clinical therapy of PD combined with dopa preparation in China, which might contribute to relieving the symptoms of PD [9].

In this article, a meta-analysis is done to assess the clinical effects and safety of BYGS used together with dopa preparation for PD therapy to explore whether it can enhance the clinical effects of therapy of PD, and lessen side effects.

Methods

Literature search strategy

Four investigators (Xiaoqian Hao, Zifeng Huang, Yu Zhu, and Wenwen Si) independently searched CNKI, WanFang, EMBASE, PubMed, Medline, Cochrane Library, and Chinese Science and Technique Journals Database (VIP) to acquire all related trials [10]. All of the articles were published before October 2019. We employed Medical Subject Heading (MeSH) terms bond with free texts as the following searching terms: (“Buyi Ganshen” OR “Zibu Ganshen” OR “Buyi Ganshen and dopa preparation” OR “Zibu Ganshen and dopa preparation”) AND (“Parkinson’s disease” OR “tremor syndrome”). When retrieving a Chinese database these terms were translated into Chinese. The publication languages of all the articles were Chinese and English only.

Articles inclusion and exclusion criteria

Inclusion criteria. Type of articles: the articles were randomized controlled trials (RCTs) that assess the influence of BYGS bonded with dopa preparation in the therapy of PD, regardless of the extent of therapy.

Type of participators: according to the UK Brain Bank criteria [11], Chinese National Diagnosis Standard updated version in 2006 for PD [12], Chinese National Diagnosis Standard for PD in 1984 [13], or other formal comparable criteria, participants were confirmed diagnosed with PD regardless of age and gender.

Type of interventions: PD was treated by BYGS combined with dopa preparation. Therapy that incorporated there none dopa preparation were not enrolled.

Type of results test: the main results were clinical efficacy, total Unified Parkinson’s Disease Rating Scale (UPDRS) score, UPDRS I (mental score), UPDRS III (motor score), UPDRS II (activities of daily life), and UPDRS IV (complications of treatment), the subordinate results were the SPOCA-AUT scores, TCM syndromes, and adverse reactions.

Exclusion criteria. Excluded articles all accord with the following criteria: nontherapeutic clinical studies, review research, the language of references was not English or Chinese; and animal articles; cannot be compared the balance of the two groups; no relevant outcome indicators in the study; dates extracted from studies with duplicate publication; the subjects had severe liver and kidney damage before inclusion in the study.

Documents screening and data extraction

Three reviewers (Ye Tian, Yichun Ji, and Dongfeng Chen) evaluated the enrolled researches all alone by inspecting titles and abstracts and eliminating the articles which did not conform to the inclusion criteria. The authors’ names and institutions were blinded to the reviewer to averted subjectivity. By discussing with the third reviewer, we removed all the disagreements (Meiling Zhu). We extract the following information from each of the included articles: first author, publication year, patients’ age, sample size, course of the disease, treatment course, outcome measures, and intervention details.

Study quality evaluation

Three investigators (Liu Jie, Xinrong Li, and Weihong Kuang) evaluated the methodological quality of trials alone using the Cochrane Collaboration risk of bias tool, via the following items: participant; therapist; allocation concealment; sequence generation; incomplete outcome data, and outcome assessor blinding; selective outcome reporting; and other sources of bias [14]. Each domain can be rated 3 categories as “ + ” (low risk of bias), “ − ” (high risk of bias), or “ ? ” (unclear risk of bias) for the degree of each potential bias. If there is a disagreement, we resolved it through consulting with a third researcher (Meiling Zhu).

Data synthesis and statistical analysis

Meta-analysis was executed with Review Manager 5.3(the Cochrane Collaboration, UK). The mean difference (MD) and the odds ratio (OR) with 95% confidence intervals (CI) of this study were calculated. Statistical heterogeneity of the outcomes across trials was evaluated by Chi-square-based Q-statistic test, and the inconsistency was calculated by I2. If homogeneity (P ≥ 0.1, I2 ≤ 50%) existed, the summary OR and the 95% CI were calculated by the fixed-effects model. If not, a random-effects model was used when P < 0.1,I2 > 50%. Furthermore, sensitivity analysis was necessary to perform to seek which of the single study strongly influenced the pooled effect. Funnel plots were used to evaluate publication bias.

Results

Description of the screening process

We use the PRISMA flow diagram (Figure 1) to record the detailed screening process. Our researches search enrolled 128 studies in CNKI, WanFang, Medline, Embase, PubMed, CENTRAL, VIP databases, and manual search. A total of 104 articles were screened based on title and abstract, and articles were retrieved after removing duplicates. Then we dislodged 48 studies that did not conform to our inclusion criteria, covering 5 animal studies, 7 theory research studies, 28 non-PD, and BYGS studies, and 8 review studies. Fifty-six articles were evaluated with full text. Then, we dislodged 26 studies on account of the following reasons: 10 unreasonable study design articles, 8 insufficient data articles, and 8 non-RCTs studies. In the end, altogether 30 studies [15–44] remained and were enrolled in our meta-analysis.

Study characteristics

The general characteristics of the enrolled studies are summarized in Table 1. Altogether 2,241 participants contributed to the therapy analysis, with sample sizes ranging from 27 [15] to people 180 [16] with PD. The average age of patients in these researches ranged from 35 to 80 years old. Average PD duration reported in these researches array of 1 to 32 years. All the research published in Chinese originated from China and referred ta o a two-arm design: a control group and an experiment group. The Control group was given dopa preparation therapy only and the experiment group was BYGS therapy plus dopa preparation therapy.

Clinical efficiency

Clinical curative efficiency. Eighteen trials [18–35] with altogether 1,275 patients showed clinical curative efficiency. The low statistical heterogeneity between studies revealed by the heterogeneity test (Chi2 = 20.41, P = 0.25, I2 = 17%). The combined OR and 95% CI as 3.77 (2.82, 5.06), P < 0.00001 was calculated by a fixed-effects model, pointing to a statistically remarkable difference between groups of dopa preparation alone and BYGS together with dopa preparation. This suggests that compared to a pure dopa preparation, BYGS together with dopa preparation could effectively improve the clinical cure efficiency (Figure 2).

UPDRS scores. UPDRS I: 8 studies [16, 19, 32–37] with altogether 745 patients recorded UPDRS I. The result of the heterogeneity test (Chi2 = 74.32, P < 0.00001, I2 = 91%) indicated statistically significant heterogeneity between articles, a random-effects model was used to analyze. The MD and 95% CI were −0.28 (−0.46, −0.10), P = 0.002, showing a meaningfully significant difference between the two groups (Figure 3A). This reveals that BYGS together with dopa preparation could meaningfully reduce the UPDRS I.

UPDRS II: 10 studies [16, 18, 19, 21, 25, 32–34, 36, 37] with a total of 870 patients evaluated UPDRS II. Meta-analysis of 10 comparisons revealed that BYGS combined with dopa preparation significantly reduced UPDRS II (heterogeneity: Chi2 = 159.34, P < 0.00001, I2 = 94%; MD: −3.27, 95% CI −4.56 to −1.98, P < 0.00001; Figure 3B) compared with the control group.

UPDRS III: 11 articles [16, 19–21, 25, 32–37] revealed that heterogeneity test (Chi2 = 49.06, P < 0.00001, I2 = 80%) indicated statistically meaningful heterogeneity between articles, random-effects model was used to analysis. The number of MD and 95% CI were −2.82 (−3.84, −1.80), P < 0.00001, suggesting a statistically meaningful difference between the two groups (Figure 3C). This reveals that BYGS together with dopa preparation could meaningfully decrease the UPDRS III.

UPDRS IV: meta-analysis of 6 studies [16, 19, 21, 33, 36, 37] with a total of 609 patients revealed that BYGS combined with dopa preparation could significantly reduce the UPDRS IV compared with dopa preparation only (heterogeneity: Chi2 = 89.37, P < 0.00001, I2 = 94%; MD: −1.40, 95% CI:−1.83 to −0.96, P < 0.00001; Figure 3D).

Total UPDRS score: 17 articles [16, 19, 26, 27, 29–34, 37–43] with a total of 1,387 patients revealed that BYGS combined with dopa preparation could significantly reduce the total UPDRS score compared with dopa preparation only (heterogeneity: Chi2 = 127.00, P < 0.00001, I2 = 87%; MD: −7.66, 95% CI: −9.48 to −5.83, P < 0.00001; Figure 3E).

SPOCA-AUT score.

Four studies [33, 37, 41, 42] assessed SPOCA-AUT score in 334 patients. The outcomes revealed that there was statistical heterogeneity between articles (Chi2 = 9.16, P = 0.03, I2 = 67%, MD and 95% CI as −4.26 (−5.48, −3.05). Sensitivity analyses aimed to seek underlying sources of heterogeneity. The trial [17] had a different treatment course from the other three studies. The three comparisons showed that BYGS combined with dopa preparation was still superior to the dopa preparation only (MD: −3.68, 95% CI: −4.38 to −2.98, P < 0.00001; heterogeneity: Chi2 = 1.98, P = 0.37, I2 = 0%) after wipe off the trial. This suggests BYGS together with dopa preparation might reduce SPOCA-AUT score to elevate the quality of life compared with the therapy of dopa preparation alone (Figure 4).

TCM syndromes. Ten studies [17, 18, 22, 31, 32, 40−44] included 676 patients to assess the change of TCM syndromes. The heterogeneity test showed Chi2 = 255.64, P < 0.00001, and I2 = 96%, manifesting meaningful statistical heterogeneity between articles. The MD and 95% CI were −7.31 (−9.93, −4.70), P < 0.00001. This reveals that BYGS together with dopa preparation for the therapy of PD could significantly ameliorate the TCM syndromes (Figure 5).

Adverse Events

Seven articles [18–20, 26, 27, 30, 38] including 423 patients, reported adverse events. The heterogeneity test showed Chi2 = 9.58, P = 0.14, I2 = 37% in the meta-analysis, suggesting that there is no statistical heterogeneity between studies, so the fixed-effects model to calculate the combined OR and 95% CI, which were 0.32 (0.18, 0.58), P = 0.0001 (Figure 6), indicating that statistical difference between the two groups, which explains that BYGS therapy together with dopa preparation in the treatment of PD could reduce the adverse events when compared with dopa preparation alone.

Risk of Bias

To assess the risk of bias for each enrolled research, we systematic reviews of interventions by using the guidelines of the Cochrane Handbook [14]. 21 of the 30 enrolled articles [15–17, 19, 21, 22, 24, 26–29, 31–36, 38, 41, 42, 44] depicted the randomization, but no methods of randomization were mentioned. Only 9 studies [18, 20, 23, 25, 30, 37, 39, 40, 43] reported the method of randomization. Only one study [39] described reported blinding of participants and personnel, all other studies were not described personnel, allocation concealment, outcome assessment, and selective reporting. there are no incomplete outcome data and other sources of bias, so we regarded the other bias as low risk (Figure 7 and Figure 8).

Publication Bias Analysis

Figures 9–11 show the funnel plots that come from articles with data on clinical curative efficiency, UPDRS scores, and TCM syndromes. The funnel plots revealed that all nodes were asymmetrical, which may affect the outcomes of our study which there might exist publication bias in our included studies.

Composition of BYGS

Table 2 shows the traditional composition of BYGS. The basic composition is Heshouwu (Polygonum multiflorum Thunb), Guijia (Chinemys reevesii), Baishao (Paeonia lactiflora Pall), Shengdihuang (Rehmannia glutinosa Libosch), Shudihuang (Radix Rehmannia preparata), Danggui (Angelica), Roucongrong (Cistanche deserticola), Shanzhuyu (Fructus Corni), Chuanniuxi (Cyathula officinalis Kuan), Mudanpi (Paeonia suffruticosa Andr), Bajitian (Morinda Officinalis How), Sangjisheng (Taxillus Chinensis), Muli (Ostrea gigas Thunberg), Gouqi (Chinese wolfberry). These herbs work together to “strengthen the Liver and Kidneys and regulate Yin and Yang” in TCM.

Discussion

Summary of main results

The “Liver and Kidney Deficiency” is the most cause of PD according to Chinese medicine [45], and further dysfunction of organs such as phlegm agglutination, Qi Stagnation, Spleen and Stomach, and Blood Stasis eventually result in the production of PD. Thus, the main principle of TCM therapy of PD is to “Tonifying the Liver and Kidney” (this is the definition of BYGS). A meta-analysis of data was done that supports the efficacy of this therapy method. As a subsidiary treatment for PD, BYGS together with dopa preparation reduced the total UPDRS score, UPDRS I II III IV score, SPOCA-AUT score, and TCM syndromes score, and increased the efficiency of clinical curative effect. Besides, patients who were treated by BYGS combined with dopa preparation revealed decreased adverse events.

Analysis of BYGS formulation

Plenty of articles has revealed that the drugs contained in BYGS display clinical neuroprotective effects in PD patients. It is believed that mitochondrial dysfunction, oxidative stress, inflammation, protein misfolding and aggregation, and apoptotic cell death play important roles in PD pathogenesis, but the exact pathogenic mechanisms underlying selective dopaminergic neurons loss in PD still dimness [46]. PD is a combination of interconnected events not a result of the dysfunction of one specific pathway. The development of neuroprotective therapy targeting more potential signal pathways is the urgent need of therapy PD [47]. There are some anti-PD mechanisms of the main active ingredients of herbs in vivo or in vitro trials. The study contains catalpol that can lighten oxidative stress by decreasing reactive oxygen species levels [48]. Another research revealed that the active ingredients of Echinacoside (Cistanche deserticola) displayed a stronger inhibition on the productions and/or expression of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1α, nitric oxide, IL-1β, and IL-6 [49]. The 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside (Polygonum multiflorum Thunb) can dilute mitochondrial dysfunction by banning the weakening of cellular ATP levels and mitochondrial membrane potential [50]. n-Butylidenephthalide (Angelica) exerted antiapoptotic capacity by inhibiting the rise of the ratio of Bax/Bcl-2 and activating caspase-3 and caspase-8 [51]. Besides, we can explore the best formula combination for the high frequency used herbs, and this also lights the traditional herb medicine therapy method for PD patients.

This meta-analysis found that BYGS therapy indeed improves the clinical effect and the quality of survival. Additionally, BYGS reduced the adverse effects. However, possibly due to the small sample size, little effects on E-rosette were shown. These effects may address the details more comprehensively by future large-scale studies. In short, this analysis showed the safety and effectiveness of the use of TCMBYGS combined with dopa preparation for the therapy of PD.

Limitations

The meta-analysis is the brand-new system review about BYGS therapy combined with dopa preparation in the therapy of patients with PD. The benefits of our meta-analysis enrolled many specific results of clinical efficacy, clinical response rate, total UPDRS score, UPDRS IV, UPDRS III, UPDRS II, UPDRS I. The secondary outcomes were the SPOCA-AUT score, TCM syndrome, and other adverse reactions. However, there are some limitations of this research that block us from attaining definite conclusions. First, none of the included studies was registered in a clinical trial registry before enrolling subjects in the study [52]. Second, the methodological quality of the enrolled RCTs was commonly low. All the enrolled articles did not describe the blinding of outcome assessment and allocation concealment. Only one trial [39] reported the right method of blinding of participants and personnel. Publication bias might be present. Third, the research results may lower the validity and reliability for the high clinical heterogeneity. Finally, the search strategy may not discern all relevant research. Due to the above limitations, large research is needed to affirm this research.

Conclusion

TCM BYGS therapy combined with dopa preparation in the therapy of PD might increase the immunity of patients to enhance clinical safety and efficacy. But the deep-seated mechanism of how BYGS works combined with dopa preparation is still unknown and the quality of the enrolled articles was relatively insufficient. So, it is a requirement to perform larger sample, multicenter, randomized, high quality, prospective, double-blind clinical trials to further evaluate the efficacy of BYGS and dopa preparation treatment for PD.

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