本文選題：補腎活血 + 膝骨關(guān)節(jié)炎��； 參考：《廣州中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：目的1.循證醫(yī)學(xué)研究評價補腎活血中藥治療膝骨關(guān)節(jié)炎的有效性及安全性。2.臨床研究評價補腎活血中藥龍鱉膠囊治療膝骨關(guān)節(jié)炎的臨床療效、患者生活質(zhì)量及安全性。3.動物實驗研究依據(jù)龍鱉膠囊對膝骨關(guān)節(jié)炎(KOA, Knee Osteoarthritis)大鼠的膝關(guān)節(jié)腫脹度及大鼠體重、臟器指數(shù)和關(guān)節(jié)滑膜、軟骨病理形態(tài)學(xué)的改善作用,觀察龍鱉膠囊對大鼠膝骨關(guān)節(jié)炎的治療作用；觀察龍鱉膠囊對膝骨關(guān)節(jié)炎大鼠血清白細胞介素-1 β(IL-Iβ)、白細胞介素-6(IL-6)、白細胞介素-6(IL-I0)水平及膝關(guān)節(jié)病變組織中P38MAPK、 NF-κB信號傳導(dǎo)通路中MEK-3/6、p38、ATF2、NF-κBp65和P-MEK-3/6、P-p38、P-ATF2、 P-NF-κ Bp65表達水平的影響,進而探討龍鱉膠囊治療膝骨關(guān)節(jié)炎的可能作用機制。方法：1.循證醫(yī)學(xué)研究計算機檢索中國生物醫(yī)學(xué)文獻數(shù)據(jù)庫(CBM)、相關(guān)期刊論文(CNKI)、萬方資源數(shù)據(jù)庫、維普期刊數(shù)據(jù)庫、Pubmed、Embase 和 Cochrane Library中關(guān)于補腎活血中藥對比非甾體類抗炎藥(Nonsteroidal Anti-inflammatory Drugs, NSAIDs)治療膝骨關(guān)節(jié)炎的隨機對照試驗文獻。對納入研究的文獻采用Jadad量表和Cochrane Handbook 5.1評估文獻質(zhì)量和偏倚性風(fēng)險,采用軟件RevMan 5.3.5進行數(shù)據(jù)分析,并運用GRADE系統(tǒng)對本研究得到的證據(jù)進行質(zhì)量評價。2.臨床研究采用簡單隨機對照將符合納入標準的88例患者,隨機分為龍鱉膠囊組44例和塞來昔布組44例,分別給予口服龍鱉膠囊和塞來昔布,兩組均以4周為觀察期,對兩組患者治療后的臨床療效、VAS評分、Lequesne指數(shù)、胃腸道不良反應(yīng)及關(guān)節(jié)炎影響測定量表評分進行評價。3.動物實驗研究建立膝骨關(guān)節(jié)炎大鼠模型,于造模后開始給予低、中、高劑量的龍鱉膠囊灌胃(0.3125,0.625,0.9375g·kg-1),連續(xù)4周,觀察龍鱉膠囊對KOA大鼠的膝關(guān)節(jié)腫脹度及大鼠體重、臟器指數(shù)的影響,HE染色觀察光鏡下關(guān)節(jié)滑膜、軟骨的一般形態(tài),并對滑膜組織的病理學(xué)進行評分,Masson染色觀察光鏡下關(guān)節(jié)軟骨的一般形態(tài),并對軟骨進行Mankin's評分；ELISA法檢測血清白細胞介素-1 β(IL-I β)、白細胞介素-6(IL-6)及白細胞介素-10(IL-I0)水平,免疫組化SP法檢測滑膜和軟骨組織中MEK-3/6、p38、ATF2、NF-κ Bp65和P-MEK-3/6、P-p38、P-ATF2、P-NF-κ Bp65的表達情況。結(jié)果：1.循證醫(yī)學(xué)研究納入22篇隨機對照試驗文獻,共2029例,其中補腎活血中藥1022例,NSAIDs組1007例。Meta分析提示：與NSAIDs相比,補腎活血中藥具有更高的總有效率(RR=1.10,95%CI[1.06,1.15],P0.00001)和臨床控制率(RR=1.48,95%CI[1.19,1.84],P=0.0003),更低的胃腸道不良反應(yīng)(RR=0.18,95%CI[0.09,0.35],P0.00001)。補腎活血中藥和NSAIDs在改善WOMAC評分、Lequesne指數(shù)、KSS評分、Lysholms評分和VAS評分方面比較,差異均無統(tǒng)計學(xué)意義(P005)。GRADE證據(jù)質(zhì)量評價提示：補腎活血中藥的總有效率高于NSAIDs(低質(zhì)量證據(jù)),補腎活血中藥的臨床控制率高于NSAIDs(氏質(zhì)量證據(jù)),補腎活血中藥與NSAIDs在改蓋WOMAC評分、Lequesne指數(shù)、KSS評分、Lysholms評分和VAS評分方面無差異(極低質(zhì)量證據(jù)),補腎活血中藥的胃腸道不良反應(yīng)低于NSAIDs(低質(zhì)量證據(jù))。2.臨床研究龍鱉膠囊組總有效率92.25%,塞來昔布組總有效率90.00%,兩組總有效率差異無統(tǒng)計學(xué)意義(P0.005)。與治療前比較,龍鱉膠囊組和塞來昔布組的VAS評分、Lequesne旨數(shù)、關(guān)節(jié)炎影響測定量表評分均較前明顯改善,差異均有統(tǒng)計學(xué)意義(P001)。治療后組間比較,龍鱉膠囊組和塞來昔布組在VAS評分、Lequesne旨數(shù)方面差異均無統(tǒng)計學(xué)意義(P005)；龍鱉膠囊組的關(guān)節(jié)炎影響測定量表評分低于塞來昔布組,差異有統(tǒng)計學(xué)意義(P0.01)。治療期間,龍鱉膠囊組出現(xiàn)胃腸道反應(yīng)4例,塞來昔布組出現(xiàn)胃腸道反應(yīng)3例,兩組不良反應(yīng)發(fā)生率比較,差異無統(tǒng)計學(xué)意義(P0.05)。3.動物實驗研究造模后,造模組的膝關(guān)節(jié)腫脹度高于對照組(P0.01)。給藥2周后,與造模組及龍鱉低、高劑量組比較,龍鱉中劑量組的膝關(guān)節(jié)腫脹度消退較快(P0.01)。給藥3周后,龍鱉低、中、高劑量組的膝關(guān)節(jié)腫脹度消退均快于造模組(P0.01),其中,龍鱉中劑量組的膝關(guān)節(jié)腫脹已消退至對照組水平(P0.05)。給藥4周后,與對照組比較,龍鱉低、中、高劑量組的膝關(guān)節(jié)腫脹度均己消退(P0.05)。造模后,造模組的體重和胸腺指數(shù)低于對照組(P0.05),造模組的脾臟指數(shù)與對照組比較,差異有統(tǒng)計學(xué)意義(P0.05)。給藥2周后,龍鱉中劑量組的體重重于對照組(P0.05)；而龍鱉低、高劑量的體重與對照組比較,差異均無統(tǒng)計學(xué)意義(P0.05)。給藥4周后,龍鱉低、中、高劑量的體重均重于對照組(P0.05),而龍鱉中劑量組的體重又重于龍鱉低、高劑量組(P0.05)。給藥2周后,各組之間的脾臟指數(shù)兩兩比較,差異均無統(tǒng)計學(xué)意義(P0.05)。給藥4周后,龍鱉低、中、高劑量組的脾臟指數(shù)均高于同期對照組和造模組(P0.05)。給藥2周后,龍鱉低、中、高劑量組的胸腺指數(shù)均高于同期造模組(P0.05)。給藥4周后,各組組間的胸腺指數(shù)比較,差異無統(tǒng)計學(xué)意義(P0.05)。給藥2周、4周后,龍鱉低、中、高劑量組的軟骨結(jié)構(gòu)破壞程度和滑膜炎癥程度均較造模組輕,龍鱉低、中、高劑量組的膝關(guān)節(jié)滑膜組織病理評分值均低于造模組(P0.01)。給藥4周后,龍鱉中劑量組的膝關(guān)節(jié)滑膜組織病理評分值與龍鱉高劑量組比較,差異有統(tǒng)計學(xué)意義(P0.05)。給藥2周、4周后,龍鱉低、中、高劑量組的膝關(guān)節(jié)軟骨M ankin評分值均低于造模組(P0.01),同期龍鱉低、中、高劑量組的膝關(guān)節(jié)軟骨Mankin評分值組間兩兩比較,差異均無統(tǒng)計學(xué)意義(P0.05)。造模后,造模組的IL-1 β、IL-6水平均高于對照組(P0.01),而IL-10水平低于對照組(P0.01)。給藥2周、4周后,造模組的IL-1 β水平均高于同期對照組及龍鱉低、中、高劑量組(P0.05)；龍鱉低、中、高劑量組的IL-1β水平均高于同期對照組(P0.05)；龍鱉中劑量組IL-1 β水平均低于同期龍鱉低、高劑量組(P0.05)。給藥2周、4周后,造模組IL-6水平均高于同期對照組及龍鱉低、中、高劑量組(P0.01)；龍鱉低劑量組IL-6水平均低于同期龍鱉中、高劑量組(P0.01)。給藥2周后,龍鱉低、中、高劑量組IL-6水平均高于對照組(P0.01)；給藥4周后,龍鱉膠囊低劑量組IL-6水平與對照組比較,差異無統(tǒng)計學(xué)意義(P0.05)。給藥2周、4周后,龍鱉低、中、高劑量組IL-10水平均高于同期對照組和造模組(P0.01),而其中龍鱉中劑量組IL-10水平均高于同期龍鱉低、高劑量組(P0.01)。在滑膜組織中,給藥2周、4周后,各組細胞均有MEK-3/6、p38、ATF2、 NF-κ Bp65 和 P-MEK-3/6、P-p38、P-NF-κ Bp65陽性表達,其中造模組MEK-3/6、p38、ATF2、NF-κ Bp65和P-MEK-3/6、P-p38、P-NF-κ Bp65陽性細胞百分比均高于對照組和龍鱉低、中、高劑量組(P0.01)。給藥2周、4周后,各組細胞均有P-ATF2弱陽性表達；2周后,造模組P-ATF2陽性細胞百分比高于對照組和龍鱉低、中、高劑量組(P0.05)；4周后,各組間P-ATF2陽性細胞百分比比較,差異均無統(tǒng)計學(xué)意義(P0.05)在軟骨組織中,給藥2周、4周后,各組細胞均有MEK-3/6、p38、NF-κ Bp65和P-MEK-3/6、P-p38、P-NF-κ Bp65陽性表達,其中造模組MEK-3/6、p38、NF-κ Bp65和P-MEK-3/6、P-p38、P-NF-κ Bp65陽性細胞百分比均高于對照組(P0.01),龍鱉低、中、高劑量組MEK-3/6、p38、NF-κ Bp65和 P-MEK-3/6、P-p38、P-NF-κ Bp65陽性細胞百分比均低于造模組(P0.05)。給藥2周、4周后,各組細胞均有ATF2和P-ATF2弱陽性表達,且造模組ATF2和P-ATF2陽性細胞百分比均高于對照組(P0.01)；給藥2周后,龍鱉低、中、高劑量組ATF2陽性細胞百分比均低于造模組(P0.01);給藥4周后,龍鱉低、中、高劑量組ATF2陽性細胞百分比與造模組比較,差異無統(tǒng)計學(xué)意義(P0.05)；給藥2周、4周后,龍鱉低、中、高劑量組P-ATF2陽性細胞百分比均低于造模組(P005)。結(jié)論：1.循證醫(yī)學(xué)研究補腎活血中藥是治療膝骨關(guān)節(jié)炎的有效方法,不良反應(yīng)較少。由于納入文獻的樣本量較小、方法學(xué)質(zhì)量不高,本研究的結(jié)論仍亟需更多高質(zhì)量的臨床隨機對照試驗予以支持。2.臨床研究采用龍鱉膠囊和塞來昔布治療膝骨關(guān)節(jié)炎,均可有效緩解癥狀、改善膝關(guān)節(jié)功能,具有良好的有效性和安全性；但龍鱉膠囊在改善生活質(zhì)量方面優(yōu)于塞來昔布。3.動物實驗研究龍鱉膠囊能消除膝骨關(guān)節(jié)炎大鼠的膝關(guān)節(jié)腫脹,抑制造模引起的大鼠體重下降,增加膝骨關(guān)節(jié)炎大鼠的體重和脾臟指數(shù),使造模降低的胸腺指數(shù)恢復(fù)至正常水平,可減輕膝骨關(guān)節(jié)炎大鼠軟骨結(jié)構(gòu)破壞的范圍和嚴重程度,顯著減輕滑膜炎癥,并具有促進軟骨細胞增生的作用。實驗表明,龍鱉膠囊緩解膝骨關(guān)節(jié)炎大鼠炎癥反應(yīng)與其增強大鼠免疫器官的功能密切相關(guān)。龍鱉膠囊可增強膝骨關(guān)節(jié)炎大鼠免疫器官的功能,降低血清炎性細胞因子IL-1β、IL-6的表達水平和升高抑炎細胞因子IL-I0的表達,抑制過度亢進的p38MAPK和NF-κB信號,抑制骨關(guān)節(jié)炎滑膜和軟骨細胞中p38MAPK和NF-K B信號通路的活化,是龍鱉膠囊發(fā)揮治療作用的重要機制。
[Abstract]:Objective 1. evidence-based medicine to evaluate the efficacy and safety of tonifying kidney and activating blood Chinese medicine for the treatment of knee osteoarthritis.2. clinical study on the treatment of knee osteoarthritis with dragon and turtle capsule of tonifying kidney and blood circulation, the quality of life and safety of the patients.3. animal experiment research according to long turtle capsule to KOA (Knee Osteoarthritis). The swelling of the knee joint and the weight of rats, organ index, joint synovial membrane, and cartilage pathomorphology improved the therapeutic effect of dragon shell capsule on knee osteoarthritis in rats, and observed the level of serum interleukin -1 beta (IL-I beta), interleukin -6 (IL-6) and interleukin -6 (IL-I0) in the serum of rats with knee osteoarthritis. The effect of MEK-3/6, p38, ATF2, NF- kappa Bp65 and P-MEK-3/6, P-p38, P-ATF2, P-NF- kappa expression level in the P38MAPK, NF- kappa B signal transduction pathway in the pathological tissue of the knee joint, and then to explore the possible mechanism of the action of dragon shell capsule on the treatment of knee osteoarthritis. Method: 1. evidence-based medicine research computer retrieval Chinese biomedical literature database, Chinese journal full text database (CNKI), Wanfang resource database, VIP journal database, Pubmed, Embase, and Cochrane Library for the comparison of non steroidal anti-inflammatory drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs) in the treatment of knee osteoarthritis in comparison with non steroidal anti-inflammatory drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs) in the treatment of knee osteoarthritis. The table and Cochrane Handbook 5.1 assessed the literature quality and bias risk, using the software RevMan 5.3.5 for data analysis, and using the GRADE system for the quality evaluation of the evidence obtained in this study.2. clinical studies using a simple random control will be in line with the inclusion criteria of the 88 patients, randomly divided into 44 cases of dragon shell capsule group and 44 celecoxib group. The two groups were given 4 weeks as the observation period. The clinical efficacy, the VAS score, the Lequesne index, the gastrointestinal tract adverse reaction and the arthritis influence measurement scale were evaluated in the two groups. The rat model of the knee osteoarthritis was established by the.3. animal experiment. The high dose of dragon turtle capsule was gavage (0.3125,0.625,0.9375g. Kg-1) for 4 weeks. The effect of dragon and turtle Capsule on the swelling of knee joint and the body weight and organ index of rats in KOA rats was observed. The joint synovial membrane and the general shape of cartilage under light microscope were observed by HE staining, and the pathology of the synovial tissue was scored by Masson staining, and the soft joints under the light microscope were observed by Masson staining. The general morphology of the bone, and the Mankin's score of the cartilage, the ELISA assay of serum interleukin -1 beta (IL-I beta), interleukin -6 (IL-6) and interleukin -10 (IL-I0), and the immunohistochemical SP method for the detection of MEK-3/6, p38, ATF2, ATF2, ATF2, IL-I0, and cartilage tissue. 1. evidence-based medicine (EBM) included 22 randomized controlled trials in 2029 cases, including 1022 cases of tonifying kidney and activating blood and 1007 cases of.Meta in group NSAIDs: compared with NSAIDs, the traditional Chinese medicine of tonifying kidney and activating blood has higher total effective rate (RR=1.10,95%CI[1.06,1.15], P0.00001) and clinical control (RR=1.48,95%CI[1.19,1.84], P=0.0003) and lower stomach. RR=0.18,95%CI[0.09,0.35] (P0.00001). There was no significant difference in the improvement of WOMAC score, Lequesne index, KSS score, Lysholms score and VAS score in the improvement of the kidney and activating blood circulation Chinese medicine and NSAIDs (P005).GRADE evidence quality evaluation suggested that the total effective rate of the traditional Chinese medicine for reinforcing kidney and blood circulation was higher than that of NSAIDs (low quality evidence). The clinical control rate of kidney Huoxue Chinese medicine was higher than that of NSAIDs (quality evidence). There was no difference in WOMAC score, Lequesne index, KSS score, Lysholms score and VAS score for kidney invigorating and activating blood circulation Chinese medicine and NSAIDs (extremely low quality evidence). The gastrointestinal tract adverse reaction of Chinese traditional Chinese medicine for invigorating kidney and promoting blood circulation should be lower than NSAIDs (low quality evidence).2. clinical study long turtle capsule group The total effective rate was 92.25%, the total effective rate of celecoxib group was 90%, the total effective difference between the two groups was not statistically significant (P0.005). Compared with the pre treatment group, the VAS score of the dragon and the celecoxib group and the celecoxib group were significantly improved by the scores of Lequesne, and the difference was statistically significant (P001). There was no significant difference in the VAS score between the BIE capsule group and the celecoxib group in the Lequesne purpose (P005). The Arthritis Impact Measurement score of the Dragon shell capsule group was lower than the celecoxib group, and the difference was statistically significant (P0.01). During the treatment, 4 cases of gastric bowel reaction were found in the Dragon shell capsule group and 3 cases of the celecoxib group had gastrointestinal reaction. There was no significant difference in the incidence of adverse reactions between the two groups (P0.05) the swelling degree of the knee joint in the model group was higher than that of the control group (P0.01) after the model of.3. animal experiment. After 2 weeks of administration, the knee swelling degree of the middle dose group was faster than the model group and the low and high dose group of the soft shelled turtle (P0.01). After 3 weeks of administration, the Dragon shelled Turtle was low, middle and high. The knee swelling degree of the knee joint in the dose group was faster than the model group (P0.01), and the knee swelling of the middle dose group of the Dragon shelled turtle had subsided to the control group (P0.05). After 4 weeks of administration, the knee swelling degree of the high dose group was lower than that of the control group (P0.05). The body weight and thymus index of the model group were lower than those of the control group. P0.05), the spleen index of the model group had a significant difference compared with the control group (P0.05). After 2 weeks of administration, the weight of the medium dose group was heavier than the control group (P0.05), but the high dose weight of the dragon and soft shelled Turtle was lower than that of the control group (P0.05). After 4 weeks of administration, the low, middle and high dose weight of the dragon and soft shelled turtle were all heavier than the control group (P 0.05), and the weight of the medium dose group was heavier than the low and high dose group (P0.05). After 2 weeks of administration, the spleen index 22 was no significant difference (P0.05). After 4 weeks of administration, the spleen index of the low, middle and high dose group was higher than that of the same stage control group and the model group (P0.05). After the administration, the low, middle, and high doses of the soft shelled turtle were low, medium and high. The thymus index of the group was higher than that of the same model group (P0.05). After 4 weeks of administration, the thymus index was not statistically significant (P0.05). After 2 weeks of administration, the degree of cartilage destruction and synovitis in the low, middle and high dose groups were lighter than those of the model group, and the knee joint synovitis in the low, middle and high dose group of dragon and soft shelled Turtle was low. After 4 weeks of administration, the histopathological score of the knee joint synovium in the middle dose group of the dragon and shelled Turtle was compared with the high dose group (P0.05). After 2 weeks of administration, the M ankin score of the knee cartilage in the low, middle and high dose group was lower than that of the model group (P0.01), and the low, middle and high level of the dragon and soft shelled turtle were low, middle and high in the same period. There was no significant difference between the 22 groups of the Mankin score of the knee cartilage in the dose group (P0.05). After the model, the IL-1 beta and IL-6 water in the model group were higher than the control group (P0.01), and the IL-10 level was lower than that of the control group (P0.01). The level of IL-1 beta in the model group was higher than that of the control group and the low, middle and high dose group (P0 group (P0) after 4 weeks. .05): the level of IL-1 beta in low, middle and high dose groups was higher than that in the same control group (P0.05), and the level of IL-1 beta in middle dose group was lower than that of low and high dose group (P0.05). After 2 weeks, the average IL-6 water in the model group was higher than that of the control group and the middle and high dose group (P0.01), and the average of IL-6 water in the low dose group of the dragon and the Turtle was lower than that of the same group. After 2 weeks of administration, the average IL-6 water in the low, middle and high dose group was higher than the control group (P0.01) after 2 weeks of administration. After 4 weeks of administration, the level of IL-6 in the low dose group was not statistically significant (P0.05). After 2 weeks and 4 weeks, the level of IL-10 in the low, middle and high dose group was higher than that of the control group and the model group. Group (P0.01), but the level of IL-10 in medium dose group was higher than that of low and high dose group (P0.01) in the same period. In synovial tissue, the cells were given MEK-3/6, p38, ATF2, NF- kappa Bp65 and P-MEK-3/6, P-p38, P-NF- kappa Bp65 in synovial tissue for 2 weeks. The percentage of positive cells was higher than that in the control group and the low, high dose group (P0.01). After 2 weeks of administration, the cells in each group had P-ATF2 weak positive expression. After 2 weeks, the percentage of P-ATF2 positive cells in the model group was higher than that of the control group and the low, middle and high dose group (P0.05). After 4 weeks, the percentage of P-ATF2 positive cells in each group was no more than that of the other groups. MEK-3/6, p38, NF- kappa Bp65 and P-MEK-3/6, P-p38, P-NF- kappa Bp65 positive expression in the cartilage tissue (P0.05) in cartilaginous tissue, and P-p38, P-NF- kappa Bp65 positive in each group. The percentage of kappa Bp65 and P-MEK-3/6, P-p38, P-NF- kappa Bp65 positive cells were lower than that of the model group (P0.05). After 2 weeks of administration, the cells all had weak positive expression of ATF2 and P-ATF2, and the percentage of ATF2 and P-ATF2 positive cells in the model group were higher than those of the control group (P0.01). After 2 weeks of administration, the percentage of the positive cells of the ATF2 cells was low in the low, middle and high dose groups of the dragon and soft shelled turtle. After 4 weeks of administration, the percentage of ATF2 positive cells in the low, middle and high dose group was compared with the model group, the difference was not statistically significant (P0.05). After 2 weeks and 4 weeks, the percentage of P-ATF2 positive cells in the low, middle and high dose group was lower than that of the model group (P005). Conclusion: 1. evidence-based medicine research on tonifying kidney and activating blood is the treatment of knee bone. The effective methods of arthritis are less adverse. Due to the small sample size and low methodological quality in the literature, the conclusion of this study still needs more high quality clinical randomized controlled trials to support.2. clinical study with the use of dragon shell capsule and celecoxib in the treatment of knee osteoarthritis, which can effectively alleviate the symptoms and improve the knee joint work. It has good effectiveness and safety, but the Dragon turtle capsule is superior to celecoxib.3. in improving the quality of life. The capsule can eliminate the swelling of the knee joint of the knee osteoarthritis rats, reduce the weight loss of rats caused by the model, increase the weight and spleen index of the knee osteoarthritis rats, and make the model cut down. The restoration of the gland index to the normal level can reduce the extent and severity of the cartilage structural damage in the knee osteoarthritis rats, significantly reduce the synovitis and promote the proliferation of chondrocytes. The experiment shows that the inflammation of the knee osteoarthritis rats by the Dragon shell capsule is closely related to the function of the immune organs of the rat. The capsule can enhance the function of immune organs of the rats with knee osteoarthritis, reduce the expression of serum inflammatory cytokine IL-1 beta, IL-6, and increase the expression of IL-I0, inhibit the excessive hyperactivity of p38MAPK and NF- kappa B signals, inhibit the activation of p38MAPK and NF-K B signaling pathway in osteoarthritis synovitis and cartilage cells. An important mechanism for the therapeutic effect.

【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R274.9

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