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Efficacy of Tiaoqiheying decoction in the treatment of spasmodic pain and lipid metabolism after acute ischemic stroke

Objective To investigate the efficacy and safety of Tiaoqiheying decoction in treating acute ischemic stroke. Methods This prospective randomized study enrolled 102 patients with ischemic stroke who were randomly assigned to the control (placebo), external (external Tiaoqiheying decoction), and external/internal groups (oral and external Tiaoqiheying decoction) groups. Cholesterol (CHO), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels and the National Institute of Health Stroke Scale (NIHSS), modified Ashworth scale (AMS), visual analog scale (VAS), Barthel Index (BI), and Fugl–Meyer score (FMS) were determined before and after treatment. Results NIHSS scores were lower in the external/internal group than in the external and placebo groups. MAS and VAS scores for all patients were also lower after 4 weeks than before treatment, and they were significantly lower in the external/internal group versus the control group. CHO, TG, and LDL levels were significantly lower after 2 and 4 weeks, and their levels were lower in the external/internal group than in the other two groups. BI and FMS were higher in the external/internal group than in the other groups after 2 and 4 weeks of treatment. Conclusion Tiaoqiheying decoction may improve spasmodic pain and lipid metabolism after stroke.


Introduction
Stroke is a leading cause of death and severe disability worldwide, with 1.5 to 2 million new cases reported every year in China. 1,2 Because most strokes are ischemic, the only effective treatment strategy is restoration of cerebral blood flow to rescue the infarcted tissue. 3,4 However, excessive reperfusion may cause severe ischemia reperfusion (I/R) injury. 5,6 Thus, patient recovery could be hampered after the treatment of ischemic stroke.
Spasmodic pain is a typical symptom of ischemic stroke. 7 Approximately 30% to 82% of patients experience shoulder pain after stroke. 8,9 Currently, antihypertensive drugs, 10 hypoglycemic and antiplatelet aggregation drugs, 11,12 and constraintinduced movement therapy 13 are the main treatment methods to ensure recovery after stroke. However, new treatment methods are required to enhance patient recovery and improve their symptoms after stroke.
Traditional Chinese medicine has a long history, and many Chinese medicine herbs are applied to treat different diseases including stroke. 14 However, because the treatment efficacy is unclear, many Chinese medicines need to be investigated using clinical investigation methods to confirm their efficacy and safety and to determine their molecular mechanisms. 15 Based on our own clinical experience, we developed a Chinese medicine decoction called Tiaoqiheying decoction (composed of Astragalus membranaceus, Pueraria lobata, Cinnamomum cassia, Angelica sinensis, Paeonia lactiflora, Xu Changqing, and Corydalis yanhusuo) to treat patients after acute ischemic stroke. The present study investigated the efficacy and safety of Tiaoqiheying decoction for treating patients after acute ischemic stroke. This study might provide additional clinical evidence supporting the use of traditional Chinese medicine in the treatment of stroke.

Patients and treatment
This prospective, double-blind, randomized controlled study enrolled 112 consecutive patients with ischemic stroke who visited our hospital from December 2018 to April 2019 and met the inclusion criteria. The inclusion criteria were a visit to the hospital within 72 hours after stroke and a diagnosis of a first ischemic stroke using magnetic resonance imaging or computed tomography. All patients exhibited hemiplegic limb spasm and increased muscle tension. The degree of spasm in all patients using a modified Ashworth score (MAS) was !1. The exclusion criteria were as follows: previous stroke history; severe cognitive dysfunction in patients who could not complete the scales; other severe organ dysfunction such as severe liver, renal, or heart disease; prior receipt of nerve block treatment; and obvious limb diseases such as fractures. Written informed consent was obtained from all patients. The present study was approved by Tongren Hospital Affiliated to Medical College of Shanghai Jiaotong University.
The patients were randomly divided into the following three groups using a computer: placebo control group, external group, and external/internal group. During the study, 10 patients were excluded from the research because of non-compliance. Thus, 102 patients were included in the study. The basic therapeutic strategy complied with the Chinese guidelines for the prevention and treatment of cerebrovascular disease. 16 All patients were treated using standard methods including medications such as antihypertensive drugs, hypoglycemic drugs, and antiplatelet aggregation drugs, and constraint-induced movement therapy. In the external/internal group, the patients received Tiaoqiheying decoction, and each oral dose contained the following ingredients: Astragalus membranaceus, 15g; Pueraria lobata, 15 g; Cinnamomum cassia, 15 g; Angelica sinensis, 12 g; Paeonia lactiflora, 15g; Xu Changqing, 15 g; and Corydalis yanhusuo, 10 g. For external use, the decoction contained the following ingredients: Astragalus membranaceus, 15g; Pueraria lobata, 15 g; Cinnamomum cassia, 15 g; Angelica sinensis, 12 g; Paeonia lactiflora, 15g; Xu Changqing, 15 g; and Corydalis yanhusuo, 10 g. For oral use, patients received a one-half dose of the decoction twice a day (decocted in 250 mL of water each time). For external use, 200 mL of the decoction were added to 500 to 800 mL of water at a temperature of 38 to 42 C. The spasmodic limb was immersed in the decoction for 20 minutes once a day before bedtime. The patients were treated for 4 weeks. Patients in the placebo group received treatment with a placebo using the same methods. The placebo included four constituents known to have no active effect (barley, dried ripe fruit, noodle fish, and citric acid) to give a similar appearance, smell, and taste as the active treatment.

Measurement of lipid metabolism
Cholesterol (CHO), triglycerides (TG), high-density lipoprotein (HDL), and lowdensity lipoprotein (LDL) levels were evaluated before treatment and after 2 and 4 weeks of treatment. Commercial kits or automatic biochemical analyzers were used for the analysis (Beckman Coulter, Brea, CA, USA).

Data collection
Demographic data such as age, gender, and clinical information including complications and medication condition were also recorded. The National Institute of Health Stroke Scale (NIHSS) was used to determine patients' stroke condition before and after treatment. The modified Ashworth scale (MAS) was used to measure spasms, a visual analog scale (VAS) was used to assess the patients' pain, the Barthel Index (BI) was used to measure quality of life, and the Fugl-Meyer score (FMS) was used to assess motor function. All scores (VAS, MAS, BI, and FMS) were measured before treatment and after 2 and 4 weeks of treatment.

Statistical analysis
Continuous data were expressed as the mean AE standard deviation. The chisquared test was used to compare the counting materials and rates. Comparisons among the three groups were conducted via one-way analysis of variance. P < 0.05 denoted statistical significance. All calculations were performed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA).

Basic clinical characteristics
A flow chart of the study protocol is presented in Figure 1

NIHSS and spasmodic pain results after treatment with Tiaoqiheying decoction
The efficacy of Tiaoqiheying decoction in treating patients with stroke and the associated spasmodic pain was assessed using the NIHSS to determine the stroke condition. The MAS was used to evaluate spasm, and the VAS was used to determine the pain level. As shown in Table 2, the NIHSS score was significantly decreased in all patients after treatment compared with that before treatment (P < 0.05).  The NIHSS score was lower in the external/ internal group after 2 and 4 weeks of treatment than in the other two groups (P < 0.001). After 4 weeks of treatment, MAS and VAS for all patients were dramatically decreased compared with the values before treatment (MAS, P ¼ 0.001; VAS, P < 0.001). After 4 weeks of treatment, both MAS and VAS were significantly decreased in the external/internal group compared with those in the external and control groups (P < 0.05), indicating that Tiaoqiheying decoction improved spasmodic pain after stroke.

The effect of Tiaoqiheying decoction on lipid metabolism
We then measured the effect of Tiaoqiheying decoction on lipid metabolism in patients after a stroke. The results illustrated that CHO, TG, and LDL levels were significantly lower after 2 and 4 weeks of treatment than before treatment (P < 0.05, Figure 2). The external/internal group exhibited significantly lower CHO, TG, and LDL levels than the external and control groups (P < 0.05). However, no significant difference was found for HDL levels among the groups.

Quality of life and motor function after treatment with Tiaoqiheying decoction
Finally, BI and FMS were used to assess the effect of Tiaoqiheying decoction on patients' quality of life and motor function. As shown in Table 3, both BI and FMS were significantly higher in all patients after 2 weeks of treatment compared with the control values (P < 0.05). BI and FMS were also significantly higher in the external/internal group than in the control group after 2 weeks and 4 weeks of treatment (P < 0.05). These results suggest that Tiaoqiheying decoction can improve patients' quality of life and motor function.

Discussion
Despite numerous studies on stroke, treating patients with stroke and aiding their recovery remain clinical challenges. Thus, new treatment methods with fewer adverse effects are required. The present prospective study found that Tiaoqiheying decoction could improve patients' recovery after stroke by improving spasmodic pain and lipid metabolism. The application of traditional Chinese medicine or traditional herbs or extracts has been reported in many studies,   found that the application of traditional Chinese medicine to rehabilitation significantly improved Broca's aphasia after stroke. In the present study, we also observed that Tiaoqiheying decoction was effective and safe in the treatment of stroke. Decoctions of Chinese herbs to treat patients after stroke have also been reported in recent years. Lee et al. 20 investigated the traditional Chinese medicine Xue-Fu-Zhu-Yu decoction, and they found that it can improve thromboembolic stroke in rats by activating tissue plasminogen. Hu et al. 21 reported that Gua Lou Gui Zhi decoction suppressed lipopolysaccharide-induced activation of the TLR4/NF-jB pathway in BV-2 murine microglial cells. In a meta-analysis, Huang et al. 22 observed that Fuling Sini decoction is effective and safe for the treatment of patients with chronic heart failure. In this study, we also demonstrated that Tiaoqiheying decoction, consisting of Astragalus membranaceus, Pueraria lobata, Cinnamomum cassia, Angelica sinensis, Paeonia lactiflora, Xu Changqing, and Corydalis yanhusuo, could improve both spasmodic pain and lipid metabolism for patients after acute ischemic stroke. Additionally, the change in lipid metabolism is a typical symptom in patients with stroke. 23 Generally, LDL, TG, and CHO levels are believed to be elevated after stroke. 24 However, it remains unclear whether there is a link between lipid metabolism and the effects of Tiaoqiheying decoction on post-stroke spasmodic pain. Additional studies are needed to clarify this issue.
The present study also had some limitations. First, the sample size was small, and second, we did not investigate the molecular mechanisms of the effects of Tiaoqiheying decoction in the treatment of stroke. Thus, further clinical studies are required to clarify these issues.
In conclusion, we conducted a prospective study to investigate the efficacy of Tiaoqiheying decoction in the treatment of acute ischemic stroke. The results illustrated Tiaoqiheying decoction could improve patients' recovery after stroke through improving spasmodic pain and lipid metabolism. This study may provide clinical evidence for the application of traditional Chinese medicine in the treatment of stroke.

Authors' contributions
Yue Chen designed the study, edited the manuscript, performed the experiments, and wrote the manuscript. Zhixing Cai analyzed the data and supervised the entire study process. Both authors read and approved the final manuscript.

Availability of data and materials
All data that were generated or analyzed during this study are included in this published article.

Consent for publication
All patients provided consent for publication of all data concerning their personal information.

Declaration of conflicting interest
The authors declare that there is no conflict of interest.

Ethics approval and consent to participate
The present study was approved by Tongren Hospital Affiliated with the Medical College of Shanghai Jiaotong University. Written informed consent was obtained from all patients.

Funding
This research was funded by a special project for Traditional Chinese Medicine of Shanghai Municipal Health and Family Planning Commission, 2018LQ015. This study was additionally supported by the National Natural Science Foundation of China (81320108028).