BACKGROUND: Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA. METHODS: This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1:1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0-10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events. RESULTS: Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147-0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00-22.50] vs . 16.00 [11.00-27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs . 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain. CONCLUSIONS This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.
Humans ; Female ; Middle Aged ; Aged ; Osteoarthritis, Knee/drug therapy* ; Flurbiprofen/therapeutic use* ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use* ; Pain/drug therapy* ; Treatment Outcome ; Double-Blind Method

OBJECTIVE: To prepare a novel hyaluronic acid methacrylate (HAMA) hydrogel microspheres loaded polyhedral oligomeric silsesquioxane-diclofenac sodium (POSS-DS) patricles, then investigate its physicochemical characteristics and in vitro and in vivo biological properties. METHODS: Using sulfhydryl POSS (POSS-SH) as a nano-construction platform, polyethylene glycol and DS were chemically linked through the "click chemistry" method to construct functional nanoparticle POSS-DS. The composition was analyzed by nuclear magnetic resonance spectroscopy and the morphology was characterized by transmission electron microscopy. In order to achieve drug sustained release, POSS-DS was encapsulated in HAMA, and hybrid hydrogel microspheres were prepared by microfluidic technology, namely HAMA@POSS-DS. The morphology of the hybrid hydrogel microspheres was characterized by optical microscope and scanning electron microscope. The in vitro degradation and drug release efficiency were observed. Cell counting kit 8 (CCK-8) and live/dead staining were used to detect the effect on chondrocyte proliferation. Moreover, a chondrocyte inflammation model was constructed and cultured with HAMA@POSS-DS. The relevant inflammatory indicators, including collagen type Ⅱ, aggrecan (AGG), matrix metalloproteinase 13 (MMP-13), recombinant A disintegrin and metalloproteinase with thrombospondin 5 (Adamts5), and recombinant tachykinin precursor 1 (TAC1) were detected by immunofluorescence staining and real-time fluorescence quantitative PCR, with normal cultured chondrocytes and the chondrocyte inflammation model without treatment as control group and blank group respectively to further evaluate their anti-inflammatory activity. Finally, by constructing a rat model of knee osteoarthritis, the effectiveness of HAMA@POSS-DS on osteoarthritis was evaluated by X-ray film and Micro-CT examination. RESULTS: The overall particle size of POSS-DS nanoparticles was uniform with a diameter of about 100 nm. HAMA@POSS-DS hydrogel microspheres were opaque spheres with a diameter of about 100 μm and a spherical porous structure. The degradation period was 9 weeks, during which the loaded POSS-DS nanoparticles were slowly released. CCK-8 and live/dead staining showed no obvious cytotoxicity at HAMA@POSS-DS, and POSS-DS released by HAMA@POSS-DS significantly promoted cell proliferation (P<0.05). In the chondrocyte anti-inflammatory experiment, the relative expression of collagen type Ⅱ mRNA in HAMA@POSS-DS group was significantly higher than that in control group and blank group (P<0.05). The relative expression level of AGG mRNA was significantly higher than that of blank group (P<0.05). The relative expressions of MMP-13, Adamts5, and TAC1 mRNA in HAMA@POSS-DS group were significantly lower than those in blank group (P<0.05). In vivo experiments showed that the joint space width decreased after operation in rats with osteoarthritis, but HAMA@POSS-DS delayed the process of joint space narrowing and significantly improved the periarticular osteophytosis (P<0.05). CONCLUSION HAMA@POSS-DS can effectively regulate the local inflammatory microenvironment and significantly promote chondrocyte proliferation, which is conducive to promoting cartilage regeneration and repair in osteoarthritis.
Animals ; Rats ; Matrix Metalloproteinase 13 ; Microspheres ; Hydrogels ; Collagen Type II ; Diclofenac ; Inflammation ; Osteoarthritis, Knee/drug therapy* ; Hyaluronic Acid ; Aggrecans

Metabolomics based on ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) was employed to analyze the effect of Cyathulae Radix on serum and urine in rats with knee osteoarthritis, and to decipher the mechanism of Cyathulae Radix in the treatment of knee osteoarthritis. SD rats were randomized into a normal group, a model group, a positive drug group, and a Cyathulae Radix group. The knee osteoarthritis model was established by injecting 2% pa-pain and 0.03 mol·L~(-1) cysteine, and the serum levels of tumor necrosis factor-α(TNF-α) and matrix metalloproteinase-3(MMP-3) in the model group was measured to preliminarily evaluate the therapeutic effect of Cyathulae Radix on knee osteoarthritis. UHPLC-Q-TOF-MS was employed to establish the metabolic profile of endogenous small molecule metabolites in the four groups. Potential biomarkers were screened out by multivariate analysis methods such as partial least squares discriminant analysis(PLS-DA) and orthogonal partial least squares discriminant analysis(OPLS-DA) in combination with t-test, variable importance for projection(VIP), and fold-change. The related metabolic pathways were enriched with the help of MetaboAnalyst 5.0. The results showed that Cyathulae Radix alleviated the general signs of rats with knee osteoarthritis, and reduced the levels of TNF-α and MMP-3 in the rat serum. Twenty-eight differential metabolites that might be associated with the therapeutic effect of Cyathulae Radix were screened out from serum and urine. They were mainly involved in arginine biosynthesis, nicotinate and nicotinamide metabolism, tricarboxylic acid cycle, alanine, aspartate and glutamate metabolism, riboflavin metabolism, glyoxylate and dicarboxylate metabolism, and pyrimidine metabolism. Through metabonomics analysis, this study predicted the possible mechanism of Cyathulae Radix in the treatment of knee osteoarthritis, which laid a foundation for further research.
Rats ; Animals ; Matrix Metalloproteinase 3 ; Osteoarthritis, Knee/drug therapy* ; Tumor Necrosis Factor-alpha ; Rats, Sprague-Dawley ; Metabolomics/methods* ; Chromatography, High Pressure Liquid/methods* ; Biomarkers

This study aims to assess the efficacy and safety of Hulisan Capsules in the treatment of knee osteoarthritis, which is expected to serve as a reference for clinical practice. To be specific, randomized controlled trial(RCT) on the treatment of knee osteoarthritis with Hulisan Capsules was retrieved from EMbase, PubMed, Cochrane Library, Web of Science, CNKI, Wanfang, SinoMed, and VIP(from inception to November 15, 2021). Two researchers independently screened the articles, extracted the data, and evaluated the risk of bias with ROB. RevMan 5.4 was used for Meta-analysis. Finally, 12 RCTs were screened out, involving 1 703 cases(1 075 in the experimental group and 628 in the control group). Meta-analysis showed that conventional treatment + Hulisan Capsules was superior to conventional treatment alone in terms of symptom relief rate(RR=1.19, 95%CI[1.09, 1.30], P<0.000 1), Lysholm score(MD=11.17, 95%CI[7.35, 15.00], P<0.000 01), visual analogue scale(VAS) score(MD=-0.99, 95%CI[-1.30,-0.68], P<0.000 01), and knee function score(RR=8.94, 95%CI[6.51, 11.37], P<0.000 01). Hulisan Capsules alone was superior to the conventional treatment alone in terms of the symptom relief rate(RR=1.38, 95%CI[1.13, 1.69], P=0.002) and knee function score(MD=2.88, 95%CI[0.81, 4.94], P=0.006), but VAS score was insignificantly different between the patients treated with Hulisan Capsules alone and those with conventional treatment alone(MD=-0.57, 95%CI[-1.42, 0.29], P=0.19). Hulisan Capsules + conventional treatment showed insignificant difference in symptom relief rate from the Zhuifeng Tougu Capsules + conventional treatment(RR=1.07, 95%CI[0.91, 1.25], P=0.44). The Lequesne score was insignificantly different between Hulisan Capsules + conventional treatment and conventional treatment/Zhuifeng Tougu Capsules + conventional treatment(MD=-2.17, 95%CI[-6.29, 1.96], P=0.30). The incidence of adverse reactions in the experimental group was significantly lower than control group(RR=0.57, 95%CI[0.34, 0.96], P=0.03). According to the available data and methods, Hulisan Capsules/Hulisan Capsules + conventional treatment could improve the symptom relief rate, Lysholm score, knee function score, and VAS score of patients with knee osteoarthritis, and alleviate the symptoms of pain, stiffness, and swelling of them. No serious adverse reactions were found yet. In the future, more large-sample and standard clinical trials are needed to verify the effect and safety of Hulisan Capsules in the treatment of knee osteoarthritis.
Humans ; Osteoarthritis, Knee/drug therapy* ; Capsules ; Pain

OBJECTIVE: To explore effects of acupotomy on pain, function, gait and serum inflammatory factors in patients with knee osteoarthritis(KOA). METHODS: From December 2017 to June 2019, 110 patients with KOA were collected and divided into acupotomy group(56 cases) and western medicine group(54 cases) by using random number table method. In acupotomy group, there were 16 males and 40 females, aged from 46 to 74 years old with an average of (62.98±6.68) years old, the course of disease ranged from 1 to 240 months with an average of 24.5(15.25, 33.00) months;were treated with acupotomy on the pain points around knee joint once a week for 3 weeks. In western medicine group, there were 18 males and 36 females, aged from 47 to 73 years old with an average of (64.19±5.98 ) years old;the course of disease ranged from 1 to 220 months with an average of 25.00(13.75, 33.00) months;were took celecoxib capsule orally, 200 mg once a day for 3 weeks. Oxford Knee Score(OKS) was performed before treatment, 3 weeks and 3 months after treatment. Gait kinematics analysis and serum levels of tumor necrosis factor-α(TNF-α) and interleukin-1β (IL-1β) were measured before and after treatment for 3 weeks. RESULTS: All patients were followed up from 6 to 24 months with an average of(15.03±4.55) months. OKS between two groups decreased significantly at 3 weeks and 3 months after treatment(P<0.001). Functional scores and overall scores in acupotomology group were significantly decreased at 3 months compared with 3 weeks after treatment(P<0.001). OKS of acupotomy group were significantly lower than those of western medicine group at 3 weeks and 3 months after treatment(P<0.05). Gait speed, frequency and length between two groups were significantly improved at 3 weeks after treatment(P<0.05). At 3 weeks after treatment, gait freguency of acupotomy group was significantly improved compared with western medicine group(P<0.05). TNF-α and IL-1β were significantly lower in both groups at 3 weeks after treatment than before treatment(P<0.05). At 3 weeks after treatment, level of IL-1 β was lower in western medicine group than in acupotomy group(P<0.05), and difference in TNF-α level was not statistically significant(P>0.05). CONCLUSION Acupotomology of pain points could significantly improve pain, function, gait, and decreased serum inflammatory factors at early to mid stage of KOA patients, in particular, it is superior to non-steroidal anti-inflammatory drugs in terms of knee function recovery and cadence improvement.
Acupuncture Therapy ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use* ; Celecoxib/therapeutic use* ; Female ; Gait ; Humans ; Interleukin-1beta ; Male ; Middle Aged ; Osteoarthritis, Knee/drug therapy* ; Pain/drug therapy* ; Tumor Necrosis Factor-alpha

To evaluate the efficacy and safety of Chinese patent medicine in the treatment of knee osteoarthritis(KOA) with network Meta-analysis, and provide evidence-based medicine evidences for clinical practice. PubMed, Cochrane Library, EMbase, CNKI, Wanfang, VIP and CBM were used to search for clinical randomized controlled trials(RCTs) on Chinese patent medicines for treatment of knee osteoarthritis, with a time limit from the establishment of each database to March 2020. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included RCTs. The network Meta-analysis was performed by Stata 14.0 software. A total of 5 788 patients in 58 RCTs were included, involving 9 kinds of Chinese patent medicines. The results of the network Meta-analysis indicated that in terms of total effective rate, the top three optimal medication regimens were Jinwu Gutong Capsules + Amino Acid Glucose(AAG), Xianling Gubao + AAG and Biqi Capsules; the top three interventions to reduce the VAS score were Panlongqi Tablets > Xianling Gubao + AAG > Xianling Gubao + non steroidal anti-inflammatory drugs(NSAIDs); the top three interventions to reduce the total score of WOMAC were Jintiange Capsules+NSAIDs> Jinwu Gutong Capsules + AAG > Biqi Capsules + NSAIDs; the top three medication schemes with better curative effect to reduce Lequesnse index were Xianling Gubao + NSAIDs > Biqi Capsules + NSAIDs > Jintiange Capsules + NSAIDs; the top three interventions to reduce TNF-α level Xianling Gubao + AAG > Jintiange Capsules > Jintiange Capsules + AAG=Jinwu Gutong Capsules + AAG. In terms of safety, the top five interventions with the least adverse reactions were Biqi Capsules > Jinwu Gutong Capsules > Biqi Capsules + NSAIDs > Xianling Gubao + NSAIDs > Jintiange Capsules. The combined application of Chinese patent medicine and NSADIs or AAG can improve the clinical treatment effect and reduce adverse reactions in KOA patients.
Biological Products ; China ; Drugs, Chinese Herbal ; Humans ; Network Meta-Analysis ; Nonprescription Drugs ; Osteoarthritis, Knee/drug therapy*

OBJECTIVE: To compare clinical effects of compound betamethasone and compound betamethasone with hyaluronic acid in treating moderate-severe knee osteoarthritis (KOA). METHODS: A prospective randomized controlled study was conducted in 116 patients with unilateral moderate-severe KOA patients from February 2017 to November 2017 and divided into observation group and control group, 58 patients in each group. In observation group, there were 15 males and 43 females aged from 45 to 80 years old with an average of (66.45±6.31) years old;according to Kellgren-Lawrence(K-L) classification, 42 patients were type Ⅲ and 16 patients were type Ⅳ;the courses of disease ranged from 4 to 8 years with an average of (5.25±2.21) years;the patients were treated by injecting 1 ml compound betamethasone into knee joint. In control group, there were 13 males and 45 females aged from 45 to 80 years old with an average of (64.89±6.41) years old;according to K-L classification, 43 patients were type Ⅲ and 15 patients were type Ⅳ;the courses of disease ranged from 4 to 10 years with an average of (5.41±2.35) years;the patients were treated by knee joint injection of 4 ml hyaluronic acid and 1 ml compound betamethasone. Visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC) were used to evaluate clinical effects before treatment and 1 week, 1, month, 3 and 6 months after treatment. RESULTS: Totally 55 patients in observation group were followed up for 6 months, and 3 patients were quit at 3 months after treatment for poor efficacy. Totally 56 patients in control group were followed up for 6 months, and 2 patients were withdrew from the follow-up on the first and third month respectively for poor efficacy. There were no statistical difference in VAS and WOMAC between two groups before treatment and different time points after treatment ( CONCLUSION For patients with moderate-severe KOA, there is no significant difference in therapeutic effect between compound betamethasone injection and compound betamethasone combined with hyaluronic acid injection, and long-term effect of two methods is not good.
Betamethasone ; Child ; Child, Preschool ; Female ; Humans ; Hyaluronic Acid ; Injections, Intra-Articular ; Male ; Osteoarthritis, Knee/drug therapy* ; Prospective Studies ; Treatment Outcome

Wangbi Tablets are widely used in the treatment of rheumatoid arthritis, knee osteoarthritis and other diseases at pre-sent. Long-term clinical application and research have shown that this drug has a good effect in reducing the pain of related diseases and improving symptoms. Due to the lack of guidance in the instructions and currently no relevant norms to guide the clinical application of Wangbi Tablets, in order to further improve clinicians' understanding of the drug and fully tap the clinical advantages of the drug, the Professional Committee of Orthopedics and Traumatology Drug Research of China Association of Chinese Medicine organized experts in the fields of rheumatism, orthopedics, pharmacy and methodology in Chinese and western medicine to develop expert consensus on Chinese patent medicines in accordance with the relevant requirements of the consensus methodology. Based on full consideration of clinical research evidence and expert experience, the clinical issues were summarized in the consensus, and for those clinical problems supported by evidences, the internationally recognized recommendation evaluation and formulation method GRADE was used to evaluate the evidence and form recommendations; for those clinical issues not supported by evidences, a consensus was reached through the nominal group method to form consensus recommendations. The consensus adopted a concise and clear format to form re-commendations or reach consensus suggestions on the medication regimen, medication characteristics, intervention timing, usage and dosage, course of use and safety issues for the treatment of rheumatoid arthritis and knee osteoarthritis with Wangbi Tablets. It is suggested that its application will better improve the efficacy of Wangbi Tablets in the treatment of rheumatoid arthritis and knee osteoarthritis, at the same time provide a reference for clinicians to use Wangbi Tablets in a standardized, reasonable and safe manner.
Arthritis, Rheumatoid/drug therapy* ; Consensus ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Osteoarthritis, Knee/drug therapy* ; Tablets

OBJECTIVE: To observe and evaluate the clinical effect of intra-articular injection of parecoxib in patients with early knee osteoarthritis. METHODS: From September 2016 to August 2017, 107 patients with early knee osteoarthritis were treated, including 50 males and 57 females, aged 45 to 64 (51.9±4.2) years. They were divided into basic therapy+oral glucosamine group(group A) 36 cases, oral celecoxib+basic therapy+oral glucosamine group(group B) 36 cases, intra-articular injection of parecoxib+basic therapy+oral glucosamine group(group C) 35 cases. There was no significant difference in gender, age, BMI and clinical stage(Kellgren-Lawrence classification) between the three groups before treatment. VAS score, HSS score and patient satisfaction were compared before and after treatment in the three groups. The levels of inflammatory cytokines in synovial fluid were measured before and after treatment in the three groups. RESULTS: All cases were followed up for(15.2±2.6) months on average. The VAS score and HSS score of each group were improved after treatment(<0.001). There were significant differences in VAS and HSS scores among the three groups after treatment(<0.001). The clinical efficacy of group C was better than that of group A and B(<0.001), group B was better than that of group A(<0.001), and group C had the highest satisfaction(<0.001). After treatment, the concentration of proinflammatory factor TNF-α and IL-6 in the synovial fluid of each group decreased(<0.001) and the concentration of anti-inflammatory factor IL-10 increased(<0.001). After treatment, the concentrations of TNF-α, IL-6 and IL-10 in the synovial fluid of the three groups were significantly different(<0.001). CONCLUSIONS For patients with early knee osteoarthritis, intra-articular injection of parecoxib can significantly improve clinical symptoms and avoid adverse reactions of long-term oral NSAIDs, which is an effective treatment.
Adult ; Aged ; Female ; Humans ; Injections, Intra-Articular ; Isoxazoles ; therapeutic use ; Male ; Middle Aged ; Osteoarthritis, Knee ; drug therapy

OBJECTIVES: To observe the effects of Yougui pill (Traditional Chinese Medicine) on the related factors of Wnt signal pathway of rats with knee osteoarthritis (KOA), and explore its protective mechanism. METHODS: Sixty SPF SD rats were randomly divided into the sham-operative group, model group, glucosamine sulfate group, high-dose, middle-dose, low-dose of Yougui pill treated group (=10). KOA model was established by modified Hulth method for six weeks. The rats in the high, middle and low-dose of Yougui pill group were treated with Yougui pills at the doses of 20,10 and 5 g/kg respectively by gastrogavage once a day for 8 weeks, while equal volume of normal saline was given to those in the sham and model control group and an equal volume of glucosamine sulfate (1.7 g/kg·d) was given to those in glucosamine sulfate group for 8 weeks. The knee joint was removed after the last dose of drug. The pathological changes of cartilaginous tissues were observed under a microscope. The mRNA levels of Dickkopf homolog 1(DKK1), Wnt induced secreted protein 1(WISP1), Wnt1, low density lipoprotein receptor related protein 5(LRP5) and beta -catenin in rats cartilaginous tissues were analyzed by using RT-PCR method, and the protein contents of DKK1, WISP1, Wnt1, LRP5 and beta-catenin in cartilaginous tissues were detected by Western blot. RESULTS: Compared with the sham group, the articular cartilage was severely damaged, the Mankin score was increased significantly (<0. 05), the mRNA and protein expression levels of DKK1 in cartilaginous tissue were markedly decreased(<0.05), while those of WISP, Wnt1, LRP5 and beta-catenin were increased significantly in model group(<0.05). Compared with model group, the articular cartilage lesions was light (<0.05), the Mankin Score was decreased significantly(<0.05), and the mRNA and protein levels of DKK1 in cartilaginous tissue were increased(<0.05), while those of WISP, Wnt1, LRP5 and beta-catenin were decreased in Yougui pill high-dose group and glucosamine sulfate group (<0.05). CONCLUSIONS Yougui pill has protective effects on the KOA by inhibiting the expressions of WISP, Wnt1, LRP5, beta-catenin and increasing the expression of DKK1 cytokine in the Wnt signaling pathway.
Animals ; CCN Intercellular Signaling Proteins ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Glucosamine ; pharmacology ; Intercellular Signaling Peptides and Proteins ; metabolism ; Osteoarthritis, Knee ; drug therapy ; Proto-Oncogene Proteins ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Wnt Signaling Pathway ; Wnt1 Protein ; metabolism ; beta Catenin ; metabolism