REVIEW Doi: 10.12032/TMR20191102145

REVIEW doi: 10.12032/TMR20191102145

Traditional Chinese Medicine

Efficacy and safety of traditional Chinese medicine kidney-nourishing formula for Alzheimer's disease in comparison with donepezil: a systematic review and meta-analysis

Fei-Zhou Li1, Yi-Ni Zhang1, Tong Zhang1, Ling Liu2, Ping Wang3*

1Clinical College of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China. 2Encephalopathy Department, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China. 3Institute of Gerontology, Hubei University of Chinese Medicine, Wuhan, China.

*Corresponding to: Ping Wang, Institute of Gerontology, Hubei University of Chinese Medicine, No.1, Huangjiahu West Road, Hongshan District, Wuhan, China. Email: [email protected].

Highlights

Compared with donepezil, the long-term treatment of kidney-nourishing (the change of pathological state of kidney deficiency by means of traditional Chinese medicine (TCM) treatment and so on) formula in TCM can significantly improve the Alzheimer's disease assessment scale-cognitive subscale score and the activities of daily living score.

Traditionality

The description of dementia-related symptoms can be found in historical book entitled Zuo Zhuan (The Spring and Autumn Annals) (722 B.C.E.–468 B.C.E.) in the Pre-Qin Dynasty, and the name of Chidai was first proposed by Sun Simiao in Huatuo Shenyi Mizhuan (Biography of Hua Tuo's Medicine) (618 B.C.E.–907 C.E.), a Chinese medicine classical book published in the Tang Dynasty. The Chinese medicine classical book entitled Huangdi Neijing (The Yellow Emperor's Internal Classic) (221 B.C.E.–220 C.E.) provides a theoretical basis for establishing a link between kidney and dementia. Therefore, nourishing kidney has become an important treatment for dementia by TCM clinicians nowadays.

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 337 doi: 10.12032/TMR20191102145 REVIEW

Abstract Objective: Finding an effective therapy against Alzheimer’s disease (AD) has been associate increasingly pressing issue and traditional Chinese medicine (TCM) is widespread in the prevention and treatment of AD in China. The aim of this study was to judge the efficaciousness and safety of TCM kidney-nourishing (the changes of pathological state of kidney deficiency by means of TCM treatment and so on) formula (TKNF) for AD in comparison with donepezil. Methods: The retrieval period of seven databases was from the establishment of each database to April 2019. Two authors independently identified randomized controlled trials (RCTs), fetched data and assessed bias risk. Comprehensive analysis process was conducted with review manager for eligible and appropriate RCTs. Results: A complete of 981 AD patients from 13 studies were enclosed. Meta-analysis of RCTs showed that there was no significant difference in the improvement of Alzheimer's disease assessment scale-cognitive subscale score between 2 groups in short term, but the effect of long-term treatment may exceed donepezil; there was a significant difference in the improvement of activities of daily living score between 2 groups; there was a significant difference in TCM curative efficacy between 2 groups with long-term treatment. There was no significant difference in the incidence of adverse events between 2 groups. The quality of the evidence was high or moderate. Conclusion: Compared with donepezil, TKNF was an effective drug for AD patients and the clinical application of TKNF was safe. TKNF's long-term benefits need more evidence to verify. Key words: Alzheimer's disease, Traditional Chinese medicine, Kidney-nourishing formula, Donepezil, Systematic review, Meta-analysis

Acknowledgments: This work was supported by a grant from the National Natural Science Foundation of China (No. 81573865). Abbreviations: Aβ, amyloid beta protein; AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s disease assessment scale-cognitive subscale; ADL, activities of daily living; CI, confidence interval; DSM, Diagnostic and Statistical Manual of Mental Disorders; GRADE, Grading of Recommendations Assessment, Development and Evaluation; MD, mean difference; RCTs, randomized controlled trials; RR, risk ratio; TCM, traditional Chinese medicine; TKNF, traditional Chinese medicine kidney-nourishing formula. Competing interests: The authors declare that they have no conflict of interest. The authors alone are responsible for the content of the paper. Citation: Fei-Zhou Li, Yi-Ni Zhang, Tong Zhang, et al. Efficacy and safety of traditional Chinese medicine kidney-nourishing formula for Alzheimer's disease in comparison with donepezil: a systematic review and meta-analysis. Traditional Medicine Research 2020, 5 (5): 337–354. Executive editor: Nuo-Xi Pi.

Submitted: 23 September 2019, Accepted: 25 November 2019, Online: 27 November 2019.

TMR | September 2020 | vol. 5 | no. 5 | 338 Submit a manuscript: https://www.tmrjournals.com/tmr REVIEW doi: 10.12032/TMR20191102145 toxicity and multi-target [8]. Western medicine for Background AD is limited by single-targeted therapy, which may not be suitable for the treatment of AD. So TCM Alzheimer's disease (AD) is seen as a degenerative compound has great potential in preventing and brain disease with a slow and gradual decline in treating AD by multi-link, multi-target, and cognitive function and disposing capacity. The multi-channel integration effect [9]. number of individuals living with dementedness Considering that consensus on diagnosis and worldwide nowadays is calculable at 50 million, 2/3 treatment of AD in TCM recommends the of which are AD, and this figure is predicted to reach kidney-nourishing (the change of pathological state 152 million by 2050. Since global health costs for of kidney deficiency by means of TCM treatment and dementia patients are estimated to reach $1 trillion in so on) therapy as the basic principle for the treatment 2018 and are expected to be doubled by 2030, which of AD [7], we organized this systematic review with implies AD has been identified as one of the world's meta-analysis, to assess the clinical efficacy and health priorities, the growing burden of malady can safety of traditional Chinese medicine challenge the current health care system and national kidney-nourishing formula (TKNF) in AD patients, economy [1, 2]. At the same time, AD has constituted compared with donepezil. a serious threat to human health. The average life span of typical AD patients after diagnosis is just Methods over 101 months or about 8.5 years [3]. In England and Wales, AD has even become the number one This systematic review and meta-analysis adhered to killer of health [1]. Moreover, within the coming the preferred reporting items in systematic reviews back years, the low-income and middle-income and meta-analyses statement [10]. This study has countries are predicted to be the main force in been registered on Prospero platform with an increasing the prevalence of dementia [4], which assigned number CRD42019132880. deserves the eye of researchers. Since 1998, clinical trials of 100 drugs have been Database and search strategies conducted, but solely 4 were approved for the treatment of AD, and these medications can only Two reviewers (Fei-Zhou Li and Yi-Ni Zhang) improve some of the symptoms [1]. Therapy that can independently searched the subsequent electronic alter the potential pathology of AD has not yet been databases from their inception to April 2019: discovered [5]. Donepezil, a cholinesterase inhibitor, Cochrane Central Register of Controlled Trials, is currently recommended as a drug to delay the Excerpta Medica Database, PubMed, China progression of cognitive impairment in AD. Biological Medicine Database, China National Nevertheless, its side effects cannot be ignored [6]. Knowledge Infrastructure, Wanfang Database, Therefore, it is urgent to seek new drugs for the Chinese Scientific Journals Database. The following treatment of AD. search terms were employed in combination: AD is generally diagnosed as Chidai in traditional (Alzheimer's disease OR senile dementia) AND Chinese medicine (TCM) [7]. The description of (traditional Chinese medicine OR kidney-nourishing) dementia-related symptoms can be found in AND (donepezil OR cholinesterase inhibitor OR historical book entitled Zuo Zhuan (The Spring and aricept) AND (randomized controlled trial OR Autumn Annals) (722 B.C.E.–468 B.C.E.) in the controlled clinical trial OR randomized clinical trial). Pre-Qin Dynasty, and the name of Chidai was first The retrieval strategy for PubMed can be found proposed by Sun Simiao in Huatuo Shenyi Mizhuan (Supplementary Table 1). Only Chinese and English (Biography of Hua Tuo's Medicine) (618 B.C.E.–907 documents were included. Besides, the authors also C.E.), a Chinese medicine classical book published hand-searched the reference lists to look for relevant in the Tang Dynasty. For a long time, TCM has been literature. known for its wide variety of herbs and long-standing clinical practice, who accumulated Inclusion criteria and exclusion criteria abundant clinical experience in the struggle against AD. The Chinese medicine classical book entitled Types of participants Huangdi Neijing (The Yellow Emperor's Internal All included participants were definitively diagnosed Classic) (221 B.C.E.–220 C.E.) provides a theoretical with AD according to the Diagnostic and Statistical basis for establishing a link between kidney and Manual of Mental Disorders [11], or dementia. Therefore, nourishing kidney has become Recommendations from the National Institute on an important treatment for dementia by TCM Aging-Alzheimer's Association Work Groups on clinicians nowadays. Compounds extracted from Diagnostic Guidelines for Alzheimer's Disease [12], herbal medicines have been proven to be effective in or Chinese Guidelines for the Diagnosis and alleviating dementia and have the advantages of low Treatment of Alzheimer's Disease or Other Dementia Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 339 doi: 10.12032/TMR20191102145 REVIEW [13], or National Institute of Neurological and sequence generation, allocation concealment, Communicative Diseases and Stroke/Alzheimer's blinding of participants and personnel, blinding of Disease and Related Disorders Association outcome assessment, incomplete outcome data, Alzheimer's Criteria [14]. Studies involving vascular selective reporting, and other bias. Two researchers dementia, frontotemporal degeneration, Lewy body (Fei-Zhou Li and Yi-Ni Zhang) conducted quality dementia and other types of dementia were excluded. evaluations separately, and any divergences were settled through discussions with the third reviewer Types of intervention (Ping Wang). The score ranged from 0 to 7. The intervention of the experimental groups was TKNF, regardless of the dosage, the form and the Data synthesis and statistical analysis course of treatment. The control groups were The Review Manager 5.3 software was implemented interpreted with donepezil. Studies comparing TKNF in statistical analysis [18]. The risk ratio (RR) and with acupuncture, moxibustion, massage, and other the mean difference (MD) were used as combined TCM treatments were excluded. analysis statistics for dichotomous data and continuous data respectively. The confidence interval Types of outcome measures (CI) of each effect variable was expressed in 95% CI. Alzheimer's disease assessment scale-cognitive Chi-square test and I2 index were utilized to test subscale (ADAS-Cog) [15] and activities of daily statistical heterogeneity. When the heterogeneity was living (ADL) scale were the main outcomes we low (P-value > 0.1 and I2 < 50%), a fixed effect chose. TCM curative efficacy and adverse events model was used. If P-value ≤ 0.10 in the were taken as the secondary outcome indicators. heterogeneity test, subgroup analysis or a random Standards for TCM curative efficacy refer to guiding effect model was performed. The descriptive analysis principle of clinical research on new drugs of TCM was conducted when heterogeneousness obviously [16]. existed among studies. In order to evaluate the possible publication bias, a funnel plot was applied. Types of studies The Grading of Recommendations Assessment, The authors included randomized controlled trials Development and Evaluation (GRADE) [19] (RCTs) involving TKNF compared with donepezil in methodology was used to rate the qualities of proof. the treatment of AD. As for differences like age, gender, race, the region of the research, and the blind Results method were not considered in this study. Animal experiments, case reports, and observational studies Studies search and screening results were excluded. Neither the literature without Two thousand seven hundred and sixty-three studies available outcome to analyze nor the republished were retrieved and no other documents were found literature was included in the study. by manual search. Among them, 396 articles were considered duplicates. Two thousand two hundred Study selection and data collection and ninty-two articles were removed by title and Two researchers (Fei-Zhou Li and Yi-Ni Zhang) abstract, including 1,051 animal experiments, 246 independently completed the document retrieval in reviews, 178 summaries of clinical experience, 355 step with the search strategy strictly. Firstly, non-RCTs, and 462 articles utilizing other treatments. according to the title and abstract, the literature For a further step, we screened the remaining 75 full searched were preliminarily screened. After that, texts for further identification, 28 articles were literature that meets the requirements were found for removed with reasons: 19 articles were not real RCTs, further full-text screening. In these processes, the and 9 articles were not TKNF. Thus, the left 47 RCTs reasons for eliminating documents were documented. were evaluated to assess their bias risk. Finally, only Any differences between the 2 were decided by a 13 [20–32] RCTs had a low risk of bias (more than 3 discussion with the third author (Ping Wang). Then, 2 scores) and were ultimately enclosed within the researchers (Fei-Zhou Li and Yi-Ni Zhang) severally meta-analysis (Figure 1). extracted information including the name of the first author, year of publish, title, diagnostic criteria, Quality assessment sample size, mean age, disease duration, intervention, The Cochrane bias risk score of the enclosed studies dose, course of treatment, outcome measurements, ranged from 4 to 7. Included studies were all RCTs, and follow-up time. all of which referred to randomly group. Among them, 11 studies described the distinctive methods of Assessment of risk of bias in individual studies random sequences generation, such as computer Risk bias of each study was evaluated with the tool random, table of random number, etc. And the other provided by the Cochrane Collaboration [17]. The 2 [20, 26] did not mention specific methods. Two judgment of bias risk included seven aspects: random studies [28, 32] implemented the concealment TMR | September 2020 | vol. 5 | no. 5 | 340 Submit a manuscript: https://www.tmrjournals.com/tmr REVIEW doi: 10.12032/TMR20191102145 allocation. One study [21] used a single-blind 144. All studies were carried out in China and mean experimental scheme. Two [28, 32] studies belonged aged 60.88 to 75.36 years. All studies referred to the to double-blind, double-simulated RCTs. One study disease duration before treatment, but 4 [20, 21, 29, [32] conducted a blinded evaluation of the outcome. 32] of them didn’t give the average course of the No other bias was discovered in all enclosed studies. disease. The period of therapy ranged from 40 days The bias summary and the bias for each study show to 6 months. The experimental group was given as below (Figure 2 and Figure 3). TKNF, while the control group was given donepezil. In most studies, the dose of donepezil in the control Study characteristics group was 5 mg, but the dose of donepezil given in Table 1 displays the characteristics extracted from Li, H's study [27] was 10 mg. Follow-up time was the 13 articles included. Two studies [28, 32] were illustrated solely in 1 study [28], which follow-up published in English and the left were issued in from 1 week to 48 week. The authors have listed the Chinese journal. The 13 studies enclosed within the components of prescriptions used in each literature meta-analysis involved 981 patients with AD (499 (Table 2) and briefly analyzed the frequency of each within the experience group and 482 within the component (Table 3). control group), whose sample size ranged from 30 to

Figure 1 Flow chart of study selection process

Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 341 doi: 10.12032/TMR20191102145 REVIEW Clinical efficacy

ADAS-Cog in AD patients Nine studies reported improvement of ADAS-Cog score after intervention, in which Yang [32] did not give exact values. Results of heterogeneity analysis based on the left eight studies were: P < 0.001, I2 = 99%. Thus, a subgroup analysis was conducted in accordance with the course of treatment. Heterogeneity analysis of subgroup were: P = 0.14, I2 = 54%; P < 0.001, I2 = 87%. There was still a large heterogeneity in the third subgroup. After removing Gang’s study [21] and Li, H’s study [27], which were thought of the possible sources of heterogeneousness due to short duration of treatment (40 days) and large dose of donepezil (10 mg), heterogeneity analysis of the left 6 studies were: P = 0.14, I2 = 54%; P = 0.14, I2 = 44%. Thus, we selected a fixed effect model. The results of the meta-analysis (MD = −0.91, 95% CI: −2.94, 1.12, P = 0.38) prompted that there was no significant difference between the experience groups and the control groups in the change of ADAS-Cog score in short-term (12 weeks). However, as the course of treatment extended to 24 weeks or more, there was a significant difference between 2 groups (MD = −1.92, 95% CI: −3.00, −0.83, P = 0.005) (Figure 4).

ADL in AD patients Eleven studies reported improvement of ADL score after intervention. Based on the heterogeneity analysis results (P = 0.05, I2 = 45%), a subgroup analysis was conducted in accordance with the Figure 2 Risk of bias summary course of treatment. The heterogeneity analysis results were: P = 0.13, I2 = 44%; P = 0.31, I2 = 16%. Thus, a fixed effect model was utilized.

Figure 3 Risk of bias graph

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Table 1 Characteristics of the included studies Included Eligibility No. of participants (male) Mean age (year) Disease duration before treatment Intervention drugs Course of Outco- trials criteria Experimental Control Experimental Control Experimental Control Experimental Control treatment mes

DSM-IV Experienced Wang & Donepezil 34 (13) 34 (16) 75.32 ± 7.87 73.38 ± 7.64 NM NM prescription 12 weeks ② 2002 [20] NINCDS- 5 mg KNF ADRDA

DSM-IV Gang & Chinese patent Donepezil 28 (NM) 26 (NM) NM NM NM NM 40 days ①④ 2005 [21] NINCDS- medicine FZS 5 mg ADRDA

Experienced Chen 4.92 ± 3.15 4.70 ± 3.14 Donepezil DSM-IV 37 (20) 30 (16) 73.89 ± 7.32 75.27 ± 7.62 prescription 12 weeks ①②④ 2011 [22] year year 5 mg BYCNT

Experienced Liu NINCDS- 7.95 ± 4.53 7.87 ± 4.54 Donepezil 30 (13) 30 (14) 68.43 ± 8.55 65.60 ± 9.25 prescription 12 weeks ②③④ 2014 [23] ADRDA year year 5 mg JYD

Classicial Pang NINCDS- 26.51 ± 15.8 25.83 ± 14.97 ancient Donepezil 30 (17) 30 (14) 70.9 ± 8.6 71. 5 ± 7.9 12 weeks ①②④ 2014 [24] ADRDA 4 month month prescription 5 mg MYCD DSM-IV Experienced Peng & 6.14 ± 2.41 5.73 ± 2.50 Donepezil 15 (7) 15 (6) 69.87 ± 6.09 69.67 ± 5.92 prescription 4 months ②③④ 2014 [25] NINCDS- year year 5 mg KJG ADRDA Experienced Donepezil Zhang 28.75 ± 14.2 26.72 ± 13.23 prescription 5 mg + DSM-IV 72 (26) 72 (29) 72.79 ± 6.76 72.97 ± 6.59 24 weeks ①②④ 2015 [28] 2 month month YHD + YHD donepezil simulation

Experienced Li,H. NINCDS- 1. 8 ± 0.6 2. 1 ± 0. 5 Donepezil 35 (20) 31 (19) 69. 1 ± 8.3 68. 4 ± 7.2 prescription 6 months ①② 2015 [27] ADRDA year year 10 mg BYD

DSM-IV Li & 4.73 ± 1.24 4.69 ± 1.19 Chinese patent Donepezil ①②③ 52 (30) 52 (32) 68.33 ± 8.54 67.75 ± 8.94 6 months 2015 [26] NINCDS- year year medicine RYT 5 mg ④ ADRDA

Experienced Chen Donepezil ①②③ NIA-AA 43 (18) 43 (16) 69.49 ± 7.08 69.21 ± 6.30 NM NM prescription 6 months 2017 [29] 5 mg ④ HYG

Experienced Donepezil Yang prescription 5 mg + DSM-IV 28 (9) 24 (4) 63.44 ± 6.42 60.88 ± 8.93 NM NM 6 months ①③④ 2018 [32] HYF + HYF donepezil simulation

Classicial NIA-AA Xie 2.78 ± 1.54 2.71 ± 1.54 ancient Donepezil & 48 (20) 48 (21) 74.42 ± 5.83 73.79 ± 5.82; 12 weeks ②④ 2018 [31] year year prescription 5 mg CGDTAD mSYW

NIA-AA Experienced Chi 4.93 ± 1.02 5.27 ± 1.15 Donepezil & 47 (27) 47 (24) 75.36 ± 10.28 74.17 ± 9.31 prescription 24 weeks ①② 2018 [30] year year 5 mg CGDTAD BTYP

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DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Version IV; NIA-AA, National Institute of Aging and Alzheimer's Association; CGDTAD, Chinese Guidelines for the Diagnosis and Treatment of Alzheimer's Disease or Other Dementia; NINCDS-ADRDA, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; NM, not mentioned; KNF, kidney-nourishing formula; FZS, Fu Zhi powder; BYCNT, Buyuan Congnao decoction; JYD, Jianpi Yishen decoction; MYCD, Modified Yiqi Congming decoction; KGJ, Kaixin Jiannao granule; YHD, Yishen Huazhuo decoction; BYD, Bupi Yishen decoction; RYT, Rongjia Yizhi tablets; HYG, Huoling Yizhi granule; HYF, Huannao Yicong formula; mSYW, modified Shuyuwan; BTYP, Bushen Tianjing Yisui prescription; ①: ADAS-Cog, Alzheimer's disease assessment scale-cognitive subscale; ②: ADL, activities of daily living; ③: traditional Chinese medicine curative efficacy; ④: adverse events.

Table 2 The ingredients of each prescription Studies Prescription Constitution Usage Formulation Wang 2002 [20] Experienced Shu Di Huang (Radix rehmanniae 10 mL po bid Oral solution prescription KNF preparata), Gou Qi (Fructus lycii), Shan Zhu Yu (Fructus corni) and so on. Gang 2005 [21] Chinese patent NM. 5 g po bid Powder medicine FZS Chen 2011 [22] Experienced Gou Qi (Fructus lycii) 15 g, He Shou Wu 50 mL po bid Decoction prescription BYCNT (Radix polygoni multiflori) 15 g, Bu Gu Zhi (Fructus psoraleae) 15 g, Rou Cong Rong (Herba cistanches) 15 g, Yi Zhi Ren (Fructus alpiniae oxyphyllae) 15 g, Huang Qi (Radix astragali) 20 g, Shi Chang Pu (Rhizoma acori talarinowii) 15 g, Yu Jin (Radix curcumae) 10 g, Dan Shen (Radix salviae miltiorrhiae) 15 g, Chuan Xiong (Rhizoma chuanxiong) 15 g, Ban Xia (Rhizoma pinelliae) 10g, Shui Zhi (Hirudo) 1 g, Zhi Gan Cao (Radix glycyrrhizae uralensis) 10 g. Liu 2014 [23] Experienced Dang Shen (Radix codonopsis) 30 g, Bai Zhu 200 mL po bid Decoction prescription JYD (Rhizoma atractylodis macrocephalae) 20 g, Shu Di Huang (Radix rehmanniae preparata) 30 g, Gou Qi (Fructus lycii) 20 g, Huang Qi (Radix astragali) 20 g, Shan Yao (Rhizoma dioscoreae) 20 g, Huang Jing (Rhizoma polygonati) 20 g, Dang Gui (Radix angelicae sinensis) 15 g, Chuan Xiong (Rhizoma chuanxiong) 9 g, Dan Shen (Radix salviae miltiorrhiae) 15 g, Fu Ling (Poria) 15 g, Shi Chang Pu (Rhizoma acori talarinowii) 9 g, Yu Jin (Radix curcumae) 9 g, Gan Cao (Radix glycyrrhizae) 6 g. Pang 2014 [24] Classicial ancient Hong Shen (Radix radix ginseng rubra) 15 g, 250 mL po bid Decoction prescription MYCD Huang Qi (Radix astragali) 20 g, Shu Di Huang (Radix rehmanniae preparata) 12 g, Lu Rong (Cornu cervi pantotrichum) 3 g, San Qi (Radix notoRadix ginseng) 15 g, Chen Pi (Pericarpium citri reticulatae) 12 g, Ge Gen (Radix puerariae) 12 g, Huang Bai (Cortex phellodendri) 15 g, Bai Shao (Raidix paeoniae alba) 12 g, Sheng Ma (Rhizoma cimicifugae) 9 g, Zhi Gan Cao (Radix glycyrrhizae uralensis) 6 g.

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Table 2 The ingredients of each prescription (Continued) Peng 2014 [25] Experienced Rou Cong Rong (Herba cistanches) 15 g, One dose po bid Granule prescription KJG Hong Jing Tian (Rhodiolae) 10 g, Jiang Huang (Rhizoma curcumae longae) 10 g, Ren Shen (Radix ginseng) 5 g, Fu Ling (Poria) 15 g, Shi Chang Pu (Rhizoma acori talarinowii) 5 g, Yuan Zhi (Radix polygalae) 10g, Meng Shi (Lapis micas aureus) 2 g. Zhang 2015 [28] Experienced Yin Yang Huo (Herba epimedii) 10 g, Nü 100 mL po qd Granule prescription YHD Zhen Zi (Fructus ligustri lucidi) 10 g, Bu Gu Zhi (Fructus psoraleae) 10 g, He Shou Wu (Radix polygoni multiflori) 10 g, Huang Qi (Radix astragali) 10 g, Chuan Xiong (Rhizoma chuanxiong) 6 g, Shi Chang Pu (Rhizoma acori talarinowii) 6 g. Li, H. 2015 [27] Experienced Shu Di Huang (Radix rehmanniae preparata) One dose po bid Decoction prescription BYD 30 g, Shan Zhu Yu (Fructus corni) 10 g, He /Granule Shou Wu (Radix polygoni multiflori) 15 g, Gou Qi (Fructus lycii) 20 g, Tu Si Zi (Semen cuscutae) 10 g, Yin Yang Huo (Herba epimedii) 15 g, Ren Shen (Radix ginseng) 10 g, Bai Zhu (Rhizoma atractylodis macrocephalae) 15 g, Fu Ling (Poria) 15 g, Shi Chang Pu (Rhizoma acori talarinowii) 10 g, Chuan Xiong (Rhizoma chuanxiong) 10 g, Dang Gui (Radix angelicae sinensis) 10 g. Li 2015 [26] Chinese patent NM. 4 tables po tid Tablet medicine RYT

Chen 2017 [29] Experienced Yin Yang Huo (Herba epimedii), Ci Wu Jia 150 mL po bid Granule prescription HYG (Radix acanthopanacis senticosi), Fu Ling (Poria). Yang 2018 [32] Experienced He Shou Wu (Radix polygoni multiflori), Ren 5 g po bid Granules prescription HYF Shen (Radix ginseng), Chuan Xiong (Rhizoma chuanxiong), Shi Chang Pu (Rhizoma acori talarinowii), Huang Lian (Rhizoma picrorhizae) with a weight ratio of 12:10:9:6:5. Xie 2018 [31] Classicial ancient Shan Yao (Rhizoma dioscoreae) 30 g, Shu Di 15 mL po bid Oral prescription mSYW Huang (Radix rehmanniae preparata) 24 g, solution He Shou Wu (Radix polygoni multiflori) 24 g, Dang Shen (Radix codonopsis) 20 g, Bai Shao (Raidix paeoniae alba) 20 g, Dang Gui (Radix angelicae sinensis) 20 g, Bai Zhu (Rhizoma atractylodis macrocephalae) 18 g, Fu Ling (Poria) 18 g, Gou Qi (Fructus lycii) 18 g, Yuan Zhi (Radix polygalae) 12 g, Du Zhong (Cortex eucommiae) 12 g, Chuan Xiong (Rhizoma chuanxiong) 10 g, Wu Wei Zi (Fructus schisandrae) 10 g, Shi Chang Pu (Rhizoma acori talarinowii) 14 g.

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Table 2 The ingredients of each prescription (Continued) Chi 2018 [30] Experienced Huang Qi (Radix astragali) 30 g, Zi Zhu Cao One dose po qd Decoction prescription BTYP (Folium callicarpae formosanae) 30 g, Dang Shen (Radix codonopsis) 20 g, Yi Yi Ren (Semen coicis) 20 g, He Shou Wu (Radix polygoni multiflori) 18 g, Fu Ling (Poria) 15 g, Shan Zhu Yu (Fructus corni) 15 g, Bu Gu Zhi (Fructus psoraleae) 15 g, Xian Mao (Rhizoma curculiginis) 15 g, Ji Xue Teng (Caulis spatholobi) 15 g, Yin Yang Huo (Herba epimedii) 15 g, Dang Gui (Radix angelicae sinensis) 15 g, Jiao Shan Zha (Fructus crataegi) 15 g, Tu Si Zi (Semen cuscutae) 15 g, Shu Di Huang (Radix rehmanniae preparata) 15 g, Shan Yao (Rhizoma dioscoreae) 15 g, Huang Jing (Rhizoma polygonati) 15 g, Xian He Cao (Herba agrimoniae) 15 g, Fang Feng (Radix saposhnikoviae) 12 g, Lu Jiao Pian (Cornu cervi) 10 g, Di Yu (Raidix sanguisorbae) 10 g, Ba Ji Tian (Radix morindae officinalis) 9 g, Rou Gui (Cortex cinnamomi) 6 g. NM, not mentioned; KNF, kidney-nourishing formula; FZS, Fu Zhi powder; BYCNT, Buyuan Congnao decoction; JYD, Jianpi Yishen decoction; MYCD, Modified Yiqi Congming decoction; KGJ, Kaixin Jiannao granule; YHD, Yishen Huazhuo decoction; BYD, Bupi Yishen decoction; RYT, Rongjia Yizhi tablet; HYG, Huoling Yizhi granule; HYF, Huannao Yicong formula; mSYW, modified Shuyuwan; BTYP, Bushen Tianjing Yisui prescription.

The results of the meta-analysis (MD = −1.67, treatment with TKNF were better than donepezil 95% CI: −2.81, −0.52, P = 0.004; MD = −6.79, 95% (Figure 7). CI: −12.16, −1.42, P = 0.01; MD = −3.24, 95% CI: −4.25, −2.23, P < 0.001) suggested that there was a Adverse events significant difference between the experience groups Adverse events were documented in 10 studies. and the control groups in the change of ADL score, Adverse events of TKNF were mainly manifested as regardless of the treatment course (Figure 5). After nausea, diarrhea, constipation, dry mouth, etc. The eliminating Li, H’s study [27] due to large dose of main adverse events of donepezil included dizziness, donepezil, the result of meta-analysis (MD = −2.89, nausea, loss of appetite, diarrhea, insomnia, etc. The 95% CI: −3.98, −1.80, P < 0.001; heterogeneity P = adverse events in both groups were mild, and no 0.60, I2 = 0%) was in good agreement with those serious life-threatening adverse events were found. before (Figure 6). Nine studies concluded that there was no significant difference between the 2 groups. One study [29] TCM curative efficacy found that adverse events of TKNF had a lower Five studies reported the improvement of TCM incidence than donepezil. syndromes. Based on the heterogeneity test analysis (P = 0.45, I2 = 0%), a fixed effect model was utilized. Publication bias The result (RR = 1.51, 95% CI: 1.28, 1.78, P < 0.001) Owing to the small number of studies, a publication suggested that there was a significant difference bias test for ADAS-Cog and TCM curative efficacy between the experience groups and the control couldnot be conducted. The shape of the funnel plot groups. When subgroup analysis was applied, the for ADL that was slightly asymmetrical indicated a result of meta-analysis (RR = 1.24, 95% CI: 0.94, potential publication bias (Figure 8). 1.63, P = 0.13; RR = 1.33, 95% CI: 0.82, 2.16, P = 0.24) showed that there was no significant difference The quality of the evidence between two groups in short term (12 weeks and 4 On the basis of GRADE criteria, the quality of months). However, the effective rate beyond 24 evidence was assessed as high or moderate. We weeks (RR = 1.64, 95% CI: 1.32, 2.04, P < 0.001) of summarized the results (Table 4).

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Table 3 Frequencies of usage and distribution in traditional Chinese medicine Frequ- Rate Frequ- Rate Frequ- Rate Chinese herbs Chinese herbs Chinese herbs ency (%) ency (%) ency (%) Shi Chang Pu Rou Cong Rong Ji Xue Teng 7 6.19 2 1.77 1 0.88 (Rhizoma Acori Talarinowii) (Herba cistanches) (Caulis spatholobi) Jiang Huang Chuan Xiong Tu Si Zi 6 5.31 2 1.77 (Rhizoma curcumae 1 0.88 (Rhizoma Chuanxiong) (Semen cuscutae) longae) Fu Ling Yu Jin Jiao Shan Zha 6 5.31 2 1.77 1 0.88 (Poria) (Radix curcumae) (Fructus crataegi)

He Shou Wu Yuan Zhi Lu Jiao Pian 6 5.31 2 1.77 1 0.88 (Radix Polygoni Multiflori) (Radix polygalae) (Cornu cervi) Lu Rong Shu Di Huang Zhi Gan Cao 6 5.31 2 1.77 (Cornu cervi 1 0.88 (Radix Rehmanniae preparata) (Radix glycyrrhizae uralensis) pantotrichum) Gou Qi Ba Ji Tian Meng Shi 5 4.42 1 0.88 1 0.88 (Fructus Lycii) (Radix morindae officinalis) (Lapis micas aureus) Chen Pi Huang Qi Nü Zhen Zi 5 4.42 (Pericarpium citri 1 0.88 1 0.88 (Radix Astragali) (Fructus ligustri lucidi) reticulatae) Dang Gui Ci Wu Jia (Radix Rou Gui 4 3.54 1 0.88 1 0.88 (Radix Angelicae Sinensis) acanthopanacis senticosi) (Cortex cinnamomi) Yin Yang Huo Di Yu San Qi 4 3.54 1 0.88 1 0.88 (Herba epimedii) (Raidix sanguisorbae) (Radix notoginseng) Bai Zhu Du Zhong Sheng Ma (Rhizoma Atractylodis 3 2.65 1 0.88 1 0.88 (Cortex eucommiae) (Rhizoma cimicifugae) Macrocephalae)

Bu Gu Zhi Ban Xia Shui Zhi 3 2.65 1 0.88 1 0.88 (Fructus Psoraleae) (Rhizoma pinelliae) (Hirudo) Dang Shen Fang Feng Wu Wei Zi 3 2.65 1 0.88 1 0.88 (Radix Codonopsis) (Radix saposhnikoviae) (Fructus schisandrae)

Ren Shen Gan Cao Xian He Cao 3 2.65 1 0.88 1 0.88 (Radix Ginseng) (Radix glycyrrhizae) (Herba agrimoniae)

Shan Yao Ge Gen Xian Mao 3 2.65 1 0.88 1 0.88 (Rhizoma Dioscoreae) (Radix puerariae) (Rhizoma curculiginis) Yi Zhi Ren Shan Zhu Yu Hong Shen 3 2.65 1 0.88 (Fructus alpiniae 1 0.88 (Fructus Corni) (Radix radix ginseng rubra) oxyphyllae) Bai Shao Hong Jing Tian Yi Yi Ren 2 1.77 1 0.88 1 0.88 (Raidix Paeoniae Alba) (Rhodiolae) (Semen coicis) Zi Zhu Cao Dan Shen Huang Bai 2 1.77 1 0.88 (Folium callicarpae 1 0.88 (Radix salviae miltiorrhiae) (Cortex phellodendri) formosanae) Huang Jing Huang Lian 2 1.77 1 0.88 (Rhizoma polygonati) (Rhizoma picrorhizae)

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Table 4 Quality of evidence by GRADE system

Certainty assessment No of patients Effect

Other No of Study Risk of Inconsi Indirec Imprec Relative Absolute Certainty Importance conside TKNF Donepezil studies design bias -stency -tness -ision (95% CI) (95% CI) -rations

ADAS-Cog MD 1.69 lower Not Not Not 6 RCTs Serious None 263 252 - (2.65 lower to Moderate Critical serious serious serious 0.74 lower) ADL MD 2.4 lower Not Not Not 10 RCTs Serious None 390 379 - (3.18 lower to Moderate Important serious serious serious 1.62 lower) TCM curative efficacy 261 more per RR 1.51 Not Not Not Not 130/168 84/164 1,000 (from 5 RCTs None (1.28 to High Important serious serious serious serious (77.4%) (51.2%) 143 more to 1.78) 400 more) CI, confidence interval; MD, mean difference; No, number; RR, risk ratio; RCTs, randomized controlled trials; TKNF, traditional Chinese medicine kidney-nourishing formula; GRADE, Grading of Recommendations Assessment, Development and Evaluation; ADAS-Cog, Alzheimer's disease assessment scale-cognitive subscale; RCTs, randomized controlled trials; -, not mention.

Figure 4 The comparison of ADAS-Cog between TCM kidney-nourishing formula and donepezil. CI, confidence interval; TKNF, traditional Chinese medicine kidney-nourishing formula; ADAS-Cog, Alzheimer's disease assessment scale-cognitive subscale; TCM, traditional Chinese medicine.

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Figure 5 The comparison of ADL between TCM kidney-nourishing formula and donepezil. CI, confidence interval; TKNF, traditional Chinese medicine kidney-nourishing formula; TCM, traditional Chinese medicine; ADL, activities of daily living.

Figure 6 The comparison of ADL between TCM kidney-nourishing formula and donepezil (without Li, H’s study). CI, confidence interval; TKNF, traditional Chinese medicine kidney-nourishing formula; TCM, traditional Chinese medicine; ADL, activities of daily living.

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Figure 7 The comparison of curative efficacy between TCM kidney-nourishing formula and donepezil. CI, confidence interval; TKNF, traditional Chinese medicine kidney-nourishing formula; TCM, traditional Chinese medicine.

Figure 8 Funnel plot based on ADL. ADL, activities of daily living; MD, mean difference.

TMR | September 2020 | vol. 5 | no. 5 | 350 Submit a manuscript: https://www.tmrjournals.com/tmr REVIEW doi: 10.12032/TMR20191102145 that Icariin has a remarkable memory enhancing effect Discussion [35, 36]. Gou Qi (Fructus lycii) and its extracts are believed Summary of main findings to have the antiaging, neuroprotective, anti-AD, and The main findings of meta-analysis in this paper were antioxidant effects [37, 38]. The mechanism may be as follows: (1) both TKNF and donepezil could related to amyloid beta protein (Aβ). Gou Qi (Fructus improve cognitive impairment in AD patients in terms lycii) extracts can significantly inhibit Aβ fibrillation, of ADAS-Cog score and the improvement of the 2 was decompose the formed Aβ fibrils, decrease Aβ deposits similar in short term (12 weeks). However, when the and Aβ-induced neuro-cytotoxicity in the AD mice [39, duration of treatment was more than or equal to 24 40]. weeks, the effect of TKNF was better than that of In addition, the combination of Shu Di Huang donepezil; (2) regardless of the duration of treatment, (Radix rehmanniae preparata) and Wu Wei Zi (Fructus both TKNF and donepezil could improve the ability schisandrae) can significantly increase the expression carrying out daily activities in AD patients in terms of of SYP, PSD95, BDNF, TrkB and CREB protein ADL score; (3) when it came to TCM syndrome, both related to learning and memory and the content of TKNF and donepezil could improve the TCM curative choline acetyltransferase in the brain, significantly efficacy in AD patients. When the course of treatment reduce the content of acetylcholinesterase, was less than or equal to 12 weeks, the effect of the 2 significantly reduce the content of Aβ 1–40 and Aβ was similar. However, as the course of treatment was 1–42 in the hippocampus or serum, increase the extended to 24 weeks or 6 months, the benefits of expression of Akt protein, and reduce the content of TKNF was superior to donepezil; (4) TKNF was a GSK3β, tau, app and Aβ 1–42 protein expression in relatively safe therapy for AD; (5) the quality of the AD rats model [41]. He Shou Wu (Radix polygoni evidence was moderate or high according to the multiflori) can significantly improve the learning and GRADE. memory ability of AD rat model, which may be improved by increasing the content of miRNA-101 in Summary of major herbals hippocampus [42]. Among the formulations concerned in this study, a total of 53 Chinese herbal medicines were mentioned. Limitations Among them, Shi Chang Pu (Rhizoma acori Firstly, only Chinese and English studies were talarinowii) was used most frequently, which totaling 7 included. Other trials may have been done but not times. After that, the drugs with frequency more than reported, possibly because of negative results. Since or equal to 4 times are Chuan Xiong (Rhizoma this review was restricted to published studies, chuanxiong), Fu Ling (Poria), He Shou Wu (Radix publication bias was hard to avoid. Secondly, in the polygoni multiflori), Shu Di Huang (Radix rehmanniae process of pooling data, the authors did not take into preparata), Gou Qi (Fructus lycii), Huang Qi (Radix account the differences of inclusion criteria, dementia astragali), Dang Gui (Radix angelicae sinensis), Yin seriousness, intervention, dosage, duration of treatment Yang Huo (Herba epimedii). Among them, Yin Yang and outcome measurement among studies, which may Huo (Herba epimedii), Shu Di Huang (Radix potentially bias our results. Thirdly, some detailed data rehmanniae preparata), He Shou Wu (Radix polygoni were not reported in Yang’s study [32], which were multiflori), and Gou Qi (Fructus lycii) are the most also very crucial for our analysis. These insufficient closely related to the tonifying kidney therapy of TCM. data may limit the conclusion of our analysis. In Yin Yang Huo (Herba epimedii) is closely addition, the number of subjects recruited in the trials associated with androgen hormones in TCM. The was relatively small. Finally, these studies generally pharmacological effects of Yin Yang Huo (Herba followed with interest the outcomes of intervention in epimedii) and its compounds on neuroplasticity-related a short period and most of the studies didn’t report the brain functional recovery includes its effect on follow-up period. neurotrophic factors, neurogenesis, synaptic plasticity, and axon and myelin regeneration, which associate Yin Implication for research Yang Huo (Herba epimedii) with brain functional On the one hand, these RCTs confirmed the relatively recovery [33]. Icariin is the main flavonoid in Yin good safety of TKNF and its effectiveness in relieving Yang Huo (Herba epimedii), which has various symptoms in the short-term appliance. However, pharmacological activities, and has a broad application compared with long-term RCTs that are more likely to prospect in the treatment and prevention of AD [34]. provide additional information, short-term trials are of Experiments based on rats model shows that Icariin limited value in assessing the actual clinical influence can alter synthetic plasticity and function through the of TKNF on AD. Thus, future research should pay BDNF/TrkB/Akt pathway by increasing the expression more attention to the long-term effect of TKNF and of BDNF and the photosynthesis of its receptor TrkB deserve a longer follow-up time. On the another, to as well as of Akt and CREB, which provided evidence detect clinically meaningful results, RCTs for TKNF Submit a manuscript: https://www.tmrjournals.com/tmr TMR | September 2020 | vol. 5 | no. 5 | 351 doi: 10.12032/TMR20191102145 REVIEW need to be designed to assess both clinical presentation disease: a systematic review and meta-analysis. J and brain lesions, rather than relying solely on MD in Alzheimers Dis 2014, 41: 615–631. scores between groups, which we can refer to Li’s 7. Tian J, Shi J. Consensus of traditional Chinese study [43]. In addition, recent studies [44, 45] of gut medicine specialists on Alzheimer′s disease. Chin microbiota in AD patients have shown that their J Integr Tradit West Med 2018, 38: 12–18. intestinal flora is different from that of subjects (Chinese) without dementia. Therefore, TCM scholars should 8. Wang Y, Huang LQ, Tang XC, et al. Retrospect also consider adding the detection of gut microbiota in and prospect of active principles from Chinese relevant clinical trials. herbs in the treatment of dementia. Acta Pharmacol Sin 2010, 31: 649–664. Implication for clinical practice 9. Qu X, Diwu Y. Clinical mechanism and research Our results illustrated that TKNF seemed to ameliorate situation of traditional Chinese medicine symptoms in AD patients as well as donepezil, but compound in prevention and treatment of AD. TKNF can be obtained more cheaply and easily, which Liaoning J Tradit Chin Med 2019, 46: 653–656. means that it could be a kind of available alternation (Chinese) for donepezil, particularly in developing countries like 10. Moher D, Liberati A, Tetzlaff J, et al. Preferred China. Besides, based on previous research [46, 47], reporting items for systematic reviews and which showed that conventional therapy has only nine meta-analyses: the PRISMA statement. Ann months of cognitive improvement benefits, the Intern Med 2009, 151: 264–269. long-term benefits of TKNF deserve researchers' 11. APA. Diagnostic and Statistical Manual of Mental attention. Disorders: DSM-IV. American Psychiatric 1994. 12. McKhann GM, Knopman DS, Chertkow H, et al. 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