Slower progression of amyotrophic lateral sclerosis with external application of a Chinese herbal plaster–The randomized, placebo-controlled triple-blinded ALS-CHEPLA trial

外用中藥膏減緩肌萎縮性嵴髓側索硬化症的進展 - 隨機，安慰劑對照三盲 ALS-CHEPLA 試驗

Sven Schröder

Sven Schröder

1HanseMerkur Center for Traditional Chinese Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1,†, Mingzhe Wang

Mingzhe Wang

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2,†, Dandan Sima

Dandan Sima

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2,†, Joana Schröder

Joana Schröder

1HanseMerkur Center for Traditional Chinese Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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1,2, Xuying Zhu

Xuying Zhu

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2, Xuanlu Zheng

Xuanlu Zheng

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2, Lin Liu

Lin Liu

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Department of Neurology, Qinghai Hospital of Traditional Chinese Medicine, Xining, Qinghai, China

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2,3, Tingying Li

Tingying Li

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2, Qiudong Wang

Qiudong Wang

4Department of Integrative Neurology, Pudong Traditional Chinese Medicine Hospital, Shanghai, China

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4, Thomas Friedemann

Thomas Friedemann

1HanseMerkur Center for Traditional Chinese Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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1,*,‡, Te Liu

Te Liu

5Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

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5,*,‡, Weidong Pan

Weidong Pan

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

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2,*,‡

• Author information
• Article notes文章說明
• Copyright and License information
  版權和許可 訊息

1HanseMerkur Center for Traditional Chinese Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

3Department of Neurology, Qinghai Hospital of Traditional Chinese Medicine, Xining, Qinghai, China

4Department of Integrative Neurology, Pudong Traditional Chinese Medicine Hospital, Shanghai, China

5Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Edited by: Jens Schmidt, University Medical Center Göttingen, Germany

Reviewed by: Felipe Patricio, Benemérita Universidad Autónoma de Puebla, Mexico; Ruben Van Eijk, University Medical Center Utrecht, Netherlands

✉

*Correspondence: Weidong Pan panwd@medmail.com.cn

*

Thomas Friedemann Friedemann@tcm-am-uke.de

*

Te Liu liute1979@126.com

This article was submitted to Neuromuscular Disorders and Peripheral Neuropathies, a section of the journal Frontiers in Neurology

†These authors have contributed equally to this work and share first authorship

‡These authors have contributed equally to this work and share senior authorship

Received 2022 Jul 10; Accepted 2022 Sep 13; Collection date 2022.

Copyright © 2022 Schröder, Wang, Sima, Schröder, Zhu, Zheng, Liu, Li, Wang, Friedemann, Liu and Pan.

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PMC Copyright notice

PMCID: PMC9620479  PMID: 36324375

Abstract摘要

Background

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by gradually increasing damage to the upper and lower motor neurons. However, definitive and efficacious treatment for ALS is not available, and oral intake in ALS patients with bulbar involvement is complicated due to swallowing difficulties.
肌萎縮性嵴髓側索硬化症 (ALS) 是一種慢性神經退行性疾病擁有屬性，逐漸增加對上、下運動神經元的損害。然而，目前還沒有明確有效的治療 ALS 的方法，而且由於吞嚥困難，ALS 球部受累患者的口服攝入量是複雜的。

Hypothesis/purpose假設 / 目的

This study investigated whether the external plaster application of the herbal composition Ji-Wu-Li efficiently slows ALS progression because prior studies obtained promising evidence with oral herbal applications.
這項研究調查是否外用石膏的草藥組合物冀五里有效地減緩 ALS 的進展，因為先前的研究獲得了有希望的證據與口服草藥的應用。

Study design

The randomized, triple-blinded study compared the efficacy, safety, and tolerability of the application of Ji-Wu-Li plaster (JWLP) with placebo plaster (PLAP).
本研究採用隨機、三盲對照的方法，比較了雞五理石膏 (JWLP) 與安慰劑石膏 (PLAP) 的療效、安全性和耐受性。

Methods

In total, 120 patients with definite ALS, clinically probable ALS, or clinically probable laboratory-supported ALS were randomized in a 1:1 ratio to receive JWLP or PLAP. Patients were treated and observed for 20 weeks. The primary outcome was the ALSFRS-R score, while the secondary outcomes were the ALS-SSIT score and weight loss.
共有 120 名患有確定性 ALS、臨床可能性 ALS 或臨床可能性實驗室支援的 ALS 的患者以 1:1 的比例隨機接受 JWLP 或 PLAP 治療。對患者進行為期 20 週的治療和觀察。主要結果為 ALSFRS-R 評分，次要結果為 ALS-SSIT 評分和體重減輕。

Results結果

The mean±SD decrease in the ALSFRS-R over 20 weeks differed by 0.84 points in a group comparison (JWLP, −4.44 ± 1.15; PLAP, −5.28 ± 1.98; p = 0.005). The mean increase in the ALS-SSIT over 20 weeks differed by 2.7 points in a group comparison (JWLP, 5.361.15; PLAP, 8.06 ± 1.72; p < 0.001). The mean weight loss over 20 weeks differed by 1.65 kg in a group comparison (JWLP, −3.98 ± 2.61; PLAP, −5.63 ± 3.17; p = 0.002). Local allergic dermatitis suspected as causal to the intervention occurred in 10 of 60 participants in the JWLP group and 9 of 60 participants in the PLAP group. Systemic adverse events were mild, temporary, and considered unrelated to the intervention.
在組比較中，20 週內 ALSFRS-R 的平均值 ± SD 降低差異為 0.84 分 (JWLP，-4.44 ± 1.15; PLAP，-5.28 ± 1.98; p = 0.005)。ALS-SSIT 在 20 週內的平均增加在組比較中差異為 2.7 分 (JWLP，5.361.15; PLAP，8.06 ± 1.72; p < 0.001)。在組比較中，20 週以上的平均體重減輕差異為 1.65 kg (JWLP,-3.98 ± 2.61; PLAP,-5.63 ± 3.17; p = 0.002)。在 JWLP 組的 60 名參與者中有 10 名和 PLAP 組的 60 名參與者中有 9 名被懷疑是當地異位性皮膚炎干預的原因。全身不良事件是輕微的，暫時的，被認為與干預無關。

Conclusion結論

The JWLP showed clinical efficacy in the progression of ALS, as measured by the ALSFRS-R, ALS-SSIT, and weight loss in a randomized, placebo-controlled trial. Because skin reactions occurred in both groups, the covering material needs improvement. All of the Ji Wu Li herbal ingredients regulate multiple mechanisms of neurodegeneration in ALS. Hence, JWLP may offer a promising and safe add-on therapy for ALS, particularly in patients with bulbar involvement, but a confirmative long-term multicentre study is required.
在一項隨機安慰劑對照試驗中，JWLP 顯示了 ALS 進展中的臨床療效，通過 ALSFRS-R，ALS-SSIT 和體重減輕來衡量。因為兩組皮膚都有反應，所以需要改善覆蓋材料。所有集五里草藥成分都調節肌萎縮性側索硬化症的多種神經退行性疾病機制。因此，JWLP 可能提供一個有希望的和安全的治療 ALS 的附加療法，特別是在球部受累的患者，但是一個確認的長期多中心研究是必要的。

Keywords: sporadic amyotrophic lateral sclerosis, RTC, placebo control, herbal plaster, Traditional Chinese Medicine, dysphagia
關鍵詞： 散發性肌萎縮性嵴髓側索硬化症、隨機對照試驗、安慰劑對照、草藥膏、中藥、吞嚥困難

Introduction簡介

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease that gradually results in increased damage to the upper and lower motor neurons (1). Its general characteristics include muscle weakness/atrophy in the oropharynx, limbs, or back muscles, dysarthria, dysphagia, eating difficulty, a choking cough, and dyspnoea (2). These features gravely affect the quality of life and may lead to respiratory failure within 3–5 years from disease onset (3, 4).
肌萎縮性嵴髓側索硬化症 (ALS) 是一種慢性神經退行性疾病，會逐漸增加對上、下運動神經元的損傷 ( 1 )。其一般特徵包括口咽，四肢或背部肌肉的肌肉無力 / 萎縮，構音障礙，吞嚥困難，進食困難，窒息性咳嗽和呼吸困難 ( 2 )。這些特徵嚴重影響生活質量，並可能導致發病後 3-5 年內出現唿吸衰竭 ( 3 ， 4 )。

The pathophysiology of ALS is multifactorial and includes glutamate excitotoxicity (5), neuroinflammation (6), oxidative stress (7, 8), and protein aggregation (9, 10), which lead to mitochondrial dysfunction (8, 11) and apoptosis (12). Axonal transport dysfunction ultimately induces muscle atrophy (13). There is no definitive and efficacious treatment for ALS. The only established drug, riluzole, is mainly effective in the late stages of ALS (14). Moreover, due to adverse events, riluzole discontinuation is necessary for more than 20% of patients (15). Another potential treatment, edaravone, has not been approved in many countries and can only be applied intravenously; it has recently been determined to be ineffective (16). These medications are not reimbursed by insurance in many health systems worldwide.
ALS 的病理生理機制是多因素的，包括谷氨酸興奮毒性 ( 5 )、神經炎症 ( 6 )、氧化應激 ( 7 ， 8 ) 和蛋白質聚集 ( 9 ， 10 ) ，導致線粒體功能障礙 ( 8 ， 11 ) 和細胞凋亡 ( 12 )。軸突運輸功能障礙最終導致肌肉萎縮 ( 13 )。目前還沒有明確和有效的治療 ALS。唯一建立的藥物，利魯唑，主要是有效的晚期 ALS ( 14 )。此外，由於不良事件，利魯唑停藥是必要的超過 20% 的患者 ( 15 )。另一種潛在的治療方法，依達拉奉，在許多國家尚未得到批准，只能通過靜脈注射使用；它最近被確定為無效 ( 16 )。在全世界許多衛生系統中，這些藥物沒有得到保險報銷。

Hence, inexpensive curative or symptomatic therapies with few adverse effects must be identified. Asian research groups have evaluated herbal medicines derived from Traditional Chinese Medicine (TCM) in animal models of ALS (17). Although the concept of ALS does not exist in TCM, a similar syndrome called “flaccidity syndrome, limpness–or atrophy syndrome” was described in the oldest medicinal book, Huangdi Neijing, in the context of tissue and substance loss (in TCM terms, called “Yin deficiency”) (18). Modern Chinese approaches recommend herbal drugs for ALS that are considered to have tonifying and strengthening properties (19–23).
因此，必須確定具有少量不良反應的廉價的治療或對症治療。亞洲研究小組已經在 ALS ( 17 ) 的動物模型中評估了源自中醫的草藥。儘管 ALS 的概念在中醫中不存在，但在最古老的藥典《黃帝內經》中，在組織和物質喪失 (中醫術語稱為 “陰虛”)( 18 ) 的背景下，描述了一種類似的稱為 “軟化綜合徵，跛行或萎縮綜合徵” 的綜合徵。現代中國方法推薦治療 ALS 的草藥被認為具有補益和強化的 屬性 ( 19 - 23 )。

A prior randomized clinical trial applied this concept with the oral administration of the formulation Jia Wei Si Jun-Zi Tang and found a slowing of the symptom progression of ALS in comparison to riluzole (23). The similar augmented herbal formula Ji Wu Li is a modern formula that has its basis on the classical TCM formula Si Jun Zi from the 12th century (24) and adds four herbs (Astragali Radix, Rhodiola Rosea Radix, Cistanche Radix Herba, Epimedii Herba, Table 1).
先前的一項隨機臨床試驗將這一概念應用於加味四君子湯口服給藥，發現與利魯唑 ( 23 ) 相比，ALS 的症狀進展緩慢。類似的補藥方劑冀五里是以 12 世紀中醫經典方劑四君子 ( 24 ) 為基礎，加入黃芪、紅景天、肉蓯蓉、淫羊藿、 Table 1 的現代方劑。

Table 1.表 1。

Herbal ingredients of the Ji Wu li Plaster.

Herbs	Botanical name	Family	Harvesting season	Processing處理
Ginseng Radix
(人蔘)	Root of Panax Jinseng C.A.Mey.	Araliceae	Any season	Dried by sunlight, its head is removed and sliced before use.
在陽光下曬乾，在使用前將其頭部切除。
Astragali Radix
(黃耆)	Root of Astragalus membranaceus (Fisch.) Bunge var mongholicus (Hung) Hsiao
黃芪根	Leguminosae	Spring and Autumn春秋	Sliced and dried with the removal of the head and fine roots
去頭和細根，切片乾燥
Cistanchis Radix Herba
(肉蓯蓉)	Fleshy stem of Cistanche deserticola Y. C. Ma	Orobanchaceae	Spring	Cleaned and cut into thick pieces without inflorescence
清洗後切成厚片，無花序
Atractylodis Macrocephalae Rhizoma
(白術)	Rhizome of Atractylodes macrocephala Koidz.
白術根莖。	Compositae	Winter	Processed by slicing and drying, it is stir-baked until a burnt color is achieved.
通過切片和乾燥處理，它是攪拌烘烤，直到達到燃燒的顏色。
Poria cocos孔雀椰
(茯苓)	Sclerotium of poria cocos (schw) Wolf	Polyporaceae多孔科	From July to September
從七月到九月	Piled repeatedly, dried in the sun.
反覆堆放，在陽光下曬乾。
Glycyrrhizae Radix
(甘草)	Root of Glycyrrhiza uraleusis Fisch	Leguminosae	Autumn	Applied crudely with honey for use after being processed by removing the root, slicing, and drying
加入蜂蜜，經過去根、切片、乾燥處理後使用
Rhodiola Rosea Radix
(紅景天)	Root of Rhodiola rosea L.	Crassulaceae	Autumn	Cleaned and cut into thick pieces without inflorescence
清洗後切成厚片，無花序
Epimedii Herba
(淫羊藿)	Branch and leaf of Epimedium sogittaum (Sieb. Et Zucc.) Maxim.	Berberidaceae	Spring and Autumn春秋	Dried after removal of the stem and other undesired parts. It is used roasted with sheep fat.
去除干莖和其他不需要的部分後烘乾。用於烤羊脂肪。

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However, the oral intake of TCM formulations is complicated in patients with dysphagia because herbal extracts require a larger oral intake than concentrated single-component western drugs. Our ALS study team focused on external herbal medicine in the search for a better application method.
然而，中藥製劑的口服攝入是複雜的患者吞嚥困難，因為草藥提取物需要更大的口服攝入比濃縮單一成分的西藥。我們的 ALS 研究小組集中研究外用中草藥，尋找更好的應用方法。

The external application of Chinese herbs has a long tradition. Since the fourth century, every TCM therapy book has included a chapter on external herbal therapy (25). Modern application forms for transdermal drug delivery include hot-melt adhesive plasters, which allow drug application directly to the skin (26). Mechanisms of external application of herbs include transdermal micro- and macro absorption, local increment of microcirculation, and adjustment of the neural-endocrine-immune network (27). In general, transdermal application reaches comparable efficacy to oral-dosage forms. However, the transdermal application has advantages because transdermal administration avoids the first-pass effect of metabolism associated with the oral route with improved bioavailability. Transdermal administration allows prolonged release, improving patient adherence and minimizing adverse effects due to lower drug peak concentrations (28, 29).
中草藥的外用有著悠久的傳統。自從四世紀以來，每一本中醫治療書籍都包括一章關於外部草藥治療 ( 25 )。經皮給藥的現代應用形式包括熱熔粘合膏，它允許藥物直接應用於皮膚 ( 26 )。藥物外用的機制包括經皮微觀和宏觀吸收，局部增加微循環，調節神經 - 內分泌 - 免疫網路 ( 27 )。一般來說，透皮應用達到與口服劑型相當的效果。然而，經皮給藥具有優勢，因為經皮給藥可以避免與口服途徑相關的代謝的首過效應，從而提高生物利用度。透皮給藥允許延長釋放，改善患者的依從性，並最大限度地減少由於較低的藥物峰值濃度 ( 28 ， 29 ) 的副作用。

Hence, we hypothesized that the external application of herbal medicine could have similar promising effects on the progress of ALS as in the oral application form (23). Furthermore, the advantages of the external application (28, 29) could especially become relevant in ALS patients with bulbar involvement. Accordingly, we performed the present placebo-controlled, randomized, triple-blinded ALS-CHEPLA (ALS-Chinese HErbal PLAster) trial. The study aimed to compare the efficacy, safety, and tolerability of the herbal composition Ji-Wu-Li when applied as a plaster (JWLP, Table 1) and placebo plaster (PLAP) in ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score, a self-reported instrument used to quantify the function of an individual with ALS as the disease progresses. It consists of questions covering gross motor, fine motor, oral motor, and respiratory function and shows good reliability and construct validity (30).
因此，我們假設中草藥的外用對肌萎縮側索硬化症的進展可能具有類似於口服應用形式 ( 23 ) 的有希望的效果。此外，外敷的優點 ( 28 ， 29 ) 可能特別適用於 ALS 患者的球部受累。因此，我們進行了目前的安慰劑對照，隨機，三盲 ALS-CHEPLA (ALS 中藥膏劑) 試驗。本研究旨在比較急性肌萎縮側索硬化 (ALS) 患者中藥複方吉烏力 (JWLP， Table 1 ) 和安慰劑石膏 (PLAP) 的療效、安全性和耐受性。主要結果是肌萎縮性嵴髓側索硬化症評定量表 (ALsFRS-R) 評分，這是一種自我報告的工具，用於量化 ALS 患者在疾病進展過程中的功能。問卷包括大運動、精細運動、口腔運動、呼吸功能等問題，具有良好的信度和結構效度 ( 30 )。

Materials and methods材料和方法

Ethical approval of the study protocol

研究方案的倫理批准

The Ethics Committee (Vote No.: KY-SHSG-2018-540) of Shuguang Hospital, affiliated with the Shanghai University of TCM, approved the study protocol. The study (trial registration number ChiCTR200037353) adhered to the Declaration of Helsinki of 1964 and its later amendments. The full trial protocol can be requested by email from the corresponding author. All patients gave their written informed consent to participate in the study and for data publication.
上海中醫藥大學附屬的 Shuguang Hospital 倫理委員會 (投票號碼： KY-SHSG-2018-540) 批准了該研究方案。這項研究 (試驗註冊號為 ChiCTr200037353) 遵循了 1964 年的赫爾辛基宣言及其後來的修訂。完整的試驗方案可以通過電子郵件從相應的作者要求。所有患者都書面知情同意參加研究並行表資料。

Study design

This single-center, controlled, patient- and observer-blinded, parallel-group randomized trial was conducted at the Department of Neurology within Shuguang Hospital, a specialized center for motor neuron diseases. Interested individuals older than 18 with definite or probable ALS were checked for participation eligibility. Forced vital capacity (FVC) was measured at baseline. In addition, a neurologist obtained a detailed medical history and conducted a neurological examination at baseline and weeks 4, 8, 16, and 20.
這項單中心、對照、患者和觀察者雙盲、平行組的隨機試驗是在曙光醫院神經內科進行的，曙光醫院是運動神經元疾病的專業中心。對年齡在 18 歲以上的確診或可能患有肌萎縮側索硬化症的感興趣個體進行參與資格檢查。用力肺活量 (FVC) 在基線測量。此外，一位神經科醫生獲得了詳細的病史，並在基線和第 4、8、16 和 20 週進行了神經系統檢查檢查。

Inclusion criteria

According to revised El Escorial criteria, patients with clinically definite ALS, clinically probable ALS, or clinically probable laboratory-supported ALS were eligible for inclusion (31).
根據修訂後的 El Escorial 標準，臨床確定的 ALS、臨床可能的 ALS 或臨床可能的實驗室支援的 ALS 患者有資格納入 ( 31 )。

Exclusion criteria

We excluded patients with (i) an FVC < 30%; (ii) signs of a significant psychiatric disorder and/or dementia, acute cholecystitis, or bile duct occlusion; (iii) a concomitant condition considered likely to interfere with drug adherence and outcome assessment; (iv) pregnancy; (v) short expected survival due to disease progression; and (vi) participation in other clinical trials.
我們排除了 (i) FVC <30% 的患者；(ii) 顯著的精神病和 / 或痴呆，急性膽囊炎或膽管閉塞的跡象；(iii) 被認為可能干擾藥物依從性和結果評估的伴隨病症；(iv) 妊娠；(v) 由於疾病進展而短期預期存活；和 (vi) 參與其他臨床試驗。

Recruitment, randomization, and masking

In total, 138 ALS patients were recruited and checked for eligibility; 120 met the inclusion criteria. Immediately after participants gave their written informed consent and before any study-related procedures were undertaken, site staff obtained a participant identification code. Eligible participants were randomly assigned following stratified randomization procedures (computerized random numbers, Microsoft Excel, 2016) at a 1:1 ratio to receive the JWLP (n = 60) or PLAP (n = 60). Randomization was stratified by sex (yes or no); there was no stratification of patients according to disease onset, age, or respiratory function.
總共招募了 138 名 ALS 患者並對其資格進行了檢查，其中 120 名符合納入標準。在參與者書面知情同意之後，在進行任何與研究有關的 程式之前，現場工作人員立即獲得了參與者識別程式碼。符合條件的參與者按照分層隨機化 程式 (電腦化隨機數字，Microsoft Excel，2016) 以 1:1 的比例隨機分配接受 JWLP (n = 60) 或 PLAP (n = 60)。隨機分組按性別 (是或否) 進行分層，沒有根據疾病發作、年齡或呼吸功能對患者進行分層。

An independent randomization center performed the randomization. They informed the study nurse about the number printed beforehand on the study medication batch, which was then connected to the participant's identification code. To achieve masking of random assignments, PLAP was matched to JWLP by appearance and packaging. Clinicians arranged patient treatment according to the participants' identification codes. The study drug was dispensed at baseline and as needed at study visits. Participants, their families, investigators, site staff, the steering committee, and anyone involved in outcome assessments were masked by these identification codes and randomization.
一個獨立的隨機化中心進行了隨機化。他們將預先列印在研究藥物批次上的號碼通知給研究護士，然後將號碼連接到參與者的識別碼上。為了實現隨機分配的掩蔽，PLAP 通過外觀和封裝與 JWLP 進行 對應。臨床醫生根據參與者的識別碼安排患者治療。研究藥物在基線和研究訪視需要時分配。參與者、他們的家人、調查人員、現場工作人員、指導委員會以及任何參與結果評估的人都被這些識別程式碼和隨機性所掩蓋。

Herbal and placebo preparation

草藥和安慰劑製劑

The JWLP contained 32 g of herbs (Ginseng Radix, Astragalus Radix, Cistanche deserticola Herba, Atractylodis macrocephalae Rhizoma, Poria cocos, Glycyrrhizae Radix, Rhodiola rosea Radix, and Epimedii Herba) in a ratio of 2:6:3:2:2:2:2:2. Table 1 describes the botanical name, plant family, part of the plant, harvesting season, and processing methods. The purified raw herbs were crushed and sieved with an 80-mesh sieve. The materials were mixed with 12-g melt adhesive material [including Styrene-isoprene-styrene tertiary block copolymer (35–50%), Styrene-butadiene-styrene tertiary block copolymer (0–5%), naphthenic hydroxyl-based petroleum fractions (softener, 15–20%), C-5, cyclopentadiene and m-pentadiene (Tackifier 1, 30–40%) and esters formed by the reaction of resin acids with glycerol and pentaerythritol (Tackifier 2, 10–20%)]. To complete the plaster, we covered the self-adhesive patch with a layer of heating particles containing iron powder, salt, and activated carbon. Each plaster weighed about 100 g, including 32 g of herbs, 12 g of melt adhesive material, and 52 g of heating particles. Removal of the sealed cover paper activated the heating particles via contact with air; the particles were not in direct contact with the skin. The particles reached 60°C within 20 min and maintained that temperature for at least 5 h.
JWLP 含有 32 克草藥 (人參、黃芪、肉蓯蓉、白術、茯苓、甘草、紅景天和淫羊藿) ，比例為 2:6:3:2:2:2:2:2:2。 Table 1 描述植物學名稱、植物科、植物的一部分、收穫季節和加工方法。將提純的原料藥粉碎，用 80 目篩過篩。該材料與 12g 熔體粘合材料 (包括苯乙烯 - 異戊二烯 - 苯乙烯三元嵌段共聚物 (35-50%)、苯乙烯 - 丁二烯 - 苯乙烯三元嵌段共聚物 (0-5%)、環烷羥基石油餾分 (軟化劑，15-20%)、 C-5、環戊二烯和間戊二烯 (增粘劑 1,30-40%) 以及樹脂酸與甘油和季戊四醇 (增粘劑 2,10-20%) 反應生成的酯類) 混合。為了完成石膏，我們在自貼上貼片上覆蓋了一層含有鐵粉、鹽和活性炭的加熱顆粒。每塊石膏重約 100 克，其中包括 32 克草藥、12 克熔融粘合材料和 52 克加熱顆粒。去除密封的封面紙通過與空氣接觸啟動了發熱顆粒；這些顆粒與皮膚沒有直接接觸。顆粒在 20 分鐘內達到 60 °C，並保持溫度至少 5 小時。

The PLAP was prepared similarly (according to HSFA GB2760-2007, CFDA 2006, No. 120). However, a placebo (23 g soybean powder, 23 g starch, 1 g amaranth red, and 1 g carbon black pigment) replaced the herbal material. The shape, color, weight, and heat function of the PLAP were the same as those of the JWLP, and the plasters and packaging were indistinguishable. Figure 1 shows the different layers of the plaster.
PLAP 的製備方法類似 (根據 HSFA GB2760-2007，CFDA 2006，No. 120)。然而，安慰劑 (23 克大豆粉，23 克澱粉，1 克莧菜紅，1 克碳黑色素) 取代了草藥材料。PLAP 的形狀、顏色、重量和熱功能與 JWLP 相同，石膏和包裝無法區分。 Figure 1 顯示石膏的不同層次。

Figure 1.

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The layers of the Ji-Wu-Li plaster and the placebo.
紀五理石膏的層次與安慰劑。

Application of the JWLP and PLAP

JWLP 和 PLAP 的應用

In the JWLP and PLAP groups, the rectangular 90 × 135-mm plaster was placed on the patient's back in the midline in the depression below the spinous process of the seventh cervical vertebra. Figure 2 demonstrates the plaster position on a patient. The plaster remained in place for 6 h on 6 consecutive days, followed by 1 day of rest to reduce the skin reaction before another cycle of plaster application. The patients continued their regular medical treatment; any treatment changes had to be reported, and no change to a possibly disease-altering therapy was allowed. The description of the quality certificates of the materials of the herbs can be found in the Supplementary material.
在 JWLP 組和 PLAP 組中，將長方形 90 × 135mm 石膏放置在患者背部第七頸椎棘突下方的中線凹陷處。 Figure 2 演示病人的石膏位置。石膏連續 6 天放置 6 小時，然後休息 1 天，以減少皮膚反應，然後再進行一個週期的石膏應用。患者繼續他們的常規治療；任何治療變化必須報告，不允許改變可能的疾病改變治療。草藥材料的質量證書描述可以在 Supplementary material 中找到。

Figure 2.

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Positioning of the JWLP and the PLAP in an ALS patient.
肌萎縮側索硬化患者 JWLP 和 PLAP 的定位。

Primary outcome

The primary outcome was the ALSFRS-R (30). The minimum score is 0, and the maximum is 48. The lower the score, the more function is affected. A clinical neurologist assessed ALSFRS-R by interviewing the patient at baseline and weeks 4, 8, 16, and 20. The prespecified primary endpoint was 20 weeks from the baseline assessment.
主要結果是 ALSFRS-R ( 30 )。最低分是 0，最高分是 48。分數越低，受影響的功能越多。臨床神經科醫師通過在基線和第 4、8、16 和 20 週訪談患者來評估 ALSFRS-R。預先設定的主要終點為基線評估後 20 週。

Secondary outcomes

The recently introduced ALS-SSIT (Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatments) is a clinical score reflecting the quality of life. The higher the score (a maximum score of 40), the more severe the impairment. The ALS-SSIT score has recently been validated to reflect the change in disease severity (32). A clinical neurologist assessed ALS-SSIT by interviewing the patient at baseline and weeks 4, 8, 16, and 20. A study nurse documented the participants' weight with a calibrated scale at each visit at baseline and weeks 4, 8, 16, and 20. Red blood cell count, biochemistry, kidney/liver function, and electrocardiography were assessed at baseline and trial cessation. Safety was evaluated as the prevalence and severity of adverse events and their relationship with the treatment were determined based on the results of laboratory tests, patient reports, and the judgement of the principal investigator.
最近推出的 ALS-SSIT (綜合治療中的肌萎縮性嵴髓側索硬化症症狀評分) 是反映生活質量的臨床評分。分數越高 (最高分為 40 分) ，損害越嚴重。ALS-SSIT 評分最近得到驗證，以反映疾病嚴重程度的變化 ( 32 )。臨床神經科醫師通過在基線和第 4、8、16 和 20 週訪談患者來評估 ALS-SSIT。一名研究護士在基線和第 4、8、16 和 20 週的每次訪視中用校準的體重表記錄參與者的體重。在基線和試驗停止時評估紅細胞計數、生化、腎 / 肝功能和心電掃描器。根據實驗室檢測結果、患者報告和學術帶頭人的判斷，評估不良事件的發生率和嚴重程度以及它們與治療的關係是否安全。

Sample size樣本大小

The sample size was calculated for a two-sided t-test comparing the difference between two independent means using a 1:1 allocation, an alpha of 0.05, and a power of 0.8. An effect size of 0.52 was calculated based on a previous study (TCM group 3.8 ± 4.9 and control group 7.3 ± 8.2) (23). GPower 3.1.9.4 was used for the sample size calculation. The results revealed that 120 patients were needed, 60 in the control group and 60 in the treatment group.
樣本量用雙側 t 檢驗計算，比較兩個獨立平均值之間的差異，使用 1:1 分配，alpha 為 0.05，冪為 0.8。根據以前的研究 (TCM 組 3.8 ± 4.9 和對照組 7.3.8.2)( 23 ) 計算效應大小為 0.52。G 冪 3.1.9.4 用於樣本大小計算。結果顯示，需要 120 例患者，對照組 60 例，治療組 60 例。

Statistical analysis

Statistical analysis followed the intention-to-treat principle. All randomized participants were analyzed. To have an unbiased analysis, we used a complete data set for the primary analysis [JWLP (n = 60), PLAP (n = 60)]. Imputation of missing data followed an individualized decision based on predictive parameters for the missing cases. The ALSRFS-R progression rate (ΔFS' = 48–Total ALSFRS–R score at the assessment on test date/Time from onset of symptoms to assessment on test date) (33) was used to calculate the missing values by carrying the last observed progression rate forward.
統計分析遵循意向性治療原則。所有隨機參與者進行分析。為了進行無偏分析，我們使用了完整的資料集進行初步分析 [JWLP (n = 60) ，PLAP (n = 60)]。缺失資料的填補遵循基於缺失案例預測參數的個性化決策。使用 ALSRFS-R 進展率 (ΔFS’= 48 - 總 ALSFRS-R 評分在測試日期 / 從症狀發作到測試日期評估的時間)( 33 ) 通過攜帶最後觀察到的進展速率來計算缺失值。

Repeated-measures ANOVA was conducted to test the differences among changes in outcomes at baseline and 4, 8, 12, 16, and 20 weeks of treatment for both groups. In addition, differences at baseline and the delta from baseline to endpoint between the JWLP and PLAP were analyzed using the Student's t-test. p-value < 0.05 was considered significant. SPSS 17.0 (IBM, Armonk, NY, USA) was used for statistical analyses. Data are reported as the mean ± standard deviation.
重複測量方差分析用於測試兩組在基線和 4、8、12、16 和 20 週治療後結果變化的差異。此外，使用學生 t 檢驗分析了 JWLP 和 PLAP 在基線和基線到終點之間的差異。P 值 <0.05 被認為是顯著的。使用 SPSS 17.0 (IBM，Armonk) 進行統計分析。資料以平均值 ± 標準差表示。

Results結果

Figure 3 shows the CONSORT flowchart. Between July 2017 and November 2021, 138 consecutive patients were screened for eligibility, of whom 11 were excluded because they did not meet the inclusion criteria or because they met an exclusion criterion. Of the remaining 127 patients, 120 were enrolled in the trial; seven patients declined to participate.
Figure 3 顯示 CONSORT 流程圖。在 2017 年 7 月至 2021 年 11 月期間，連續 138 名患者接受了資格篩查，其中 11 名因為不符合納入標準或因為符合排除標準而被排除在外。其餘 127 名患者中，120 名參加了試驗；7 名患者拒絕參加。

Figure 3.

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CONSORT flow diagram of the ALS-CHEPAL trial. Intent-to-treat principle, all randomized participants were analyzed.
CONSORT 的 ALS-CHEPAL 試驗流程圖。 意向治療原則，所有隨機參與者進行了分析。

Basic characteristics

All ALS cases were sporadic. There were no significant differences in sex, age, body weight, onset time of morbidity, disease progression, FVC, ALSFRS-R, or ALS-SSIT between the two groups at baseline. Thirty-three participants in the JWLP group and 37 in the PLAP group had involvement of the limbs only, 13 in the JWLP group and 12 in the PLAP group had involvement of the bulbar only, and 14 in the JWLP group and 11 in the PLAP group had involvement of both the limbs and the bulbar region. Table 2 presents the basic characteristics.
所有肌萎縮側索硬化病例均為散發性。兩組患者的性別、年齡、體重、發病時間、疾病進展、 FVC、 ALSFRS-R 或 ALS-SSIT 在基線時均無顯著性差異。JWLP 組 33 例，PLAP 組 37 例，僅累及四肢，JWLP 組 13 例，PLAP 組 12 例，僅累及球部，JWLP 組 14 例，PLAP 組 11 例。 Table 2 顯示基本特徵。

Table 2.表 2。

Characteristics of the JWLP and PLAP groups.
JWLP 和 PLAP 組的特點。

Therapy心理治療		JWLP	PLAP
Subjects實驗對象	n	60	60
Female/male sex	n	24/36	24/36
Age (years)年齡 (歲)	Mean/Sd	54.9 ± 7.97	53.87 ± 8.53
Duration of the disease (month)
病程 (月份)	Mean/SD	16.45 ± 5.92	15.62 ± 5.09
ALSFRS-R (48 point scale)
ALSFRS-R (48 分制)	Mean/SD	38.53 ± 1.99	38.50 ± 1.52
ALS-SSIT (40-point scale)	Mean/SD	20.47 ± 1.94	20.0 ± 1.76
Body weight (kg)	Mean/SD	60.45 ± 6.97	61.09 ± 6.41
Δ FS' (ALSFRS-R points/month)**	Mean/SD	0.64 ± 0.25	0.67 ± 0.24
Limbs only只有四肢	n	33	37
Bulbar only	n	13	12
Limbs and bulbar	n	14	11
Primary therapy初級治療
Riluzole	n	27	26
Edavarone	n	1	1
Riluzole + Edavarone	n	23	24
No specific ALS therapy	n	9	9
FVC (%)	Mean/SD	91.8/14.9	92.2/10.9

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**ALSFRS-R progression rate; FVC, Forced Vital Capacity.

• • ALSFRS-R 進展率；FVC，用力肺活量。

Discontinuation of the trial

終止審判

Forty-seven participants in each group completed the entire 20-week observation period. Discontinuation for personal reasons occurred in four JWLP participants (two before the 16th week and two before the 20th week) and three PLAP participants (one each before the 8th, 16th, and 20th weeks). One JWLP patient (before the 8th week) and one PLAP patient (before the 20th week) decided to participate in another trial. One patient died before the 16th week in the JWLP group, as well as three participants in the PLAP group, two before the 16th week (one for disease progression and one for pneumonia) and one before the 20th week. Discontinuation due to non-tolerable adverse effects occurred in seven JWLP participants (two before the 8th week, three before the 16th week, and two before the 20th week) and four PLAP participants (one before the 8th week and three before the 16th week).
每組 47 名參與者完成了整個 20 週的觀察期。四名 JWLP 參與者 (第 16 週之前兩名，第 20 週之前兩名) 和三名 PLAP 參與者 (第 8,16 th 和第 20 週之前各一名) 因個人原因停藥。一名 JWLP 患者 (第 8 週前) 和一名 PLAP 患者 (第 20 週前) 決定參加另一項試驗。JWLP 組中有一名患者在第 16 週之前死亡，PLAP 組中有三名參與者，第 16 週之前兩名 (一名為疾病進展，一名為肺炎) ，第 20 週之前一名。7 名 JWLP 參與者 (第 8 週之前 2 名，第 16 週之前 3 名，第 20 週之前 2 名) 和 4 名 PLAP 參與者 (第 8 週之前 1 名，第 16 週之前 3 名) 由於不可耐受的不良反應而停藥。

Efficacy功效

Primary outcome

ALSFRS-R

In the JWLP group, the ALSFRS-R continuously declined from baseline (38.53 ± 1.99) to week 4 (37.53 ± 2.35), week 8 (36.34 ± 2.27), week 12 (35.72 ± 2.22), week 16 (35.12 ± 2.24), and week 20 (34.09 ± 2.19). In the PLAP group, the ALSFRS-R also continuously declined from baseline (38.50 ± 1.53) to week 4 (37.60 ± 1.78), week 8 (35.50 ± 1.66), week 12 (34.94 ± 1.68), week 16 (34.24 ± 2.17), and week 20 (33.21 ± 2.30).
在 JWLP 組中，ALSFRS-R 從基線 (38.53 ± 1.99) 持續下降到第 4 週 (37.53 ± 2.35) ，第 8 週 (36.34 ± 2.27) ，第 12 週 (35.72.2.22) ，第 16 週 (35.12.2.24) 和第 20 週 (34.09 ± 2.19)。在 PLAP 組中，ALSFRS-R 也從基線 (38.50 ± 1.53) 持續下降到第 4 週 (37.60 ± 1.78) ，第 8 週 (35.50 ± 1.66) ，第 12 週 (34.94 ± 1.68) ，第 16 週 (34.24.2.17) 和第 20 週 (33.21 ± 2.30)。

The differences between the JWLP and PLAP were −0.03 at baseline (t = 0.09, 95% CI −0.71 to 0.78, p = 0.930), 0.07 after 4 weeks (t = 0.175, 95% CI −0.81 to 0.68, p = 0861), −0.84 after 8 weeks (t = 2.22, 95% CI 0.10 to 1.59, p = 0.027), −0.78 after 12 weeks (t = 2.05, 95% CI 0.03 to 1.52, p = 0.042), −0.87 after 16 weeks (t = 2.30, 95% CI 0.13 to 1.62, p = 0.022) and −0.87 after 20 weeks (t = 2.30, 95% CI 0.26 to 1.43, p = 0.022). Figure 4 summarizes these data. The mean decreases from baseline to the 20th week (Δbaseline to 20th week) were −4.44 ± 1.15 in the JWLP group and −5.28 ± 1.98 in the PLAP group (difference of 0.84 points, p = 0.005).
JWLP 和 PLAP 之間的差異在基線時為 -0.03 (t = 0.09,95% CI-0.71 至 0.78，p = 0.930) ，4 週後為 0.07 (t = 0.175,95% CI-0.81 至 0.68，p = 0861) ，8 週後為 -0.84 (t = 2.22,95% CI 0.10 至 1.59，p = 0.027),-12 週後 0.78 (t = 2.05,95% CI 0.03 至 1.52，p = 0.042) ,-16 週後為 0.87 (t = 2.30,95% CI 0.13 至 1.62，p = 0.022) ，20 週後為 -0.87 (t = 2.30,95% CI 0.26 至 1.43，p = 0.022)。 Figure 4 總結這些資料。JWLP 組從基線到第 20 週的平均降低 (Δ 基線至第 20 週) 為 -4.44 ± 1.15，PLAP 組為 -5.28 ± 1.98 (差異 0.84 分，p = 0.005)。

Figure 4.

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Change over time in the ALSFRS-R over the 20 week trial period. *p < 0.05, *p < 0.01.
在 20 週的試驗期間，ALSFRS-R 隨時間的變化。 p < 0.05， p < 0.01。

Secondary outcomes

ALS-SSIT

In the JWLP group, the ALS-SSIT continuously increased from baseline (20.47 ± 1.94) to week 4 (21.4 ± 2.13), week 8 (23.54 ± 1.82), week 12 (24.22 ± 1.85), week 16 (25.12 ± 1.94), and week 20 (25.83 ± 2.02). In the PLAP group, the ALS-SSIT continuously increased from baseline (20.00 ± 1.76) to week 4 (21.02 ± 1.80), week 8 (24.96 ± 1.87), week 12 (25.91 ± 1.84), week 16 (27.07 ± 2.07), and week 20 (28.06 ± 2.20). The increase in both groups was statistically significant for every 4 weeks compared to the previous score and baseline (p < 0.01).
在 JWLP 組中，ALS-SSIT 從基線 (20.47 ± 1.94) 持續增加到第 4 週 (21.4.2.13) ，第 8 週 (23.54 ± 1.82) ，第 12 週 (24.22.1.85) ，第 16 週 (25.12.1.94) 和第 20 週 (25.83 ± 2.02)。在 PLAP 組中，ALS-SSIT 從基線 (20.00 ± 1.76) 持續增加到第 4 週 (21.02 ± 1.80) ，第 8 週 (24.96 ± 1.87) ，第 12 週 (25.91 ± 1.84) ，第 16 週 (27.07 ± 2.07) 和第 20 週 (28.06 ± 2.20)。與之前的評分和基線相比，兩組患者每 4 週的增加有統計學意義 (p < 0.01)。

The differences between the JWLP and PLAP groups were 0.47 at baseline (t = 1.32, 95% CI −0.23 to 1.16, p = 0.188), 0.38 after 4 weeks (t = 1.08, 95% CI −0.31 to 1.08, p = 0.280), −1.42 after 8 weeks (t = 4.01, 95% CI −2.12 to −0.73, p < 0.001), −1.69 after 12 weeks (t = 4.77, 95% CI −2.38 to −0.99, p < 0.001), −1.96 after 16 weeks (t = 5.52, 95% CI −2.65 to −1.26, p < 0.001) and −2.23 after 20 weeks (t = 6.30, 95% CI −2.93 to −1.54, p < 0.001). Figure 5 summarizes these results. The increases in the ALS-SSIT within 20 weeks were 5.36 ± 1.15 points in the JWLP group and 8.06 ± 1.72 points in the PLAP group (difference of 2.7 points, p < 0.001).
JWLP 組和 PLAP 組之間的差異在基線時為 0.47 (t = 1.32,95% CI-0.23 至 1.16，p = 0.188) ，4 週後為 0.38 (t = 1.08,95% CI-0.31 至 1.08，p = 0.280) ，-8 週後為 1.42 (t = 4.01,95% CI-2.12 至 -0.73，p < 0.001)，12 週後 -1.69 (t = 4.77,95% CI-2.38 至 -0.99，p < 0.001) ,- 16 週後 1.96 (t = 5.52.95% CI-2.65 至 -1.26，p < 0.001) 和 20 週後 -2.23 (t = 6.30,95% CI-2.93 至 -1.54，p < 0.001)。 Figure 5 總結了這些結果。20 週內 ALS-SSIT 的增加在 JWLP 組為 5.36 ± 1.15 分，PLAP 組為 8.06 ± 1.72 分 (差異 2.7 分，p < 0.001)。

Figure 5.

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Change over time in the ALS-SITT over the 20 week trial period. *p < 0.01.
ALS-SITT 在 20 週試驗期間隨時間變化。 * p < 0.01。

Weight

In the JWLP group, the mean weight continuously declined from baseline (60.5 ± 6.97) to week 4 (59.58 ± 6.87), week 8 (58.01 ± 6.91), week 12 (57.72 ± 7.15), week 16 (57 ± 7.50), and week 20 (56.58 ± 7.54). In the PLAP group, the weight continuously declined from baseline (61.09 ± 6.41) to week 4 (60.07 ± 6.42), week 8 (58.03 ± 6.30), week 12 (57.37 ± 6.49), week 16 (56.64 ± 6.77), and week 20 (55.46 ± 6.86). The decrease in both groups was statistically significant for every 4 weeks compared to the previous measurement and baseline (p < 0.01). The difference between the JWLP and PLAP was not statistically significant at any measurement point. The mean weight decreases from baseline to week 20 were −3.98 ± 2.61 kg in the JWLP group and −5.63 ± 3.17 kg in the PLAP group (difference of 1.65 kg, p = 0.002). Figure 6 summarizes these findings. The results of the ALSFRS-R, ALSSITT, and weight are summarized in Table 3.
在 JWLP 組中，平均體重從基線 (60.5 ± 6.97) 持續下降到第 4 週 (59.58 ± 6.87) ，第 8 週 (58.01 ± 6.91) ，第 12 週 (57.72 ± 7.15) ，第 16 週 (57.7.50) 和第 20 週 (56.58 ± 7.54)。在 PLAP 組中，體重從基線 (61.09 ± 6.41) 持續下降到第 4 週 (60.07 ± 6.42) ，第 8 週 (58.03 ± 6.30) ，第 12 週 (57.37 ± 6.49) ，第 16 週 (56.64 ± 6.77) 和第 20 週 (55.46.6.86)。與之前的測量值和基線值相比，兩組患者每 4 週的下降有統計學意義 (p < 0.01)。在任何測量點，JWLP 和 PLAP 之間的差異均無統計學意義。從基線到第 20 週的平均體重下降在 JWLP 組為 -3.98 ± 2.61 kg，PLAP 組為 -5.63 ± 3.17 kg (差異 1.65 kg，p = 0.002)。 Figure 6 總結了這些發現。ALSFRS-R、 ALSSITT 和重量的計算結果總結在 Table 3 中。

Figure 6.

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The development of the weight over the 20 week trial period. *p < 0.01.
體重在 20 週試驗期間的變化。 * p < 0.01。

Table 3.表 3。

ALSFRS-R, ASL-SSIT, and weight over 20 weeks.
ALSFRS-R，ASL-SSIT，體重超過 20 週。

ASLFRS-R		JWLP	SD	PLAP	SD	Difference區別	95% CI	t-value	df	P-value
ASLFRS-R
(48 items score)	Baseline	38.53	1.99	38.50	1.53	−0.03- 0.03	−0.71–0.78-0.71 -0.78	0.09	590	0.930
	4th week	37.53	2.35	37.60	1.78	0.07	−0.81–0.68- 0.81-0.68	0.175	590	0.861
	8th week	36.34	2.27	35.50	1.66	−0.840.84	0.10–1.590.10-1.59	2.22	590	0.027
	12th week	35.72	2.22	34.94	1.68	−0,78- 0.78	0.03–1.520.03-1.52	2.05	590	0.042
	16th week	35.12	2.24	34.24	2.17	−0.870.87	0.13–1.620.13-1.62	2.30	590	0.022
	20th week	34.09	2.19	33.22	2.61	−0.870.87	0.13–1.610.13-1.61	2.30	590	0.022
	Δ baseline to 20th week	−4.44- 4.44	1.15	−5.28- 5.28	1.98	−0.840.84	0.26–1.430.26-1.43	2.85	118	0.005
ALS-SSIT
(40 items score)	Baseline	20.47	1.94	20.00	1.76	0.47	−0.23–1.16- 0.23-1.16	1.32	590	0.188
	4th week	21.40	2.13	21.02	1.80	0.38	−0.31–1.08-0.31-1.08	1.08	590	0.280
	8th week	23.55	1.83	24.97	1.87	−1.42- 1.42	−2.21−0.73- 2.21-0.73	4.01	590	< 0.001
	12th week	24.24	1.87	25.93	1.83	−1.69- 1.69	−2.38–0.99- 2.38-0.99	4.77	590	< 0.001
	16th week	25.15	1.99	27.10	2.06	−1.96- 1.96	−2.65−1.26- 2.65-1.26	5.52	590	< 0.001
	20th week	25.87	2.09	28.10	2.19	−2.23- 2.23	−2.93−1.54- 2.93-1.54	6.3	590	< 0.001
	Δ baseline to 20th week	5.36	1.15	8.06	1.72	2.7	2.17–3.232.17-3.23	10.11	118	< 0.001
Weight (kg)	Baseline	60.56	6.97	61.09	6.41	−0.53-0.53	−2.99–1.93- 2.99-1.93	0.43	590	0.670
	4th week	59.58	6.87	60.07	6.42	−0.48-0.48	2.94–1.982.94-1.98	0.39	590	0.670
	8th week	58.02	6.91	58.03	6.30	−0.01- 0.01	2,47–2.452.47-2.45	0.01	590	0.995
	12th week	57.72	7.15	57.37	6.49	0.35	−2.11–2.802.11-2.80	0.28	590	0.782
	16th week	57.51	7.45	56.64	6.77	0.87	−1.59–3.33- 1.59-3.33	0.69	590	0.489
	20th week	56.58	7.54	55.46	6.87	1.11	−1.35–3.57- 1.35-3.57	0.89	590	0.375
	Δ baseline to 20th week	−3.983.98	2.61	−5.63- 5.63	3.17	1.65	0.59–2.700.59-2.70	3.10	118	0.002

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Safety

Allergic dermatitis under the plaster as an adverse event with a suspected causal relationship to intervention occurred in 10 of 60 JWLP group patients (16, 70%) and 9 of 60 PLAP group patients (8.33%) (df = 2, p = 0.098). Allergic dermatitis, though moderate and local, was not tolerable in seven JWLP participants (11.6%) and five PLAP participants (8.3%) (df = 2, p = 0.34) and caused discontinuation of the therapy (dropout). After cessation of the plaster treatment, all skin symptoms completely recovered and disappeared within weeks.
在 60 名 JWLP 組患者中有 10 名 (16,70%) 和 60 名 PLAP 組患者中有 9 名 (8.33%)(df = 2，p = 0.098) 發生異位性皮膚炎，懷疑與干預有因果關係。異位性皮膚炎雖然是中度和局部的，但在 7 名 JWLP 參與者 (11.6%) 和 5 名 PLAP 參與者 (8.3%)(df = 2，p = 0.34) 中不能耐受，並導致治療中止 (輟學)。停止石膏治療後，所有皮膚症狀完全恢復，並在數週內消失。

Temporary mild adverse events (fever, sore throat, nausea, and constipation) occurred in a minority of both groups and were considered unrelated to intervention, or a causal relationship was not assessable. No treatment-related changes in normal blood levels (red blood cells, hemoglobin, haematocrit, platelets, white blood cells, creatinine, blood urea nitrogen, y-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and electrolytes), or alterations in the electrocardiogram related to treatment were detected.
臨時性輕微不良事件 (發燒，喉嚨痛，噁心，便秘) 發生在兩組中的少數，被認為與干預無關，或因果關係無法評估。正常血液水平 (紅細胞，血紅蛋白，血細胞比容，血小板，白細胞，肌酐，尿素氮，谷氨酰轉移酶，丙氨酸轉氨酶，天冬氨酸轉氨酶和電解質) 沒有與治療相關的變化，或與治療相關的心電圖的變化被檢測到。

Table 4 summarizes the adverse events.
Table 4 彙總不良事件。

Table 4.表 4。

Adverse events by MedDRA preferred terms and by treatment group.
按 MedDRA 優先術語和治療組分列的不良事件。

	JWLP	PLAP	Comparison of the number of 數目的比較
	group小組	group小組	events in-between groups
---	:-:	:-:	:-:
Event type	Subjects n/60實驗對象 n/60	**Events mild/moderate/severe
輕度 / 中度 / 重度事件**	Subjects n/60實驗對象 n/60	**Events mild/moderate/severe
輕度 / 中度 / 重度事件**	P-value Df = 2
:--	:-:	:-:	:-:	:-:	:-:
**Adverse events with a suspected causal relationship to intervention
懷疑與干預有因果關係的不良事件**
Local† allergic dermatitis	10
(16.7%)	3/7*/0	9
(15%)	4/5*/0	0.80
**Adverse events unrelated to intervention or causal relationship not assessable
與干預無關的不良事件或不可評估的因果關係**
Temporary fever	12
(20%)	12/0/0	11
(18.3%)	11/0/0	0.18
Temporary sore throat	8
(13.3%)	8/0/0	9
(15%)	9/0/0	0.25
Temporary nausea	11
(18.3%)	11/0/0	9
(15%)	9/0/0	0.17
Temporary constipation暫時性便秘	9
(15%)	9/0/0	7
(11.7%)	7/0/0	0.21

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†On the plaster application site, local skin reaction requires local symptomatic treatment with full recovery after ending of plaster application (study dropout).
† 在塗抹石膏的地方， 局部皮膚反應需要局部對症治療在塗抹石膏結束後完全恢復 (學習輟學)。

Discussion討論

To our knowledge, this is the first randomized, controlled, triple-blinded study of external herbal treatment for ALS. We used the ALSFRS-R score as the primary outcome, which is considered the gold standard for the staging and functional measurement of disease progression (34, 35) and comparison with newly proposed scales (36, 37). In our study, the decrease in the ALS-FRS-R was significantly lower in the JWLP group than in the PLAP group from the eighth week until the final examination after 20 weeks.
據我們所知，這是第一個隨機，對照，三盲研究的外部草藥治療 ALS。我們使用 ALSFRS-R 評分作為主要結果，這被認為是疾病進展分期和功能測量的金標準 ( 34 ， 35 ) ，並與新提出的量表 ( 36 ， 37 ) 進行比較。在我們的研究中，從第 8 週到 20 週後的最終檢查，JWLP 組 ALS-FRS-R 的降低明顯低於 PLAP 組。

Additionally, we examined the ALS-SSIT score as a secondary outcome. The ALS-SSIT is focused on patients' quality of life and is approved due to its feasibility, reliability, validity, and sensitivity (38). Like the ALSFRS-R, the difference between the two groups was statistically significant from the eighth week onwards but became more pronounced thereafter until the endpoint. The higher measurement sensitivity of the differences and the focus on the quality of life suggests that the ALS-SSIT should be considered in future ALS studies. Furthermore, we examined weight as an observer-independent marker of cachexia. The mean weight loss for the period of 20 weeks was 1.65 kg higher in the PLAP group than in the JWLP group, which was statistically significant.
此外，我們檢查 ALS-SSIT 評分作為次要結果。ALS-SSIT 主要關注患者的生活質量，因其可行性、信度、效度和靈敏度 ( 38 ) 而獲得批准。像 ALSFRS-R 一樣，兩組之間的差異從第八週開始在統計學上是顯著的，但是在終點之前變得更加明顯。對差異較高的測量靈敏度和對生活質量的關注提示 ALS-SSIT 應該在未來 ALS 研究中考慮。此外，我們檢查了體重作為一個觀察者無關的惡病質標誌物。PLAP 組 20 週的平均體重減輕量比 JWLP 組高 1.65 kg，具有統計學意義。

One novelty of this study was the introduction of the external application of herbs into ALS treatment. This approach is useful for patients with bulbar involvement. In general, transdermal application has comparable efficacy to oral administration. The mechanisms underlying the external application of herbs include transdermal micro-/macroabsorption, local augmentation of microcirculation, and adjustment of the neural-endocrine-immune network (27). Transdermal application has advantages because it avoids the first-pass effect of metabolism associated with the oral route, leading to improved bioavailability (39, 40).
本研究的一個新穎之處是將中藥外用引入肌萎縮側索硬化的治療。這種方法是有用的患者球部受累。一般而言，透皮貼劑的效果與口服給藥相若。藥物外用的機制包括經皮微量 / 大量吸收，局部增強微循環，調節神經 - 內分泌 - 免疫網路 ( 27 )。經皮應用具有優勢，因為它避免了與口服途徑相關的代謝的第一通道效應，導致改善的生物利用度 ( 39 ， 40 )。

Furthermore, it allows prolonged release, improves patient adherence, and minimizes adverse effects due to lower drug peak concentrations (29). Transdermal application may avoid gastrointestinal irritation, low absorption, and a short half-life, necessitating frequent dosing. Thus, a lower daily dose can elicit an equivalent therapeutic effect. The most significant disadvantages are the lower permeability of the skin for some herbal ingredients, the slow permeation of hydrophobic ingredients, differences from person to person and with age, and the possibility of local irritation at the application site (26). Skin reactions were the only adverse effects leading to trial cessation in this study. However, the termination rate in the JWLP group was half the rate reported for riluzole, and the adverse events were less severe (15).
此外，它允許延長釋放，改善患者的依從性，並最大限度地減少由於較低的藥物峰值濃度 ( 29 ) 的副作用。經皮給藥可以避免胃腸道刺激，低吸收，半衰期短，需要頻繁給藥。因此，較低的每日劑量可以引起相當的治療效果。最顯著的缺點是某些草藥成分的皮膚滲透性較低，疏水成分的滲透緩慢，人與人之間和年齡的差異，以及在應用部位 ( 26 ) 局部刺激的可能性。在這項研究中，皮膚反應是導致試驗停止的唯一不良反應。然而，JWLP 組的終止率是利魯唑報告率的一半，不良事件較輕 ( 15 )。

Furthermore, the PLAP patients experienced similar skin symptoms. Hence, the adverse effects are partly not medication-generated but a reaction to the plaster material (melt adhesive material) or heat. Therefore, the material needs future improvement, and a periodic change in the plaster position might be an option.
此外，PLAP 患者也有類似的皮膚症狀。因此，副作用部分不是藥物產生的，而是對石膏材料 (熔融粘合材料) 或熱的反應。因此，材料需要未來的改進，並在石膏位置的週期性變化可能是一個選擇。

The location of the plaster was chosen for practical considerations because placement in this region does not significantly hinder movement or function. Furthermore, it covers the paravertebral muscles, the trapezius muscle, and the rhomboid, which are well perfused. In addition, the plaster is positioned above reflex areas, which are traditionally considered to have toning and strengthening properties and whose stimulation leads to activation of the thoracic sympathetic trunk with sympathetic afferent neural induction of the increased perfusion of skeletal muscles. This is relevant because the sympathetic nervous system regulates skeletal muscle motor innervation and acetylcholine receptor stability. A progressive decline in sympathetic innervation is frequent in ALS with impaired adaptation to physiological stressors (41).
選擇石膏的位置是出於實際考慮，因為放置在這個區域不會嚴重阻礙運動或功能。此外，它還包括椎旁肌、斜方肌和菱形肌，這些部位的血流灌注良好。此外，石膏位於反射區上方，傳統上認為反射區具有調色和增強 屬性，其刺激導致胸部交感神經幹活化，交感神經傳入神經誘導增加骨骼肌灌注。這是相關的，因為交感神經調節骨骼肌運動神經支配和乙酰膽鹼受體穩定性。漸進性交感神經支配的下降在 ALS 中是常見的，對生理應激的適應性受損 ( 41 )。

ALS has multifactorial mechanisms of neurodegeneration that lead to mitochondrial dysfunction (8, 11) and apoptosis (12), with a consequent dysfunction in axonal transport and muscle atrophy (13). The classical pharmacological approach that focuses on a single target of the ingredients can only have limited success (42), as shown for riluzole, which affects glutamate excitotoxicity (43), and edaravone, which affects oxidative stress alone (44)—the herbs of JWL target the pathophysiological mechanism of ALS. Taken together, these herbs target oxidative stress and neuroinflammation and potentially protect against mitochondrial dysfunction and apoptosis. Furthermore, Ginseng Radix, Astragalus Radix, Atractylodis macrocephalae Rhizoma, Glycyrrhizae Radix, Rhodiola rosea Radix, and Epimedii Herba can prevent glutamate excitotoxicity while Ginseng Radix, Astragalus Radix, Glycyrrhizae Radix, and Rhodiola rosea Radix can ameliorate skeletal muscle atrophy (Supplementary Figure 1 summarizes these findings, while Supplementary Tables 1a,b, describe the herbs, their constituents and their mechanisms of action on the targets). Overall, the ingredients of every single herb of JWL have effects on almost all known mechanisms of ALS (45–58). Hence, JWL is a promising combination of herbs that counteracts multiple mechanisms of ALS.
ALS 具有多神經退行性疾病機制，導致線粒體功能障礙 ( 8 ， 11 ) 和細胞凋亡 ( 12 ) ，從而導致軸突運輸和肌肉萎縮功能障礙 ( 13 )。經典的藥理學方法只能針對一個單一的成分靶點 ( 42 ) ，如利魯唑 (影響谷氨酸興奮毒性) 和依達拉奉 (單獨影響氧化應激 ( 44 )) ーー JWL 的草藥靶向 ALS 的病理生理機制。綜上所述，這些草藥作用於氧化應激和神經炎症，有可能防止線粒體功能障礙和細胞凋亡。此外，人參、黃芪、白術、甘草、紅景天和 Epimedii Herba 可以預防谷氨酸興奮性中毒，而人參、黃芪、甘草和紅景天可以改善骨骼肌萎縮 ( Supplementary Figure 1 總結了這些發現， Supplementary Tables 1a 、 b 描述了這些草藥、它們的成分和它們對靶標的作用機制)。總的來說，JWL 的每一種中草藥的成分對幾乎所有已知的 ALS ( 45 - 58 ) 機制都有影響。因此，JWL 是一種有前途的草藥組合，可以抵消 ALS 的多種機制。

The present study has certain limitations. First, the work was conducted at a single center. A multicentre study is advisable for confirmation. In addition, the study evaluated only 20 weeks. Future studies should confirm the effects in a long-term clinical trial.
本文的研究具有一定的侷限性。首先，這項工作是在一個單一的中心進行的。建議進行多中心研究以確認。此外，這項研究只評估了 20 週。未來的研究應該在長期的臨床試驗中證實這種作用。

Furthermore, the therapeutic concept is based on traditional experience with external applications and herbal studies with oral medications. However, there is limited knowledge on the absorption rate of single ingredients or the pharmacokinetics and pharmacodynamics. Hence, targeted selective animal and human studies are mandatory to substantiate the clinical use of the JWLP in ALS patients.
此外，治療的概念是基於傳統的經驗與外部應用和草藥研究與口服藥物。然而，有關單一配料或藥代動力學和藥效學的吸收率的知識有限。因此，有針對性的選擇性動物和人類研究必須證實 JWLP 在 ALS 患者中的臨床應用。

Nevertheless, while there are not enough established and effective therapies for ALS, there is sufficient knowledge of the toxicology and pharmacovigilance of the single herbs of JWL. Furthermore, their use is well-established, and relevant systemic adverse effects did not occur during this study. Hence, combining TCM formulations with western medicine is an encouraging way to help alleviate symptoms and delay ALS progression.
儘管如此，雖然目前還沒有足夠的治療 ALS 的既定有效方法，但我們對 JWL 單一草藥的毒理學和藥物安全有足夠的瞭解。此外，他們的使用是公認的，相關的全身不良反應沒有發生在這項研究期間。因此，中西醫結合是一個令人鼓舞的方法，以幫助緩解症狀和延緩 ALS 進展。

Conclusions結論

The JWLP showed clinical efficacy in a randomized, controlled, placebo-controlled trial, measured by the ALSFRS-R, ALS-SSIT, and weight loss. The study revealed no systemic adverse effects. Because skin reactions occurred in the verum and placebo groups, the covering material needs improvement. Hence, JWLP offers a promising add-on therapy for ALS, particularly in patients with bulbar involvement.
JWLP 在一項隨機、對照、安慰劑對照試驗中顯示了臨床療效，該試驗通過 ALSFRS-R、 ALS-SSIT 和體重減輕來衡量。研究顯示沒有全身不良反應。因為皮膚反應發生在真皮組和安慰劑組，覆蓋材料需要改進。因此，JWLP 為 ALS 提供了一種有前途的附加療法，特別是對於球部受累的患者。

Data availability statement

資料可用性聲明

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.
在研究中提出的原始貢獻包括在文章 / Supplementary material 中，進一步的詢問可以直接向相應的作者。

Ethics statement

The studies involving human participants were reviewed and approved by Ethics Committee of Shuguang Hospital Affiliated with the Shanghai University of TCM. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
本研究由上海中醫藥大學曙光醫院倫理委員會稽核並批准。患者 / 參與者提供了他們的書面知情同意參加這項研究。書面知情同意是從個人獲得的公佈任何潛在的可識別的圖像或封包括在本文中。

Author contributions作者貢獻

WP, TLiu, TF, and SS conceived and designed the study and supervised the experiments. MW, DS, JS, XZhe, LL, TLi, and XZhu performed the trial, data collection, literature research, and data analysis. QW and TF performed and controlled the statistical analysis, WP and SS drafted the manuscript. All data were generated in-house and no paper mill was used. All authors corrected the draft manuscript, agreed to be accountable for all aspects of the work, ensuring integrity, and accuracy.
WP、 TLiu、 TF 和 SS 構思並設計了研究並監督了實驗。MW、 DS、 JS、 XZhe、 LL、 TLi 和 XZhu 進行了試驗、資料收集、文獻研究和資料分析。QW 和 TF 進行對照統計分析，WP 和 SS 起草稿件。所有資料都是內部產生的，沒有使用造紙廠。所有作者修改了草稿，同意對工作的各個方面負責，確保完整性和精準性。

Funding

The present study was supported by a grant from the National Natural Science Foundation of China (81373619) and the Clinical Research Plan of Shanghai Shenkang Hospital Development Center (SHDC2020CR2027B). Funding was also received from the Shanghai Municipal Health and Family Planning Commission (ZY3-CCCX-3-3030).
本研究得到了國家自然科學基金 (81373619) 和上海申康醫院發展中心臨床研究計畫 (SHDC2020CR2027B) 的資助。資金也來自上海市衛生和計畫生育委員會 (ZY3-CCCX-3-3030)。

Publisher's note出版商的說明

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
本文中表達的所有權利主張只是作者的權利主張，不一定代表其附屬機構的權利主張，也不一定代表出版商、編輯和審稿人的權利主張。任何在本文中可能被評估的產品，或者由其製造商提出的聲明，都不能得到出版商的保證或認可。

Acknowledgments

We are grateful to all the study participants for their contributions. We also thank Shanghai NUANYOU Industry Co. Ltd. for preparing and providing the JWLP and PLAP for this study. Supplementary Figure 1 was created with the free version of the Biorender.com.
我們感謝所有參與研究的人員所做的貢獻。我們還要感謝上海暖友實業有限公司為本研究所做的準備和提供的 JWLP 和 PLAP。 Supplementary Figure 1 是使用 Biorender.com 的空閒版本建立的。

Glossary

Abbreviations

ALS

amyotrophic lateral sclerosis
肌萎縮性嵴髓側索硬化症

ALS-CHEPLA

ALS-Chinese HErbal PLAster
ALS - 中草藥膏劑

JWLP

Ji Wu Li plaster

PLAP

placebo plaster

ALS-SSITS

amyotrophic lateral sclerosis symptom score in integrative treatment scale
綜合治療量表肌萎縮性嵴髓側索硬化症症狀評分

ALSFRS-R

amyotrophic lateral sclerosis rating scale-revised
肌萎縮性嵴髓側索硬化症評級表 - 修訂

FVC

forced vital capacity

TCM

Traditional Chinese Medicine
中醫藥

EMG

electromyography

CINHAL

Cumulative Index to Nursing and Allied Health Literature

CNKI

China National Knowledge Infrastructure
中國國家知識基礎設施

MeSH

Medical Subject Headings

HSFA

(Chinese) Health Standards for the Use of Food Additives
食物加入劑衛生標準

CFDA

China Food and Drug Administration.
中國食品藥品監督管理局。

Supplementary material補充材料

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2022.990802/full#supplementary-material
本文的補充材料可在以下網址找到： https://www.frontiersin.org/articles/10.3389/fneur.2022.990802/full#supplementary-material

Click here for additional data file. (18.2KB, docx)

Supplementary Figure 1

Pharmacological treatment targets in relation to ALS disease mechanism.
藥物治療靶點與 ALS 發病機制的關係。

Click here for additional data file. (1.2MB, jpeg)

Supplementary Table 1a補充表 1a

Antioxidative and anti-inflammatory activities of the main constituents of Ji Wu Li.

Click here for additional data file. (361.3KB, docx)

Supplementary Table 1b補充表 1b

Neuroprotective and Glutamate excitotoxicity- and muscle atrophy attenuating effects of Ji Wu Li constituents. ABTS, 2,2′-Azino-bis(3-Ethylbenzothiazoline-6-Sulfonic Acid); AChE, Acetylcholinesterase; AIF, apoptosis-inducing factor; AMPK, AMP-activated protein kinase; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; CARM1, co-activator-associated arginine methyltransferase 1; CAT, Catalase; COX2, Cyclooxygenase-2; DAPK1, Death Associated Protein Kinase 1; DNA, deoxyribonucleic acid; DPPH, 2,2-Diphenyl-1-picrylhydrazyl; ERK, Extracellular-signal Regulated Kinases; GLT-1, Glutamate transporter-1; GPx, Glutathione peroxidase; GSH, Glutathion in its reduced form; GSH-PX, Glutathionperoxidase; GSK3β, Glycogen synthase kinase 3 beta; HSP-16.2, Heat-shock-protein 16.2; Iba1, Ionized calcium-binding adapter molecule 1; IFN-γ, Interferone gamma; IL, Interleukin; I/R, ischemia/reperfusion; iNOS, Inducible nitric oxide synthase; IP-10, interferon-gamma induced protein 10; MDA, Malondialdehyde; MEK, MAPK/ERK Kinase; MMP, Matrix metallopeptidase; mTOR, mammalian Target of Rapamycin; NF-κB, Nuclear factor kappa B; NMDAR, N-Methyl-d-aspartate receptor; NO, Nitric oxide; NOX4, NADPH Oxidase 4; NQO1, NAD(P)H Quinone Dehydrogenase 1; ODG/R, Oxygen glucose deprivation and reperfusion; PCP, Poria cocos polysaccharide; PGE2, Prostaglandin E2; PI3K, Phosphoinositide 3-kinases; PON2, Paraoxonase 2; ROS, Reactive oxygen species; SKP2, S-Phase-kinase-associated-protein; SOD, Superoxide Dismutase; STAT, signal transducer and activator of transcription; S100β, S100 calcium-binding protein B; XOD, xanthine oxidase; TNF-α, Tumor-necrosis-factor-alpha; TXNIP, Thioredoxin-interacting-protein. A Literature search was performed from the databases from inception to February 2022 using MEDLINE, Google Scholar, Cochrane Database, CINHAL, CNKI, and Wanfang Med Online. The keywords “Ginseng Radix, Astragalus Radix, Cistanche deserticola Herba, Atractylodis macrocephalae Rhizoma, Poria cocos, Glycyrrhiza Radix, Rhodiola rosea Radix, Epimedii Herba” AND “neurodegeneration, glutamate excitotoxicity, neuroinflammation, oxidative stress, protein aggregation, mitochondrial dysfunction, axonal transport dysfunction, muscle atrophy, spasticity, and ALS” were used as MeSH terms.
雞五里成分的神經保護作用及谷氨酸興奮毒性和肌萎縮減毒作用。乙酰膽鹼酯酶；AIF，凋亡誘導因子；AMPK，AMP 活化蛋白激酶；Bax，Bcl-2 相關 X 蛋白；Bcl-2，B 細胞淋巴瘤 2; CARM1，共啟動劑相關精氨酸甲基轉移酶 1; CAT，過氧化氫酶；COX2，環氧合酶 -2; DAPK1，死亡相關蛋白激酶 1; DNA，去氧核醣核酸；2,2 - 二苯基 -1 - 苦基肼；ERK，細胞外訊號調節激酶；GLT-1，谷氨酸轉運蛋白 -1; GPx，谷胱甘肽過氧化物酶；還原形式的 Glutathion 谷胱甘肽；Iba1，電離鈣結合銜接分子 1; IFN-γ，干擾素 γ; IL，白細胞介素；I/R，缺血 / 再灌注；iNOS，Inducible 一氧化氮合酶；IP-10，interferon-gamma 誘導蛋白 10; MDA，Malondialdehyde; MEK，MAPK/ERK 激酶；MMP，基質金屬蛋白酶；mTOR，哺乳動物雷帕黴素靶點；核因子 κB，核因子 κB; NMDAR，N - 甲基 - D - 天門冬胺酸受體；NO，一氧化氮；NOX4，NADPH 氧化酶 4; NQO1，NAD (P) H 醌脫氫酶 1; ODG/R，氧葡萄糖剝奪和再灌注；五氯酚，茯苓多糖；PGE2，前列腺素 E2; PI3K，磷酸肌醇 3 - 激酶；PON2，對氧磷酶 2; ROS，活性氧類；SKP2，S 期激酶相關蛋白；SOD，超氧化物歧化酶；STAT，訊號轉導和轉錄啟動因子；S100β，S100 鈣結合蛋白 B; XOD，黃嘌呤氧化酶；TNF-α，腫瘤壞死因子 α; TXNIP，硫氧還蛋白相互作用蛋白。 從開始到 2022 年 2 月，使用 MEDLINE，Google Scholar，Cochrane Database，CINHAL，CNKI 和 Wanfang Med Online 對資料庫進行文獻檢索。關鍵詞 “人參、黃芪、肉蓯蓉、白術、茯苓、甘草、紅景天、 Epimedii Herba” 和 “神經退行性疾病、谷氨酸興奮毒性、神經炎症、氧化應激、蛋白質聚集、線粒體功能障礙、軸突運輸功能障礙、肌肉萎縮、痙攣和肌萎縮性側索硬化症” 被用作 meSH 術語。

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.
本節收集本文中包含的任何資料引用、資料可用性陳述或補充材料。

Supplementary Materials

Click here for additional data file. (18.2KB, docx)

Supplementary Figure 1

Pharmacological treatment targets in relation to ALS disease mechanism.
藥物治療靶點與 ALS 發病機制的關係。

Click here for additional data file. (1.2MB, jpeg)

Supplementary Table 1a補充表 1a

Antioxidative and anti-inflammatory activities of the main constituents of Ji Wu Li.

Click here for additional data file. (361.3KB, docx)

Supplementary Table 1b補充表 1b

Neuroprotective and Glutamate excitotoxicity- and muscle atrophy attenuating effects of Ji Wu Li constituents. ABTS, 2,2′-Azino-bis(3-Ethylbenzothiazoline-6-Sulfonic Acid); AChE, Acetylcholinesterase; AIF, apoptosis-inducing factor; AMPK, AMP-activated protein kinase; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; CARM1, co-activator-associated arginine methyltransferase 1; CAT, Catalase; COX2, Cyclooxygenase-2; DAPK1, Death Associated Protein Kinase 1; DNA, deoxyribonucleic acid; DPPH, 2,2-Diphenyl-1-picrylhydrazyl; ERK, Extracellular-signal Regulated Kinases; GLT-1, Glutamate transporter-1; GPx, Glutathione peroxidase; GSH, Glutathion in its reduced form; GSH-PX, Glutathionperoxidase; GSK3β, Glycogen synthase kinase 3 beta; HSP-16.2, Heat-shock-protein 16.2; Iba1, Ionized calcium-binding adapter molecule 1; IFN-γ, Interferone gamma; IL, Interleukin; I/R, ischemia/reperfusion; iNOS, Inducible nitric oxide synthase; IP-10, interferon-gamma induced protein 10; MDA, Malondialdehyde; MEK, MAPK/ERK Kinase; MMP, Matrix metallopeptidase; mTOR, mammalian Target of Rapamycin; NF-κB, Nuclear factor kappa B; NMDAR, N-Methyl-d-aspartate receptor; NO, Nitric oxide; NOX4, NADPH Oxidase 4; NQO1, NAD(P)H Quinone Dehydrogenase 1; ODG/R, Oxygen glucose deprivation and reperfusion; PCP, Poria cocos polysaccharide; PGE2, Prostaglandin E2; PI3K, Phosphoinositide 3-kinases; PON2, Paraoxonase 2; ROS, Reactive oxygen species; SKP2, S-Phase-kinase-associated-protein; SOD, Superoxide Dismutase; STAT, signal transducer and activator of transcription; S100β, S100 calcium-binding protein B; XOD, xanthine oxidase; TNF-α, Tumor-necrosis-factor-alpha; TXNIP, Thioredoxin-interacting-protein. A Literature search was performed from the databases from inception to February 2022 using MEDLINE, Google Scholar, Cochrane Database, CINHAL, CNKI, and Wanfang Med Online. The keywords “Ginseng Radix, Astragalus Radix, Cistanche deserticola Herba, Atractylodis macrocephalae Rhizoma, Poria cocos, Glycyrrhiza Radix, Rhodiola rosea Radix, Epimedii Herba” AND “neurodegeneration, glutamate excitotoxicity, neuroinflammation, oxidative stress, protein aggregation, mitochondrial dysfunction, axonal transport dysfunction, muscle atrophy, spasticity, and ALS” were used as MeSH terms.
雞五里成分的神經保護作用及谷氨酸興奮毒性和肌萎縮減毒作用。乙酰膽鹼酯酶；AIF，凋亡誘導因子；AMPK，AMP 活化蛋白激酶；Bax，Bcl-2 相關 X 蛋白；Bcl-2，B 細胞淋巴瘤 2; CARM1，共啟動劑相關精氨酸甲基轉移酶 1; CAT，過氧化氫酶；COX2，環氧合酶 -2; DAPK1，死亡相關蛋白激酶 1; DNA，去氧核醣核酸；2,2 - 二苯基 -1 - 苦基肼；ERK，細胞外訊號調節激酶；GLT-1，谷氨酸轉運蛋白 -1; GPx，谷胱甘肽過氧化物酶；還原形式的 Glutathion 谷胱甘肽；Iba1，電離鈣結合銜接分子 1; IFN-γ，干擾素 γ; IL，白細胞介素；I/R，缺血 / 再灌注；iNOS，Inducible 一氧化氮合酶；IP-10，interferon-gamma 誘導蛋白 10; MDA，Malondialdehyde; MEK，MAPK/ERK 激酶；MMP，基質金屬蛋白酶；mTOR，哺乳動物雷帕黴素靶點；核因子 κB，核因子 κB; NMDAR，N - 甲基 - D - 天門冬胺酸受體；NO，一氧化氮；NOX4，NADPH 氧化酶 4; NQO1，NAD (P) H 醌脫氫酶 1; ODG/R，氧葡萄糖剝奪和再灌注；五氯酚，茯苓多糖；PGE2，前列腺素 E2; PI3K，磷酸肌醇 3 - 激酶；PON2，對氧磷酶 2; ROS，活性氧類；SKP2，S 期激酶相關蛋白；SOD，超氧化物歧化酶；STAT，訊號轉導和轉錄啟動因子；S100β，S100 鈣結合蛋白 B; XOD，黃嘌呤氧化酶；TNF-α，腫瘤壞死因子 α; TXNIP，硫氧還蛋白相互作用蛋白。 從開始到 2022 年 2 月，使用 MEDLINE，Google Scholar，Cochrane Database，CINHAL，CNKI 和 Wanfang Med Online 對資料庫進行文獻檢索。關鍵詞 “人參、黃芪、肉蓯蓉、白術、茯苓、甘草、紅景天、 Epimedii Herba” 和 “神經退行性疾病、谷氨酸興奮毒性、神經炎症、氧化應激、蛋白質聚集、線粒體功能障礙、軸突運輸功能障礙、肌肉萎縮、痙攣和肌萎縮性側索硬化症” 被用作 meSH 術語。

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Data Availability Statement

資料可供使用聲明

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.
在研究中提出的原始貢獻包括在文章 / Supplementary material 中，進一步的詢問可以直接向相應的作者。

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