| Objective1. Evidence-based medicine studyTo evaluate the clinical efficacy and safety of kidney-tonifying and blood-activating medicinal for knee osteoarthritis.2. Clinical StudyTo evaluate the clinical efficacy, quality of life and safety of knee osteoarthritis patients when treating with kidney-tonifying and blood-activating medicinal LongBie Capsule.3. Animal Experimental StudyAccording to the improved effect of LongBie Capsule on knee joint swelling, body weight and organ index and pathologic change of synovium and cartilage of knee osteoarthritis rats, to observe therapeutic effect of LongBie capsule on knee osteoarthritis rats; to observe the effect of LongBie capsule on serum IL-1β, IL-6, IL-10 and the expression of MEK-3/6, p38, ATF2, NF-κ Bp65 and P-MEK-3/6, P-p38, P-ATF2, P-NF-κ Bp65 in lesion tissue of knee joint, so as to investigate the possible mechanism of LongBie capsule in the treatment of knee osteoarthritis.Methods1. Evidence-based medicine studyRCTs regarding kidney-tonifying and blood-activating medicinal compared with NSAIDs for knee osteoarthritis were retrieved and collected from Database of CBM, CNKI, WANFANG, VIP, PubMed, Embase and Cochrane Library. The quality of included literature was evaluated by Jadad scale and the risk of bias and quality evaluation of Cochrane Handbook 5.1, and the data were analyzed with the RevMan 5.3.5 of Cochrane Collaboration. The evidence quality grading evaluation of this system review was evaluated by the GRADE system.2. Clinical Study88 patients who met the inclusion criteria were randomly divided into LongBie capsule group and Celecoxib group by the method of using simple random, the LongBie capsule group was treated with LongBie capsule and the Celecoxib group was with celebrex. The observation period for the two groups was 4 weeks. The clinical efficacy, VAS Scale, Lequesne index, gastrointestinal adverse reaction, the arthritis impact measurement scale of two group were compared before and after treatment.3. Animal Experimental StudyA knee osteoarthritis rat model was established. After the mold established, LongBie capsule in the dose of 0.3125,0.625,0.9375g·kg-1 were given by gavage to the model rats for four consecutive weeks, effect of LongBie capsule on the knee joint swelling, body weight and organ index were observed; Histological changes of knee cartilage and synovium were observed after being stained with hematoxylin-eosin (HE), meanwhile, the histological score of knee synovium were evaluated. Histological changes of knee cartilage were observed again after being stained with Masson, and were evaluated by Mankin scoring method. The interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 10(IL-10) levels in the serum were determined by ELISA method. Immunohistochemistry SP(streptavidin-perosidase) method were used to detect the expression of MEK-3/6, p38, ATF2, NF-κ Bp65 and P-MEK-3/6, P-p38, P-ATF2, P-NF-κ Bp65 in synovium and cartilage tissue.Results1. Evidence-based medicine studyTwenty-two RCTs studies involving 2029 participants were included with 1022patients in kidney-tonifying and blood-activating medicinal group and 1007 patients in NSAIDs group. Meta analysis showed that when compared with NSAIDs, kidney-tonifying and blood-activating medicinal have a higher total effective rate(RR=1.10,95%CI[1.06,1.15], P<0.00001) and clinical control rate(RR=1.48,95% CI[1.19,1.84], P=0.0003), lower gastrointestinal adverse reaction(RR=0.18,95% CI[0.09,0.35], P<0.00001). There were no significant difference between kidney-tonifying and blood-activating medicinal and NSAIDs on improving WOMAC Scale, Lequesne Index, KSS Score, Lysholms Score and Visual Analogue Scale (P>0.05).The GRADE quality level of this systematic review indicated that the total effective rate of kidney-tonifying and blood-activating medicinal is higher than NSAIDs (low quality evidence), the clinical control rate of kidney-tonifying and blood-activating medicinal is higher than NSAIDs (low quality evidence), there were no significant difference between kidney-tonifying and blood-activating medicinal and NSAIDs on improving WOMAC Scale, Lequesne Index, KSS Score, Lysholms Score and Visual Analogue Scale(very low quality evidence), the gastrointestinal adverse reaction of kidney-tonifying and blood-activating medicinal is lower than NSAIDs(low quality evidence).2. Clinical StudyThe total effective rate of LongBie capsule group was 92.25%, and Celecoxib group was 90.00%, there were no significant difference between the two groupsCP >0.05).The VAS Scale, Lequesne index and the arthritis impact measurement scale of two groups after treatment were better than before treatment(P< 0.01). There were no significant difference of the VAS Scale and Lequesne between two groups after treatment (P>0.05). After treatment, the arthritis impact measurement scale of LongBie capsule group was lower than Celecoxib group (P<0.01). During treatment, there were four cases of gastrointestinal adverse reaction in LongBie capsule group and three cases in Celecoxib group, but there were no significant difference between the two groups (P>0.06).3. Animal Experimental StudyAfter the mold established, the knee joint swelling was higher than that in the control group (P<0.01). After 2 weeks of medication, the knee joint swelling of middle-dose LongBie capsule group decreased obviously than that in model group, low-dose and high-dose LongBie capsule group (P<0.01). After 3 weeks of medication, the knee joint swelling of low-dose, middle-dose and high-dose LongBie capsule groups were decreased obviously than that in model group (P<0.01), and the knee joint swelling of low-dose LongBie capsule group were not significantly different to that in control group (P>0.05). After 4 weeks of medication, the knee joint swelling of low-dose, middle-dose and high-dose LongBie capsule groups were not significantly different to that in control group (P>0.05).After the mold established, the body weight and the thymus index in model group were lower than that in the control group (P<0.05), and the spleen index in model group were not significantly different to that in control group(P >0.05). After 2 weeks of medication, the body weight of middle-dose LongBie capsule group increased obviously than that in control group (P<0.05), while the body weight of low-dose and high-dose LongBie capsule group were not significantly different to that in control group(P>0.05). After 4 weeks of medication, the body weight of low-dose, middle-dose and high-dose LongBie capsule groups were decreased obviously than that in control group (P< 0.05), and the body weight of middle-dose LongBie capsule groups were increased obviously than that in low-dose and high-dose LongBie capsule groups. After 2 weeks of medication, there was no remarkable difference on spleen index among the all groups (P>0.05). After 4 weeks of medication, the spleen index of low-dose, middle-dose and high-dose LongBie capsule groups were increased obviously than that in control group and model group (P<0.05). After 2 weeks of medication, the thymus index of low-dose, middle-dose and high-dose LongBie capsule groups were increased obviously than that in model group (P<0.05). After 4 weeks of medication, there was no remarkable difference on thymus index among the all groups(P>0.05).After 2 and 4 weeks of medication, the degree of cartilage destruction and synovial inflammation of model group were higher obviously than that in low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points, respectively (P<0.01); the histological score of knee synovium of model group were higher obviously than that in low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points, respectively (P<0.01). After 4 weeks of medication, the histological score of knee synovium of middle-dose LongBie capsule group were not significantly different to that in high-dose groups(P>0.05). After 2 and 4 weeks of medication, the Mankin scores of model group were higher obviously than that in low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points, respectively (P<0.01); there were not significantly different on Mankin scores between low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points (P>0.05).After the mold established, he serum levels of IL-1β and IL-6 in model group were higher than that in the control group (P<0.01), while the IL-10 levels were lower than that in control group (P<0.01). After 2 and 4 weeks of medication, the IL-1β levels of model group were higher obviously than that in control group, low-dose, middle-dose and high-dose LongBie Capsule groups at the identical time points (P<0.05); the IL-1β levels of low-dose, middle-dose and high-dose LongBie capsule groups were higher obviously than that in control group at the identical time points (P<0.05); the IL-1β levels of middle-dose LongBie capsule groups were lower than that in low-dose and high-dose LongBie capsule groups at the identical time points (P<0.05). After 2 and 4 weeks of medication, the IL-6 levels of model group were higher obviously than that in control group, low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points (P<0.01); the IL-6 levels of low-dose LongBie capsule groups were lower than that in middle-dose and high-dose LongBie capsule groups at the identical time points (P<0.01). After 2 weeks of medication, the IL-6 levels of low-dose, middle-dose and high-dose LongBie capsule groups were higher obviously than that in control group (P<0.01); after 4 weeks of medication, the IL-6 levels of low-dose LongBie capsule group were not significantly different to that in control group (P>0.05). After 2 and 4 weeks of medication, the IL-10 levels of low-dose, middle-dose and high-dose LongBie capsule groups were higher obviously than that in control group and model group at the identical time points (P<0.01), and the IL-10 levels of middle-dose LongBie capsule groups were higher obviously than in low-dose and high-dose LongBie capsule groups at the identical time points.In synovial tissue, after 2 and 4 weeks of medication, synovial cells in each group were have MEK-3/6, p38, ATF2, NF-κ Bp65 and P-MEK-3/6, P-p38, P-NF-κ Bp65 expression, the percentage of positive cells of MEK-3/6, p38, ATF2, NF-κ Bp65 and P-MEK-3/6, P-p38, P-NF-κ Bp65 expression of model group were higher obviously than control group and low-dose, middle-dose and high-dose LongBie capsule groups at the identical time points, respectively (P<0.01). After 2 and 4 weeks of medication, synovial cells in each group were have P-ATF2 weak expression; after 2 weeks of medication, the percentage of positive cells of P-ATF2 expression of model group were higher than control group and low-dose, middle-dose and high-dose LongBie capsule groups, respectively (P<0.05); after 4 weeks of medication, there were not significantly different on the percentage of positive cells of P-ATF2 expression between groups (P>0.05).In cartilage tissue, after 2 and 4 weeks of medication, chondrocytes in each group were have MEK-3/6, p38, NF-κ Bp65 and P-MEK-3/6, P-p38, P-NF-κ Bp65 expression, the percentage of positive cells of MEK-3/6, p38, NF-κ Bp65 and P-MEK-3/6, P-p38, P-NF-κ Bp65 expression of model group were higher obviously than control group at the identical time points, respectively (P<0.01); the percentage of positive cells of MEK-3/6, p38, NF-κ Bp65 and P-MEK-3/6, P-p38, P-NF-κ Bp65 expression of low-dose, middle-dose and high-dose LongBie capsule groups were lower obviously than model group at the identical time points, respectively (P<0.05). After 2 and 4 weeks of medication, chondrocytes in each group were have ATF2 and P-ATF2 weak expression, the percentage of positive cells of TF2 and P-ATF2 expression of model group were higher obviously than control group at the identical time points, respectively (P <0.01); after 2 weeks of medication, the percentage of positive cells of ATF2 expression of low-dose, middle-dose and high-dose LongBie capsule groups were lower obviously than model group, respectively (P<0.01); after 4 weeks of medication, there were not significantly different on the percentage of positive cells of ATF2 expression between low-dose, middle-dose and high-dose LongBie capsule groups and model group(P>0.06). After 2 and 4 weeks of medication, the percentage of positive cells of P-ATF2 expression of low-dose, middle-dose and high-dose LongBie capsule groups were lower than model group model group, respectively (P<0.05). Conclusion1. Evidence-based medicine studyKidney-tonifying and blood-activating medicinal is an effective method for knee osteoarthritis with lower adverse reaction. Since the included literatures were small sample and lower methodological quality, future large-volume, well-designed RCTs are awaited to confirm the findings of this systematic review.2. Clinical StudyBoth LongBie Capsule and Celecoxib could effectively relieved symptoms and improved the function of knee joint of knee osteoarthritis patients, with good clinical efficacy and safety. LongBie Capsule was better in improving the quality of life than celecoxib.3. Animal Experimental StudyLongBie capsule can relieve the knee joint swelling of knee osteoarthritis rats, inhibite the weight loss caused by the molding method, increase the body weight and spleen index of knee osteoarthritis rats, and made the lowered thymus increased to normal levels, reduce the degree and scope of cartilage destruction, reduce the inflammation of the synovium, and has the function of promoting the proliferation of cartilage cells. The experiment shows that LongBie capsule capable of alleviating the inflammatory reaction of knee osteoarthritis rats was related to the improving function of the immune organs.LongBie capsule can improve the function of immune organs of knee osteoarthritis rats, decrease of serum inflammatory cytokines IL-1β and IL-6 levels, and increase of serum anti-inflammatory cytokines IL-10 levels, inhibit the over expression signal of p38MAPK and NF-κB, inhibit the activation of p38MAPKs and NF-κB signaling pathway in synovial cells and chondrocytes, which may be the important mechanisms of LongBie Capsule in the treatment of knee osteoarthritis. |
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