Effect of oral diacerein (DAR) in an experimental hip chondrolysis model.

We aimed to reproduce the articular cartilage structural changes in a joint exposed to a metallic implant as in the adolescent pinned hip with persistent joint penetration and secondly, to test the effect of an interleukin inhibitor, diacerein (DAR) in the ensuing articular cartilage lesion. Twenty immature beagles were submitted to a surgical K-wire implantation in the hip with the material left in the joint space for 6 months. Twelve animals were sacrificed for histological and biochemical tests. Eight animals were sacrificed at 10 months (half of them treated with DAR) and analyzed by scanning electron microscopy (SEM) and biochemistry of the articular cartilage. Preoperative and monthly C3 and C4 complement and immunoglobulins serum levels were determined. The histological and the electrophoretic profile changes were significative at 6 months. At 10 months the migration profile (CaCl2) recovered to normal levels in the operated hip and the SEM scores for the acetabulum were similar to the non operated control hip after treatment. The serum level of IgA was elevated at the 4th and 6th month postoperatively. The persistence of a metallic implant resulted in degenerative changes parallel to that described for hip chondrolysis as a complication of in-situ pinning; and the cartilage lesion improved with DAR treatment.     

双醋瑞因减轻小鼠角膜碱烧伤炎症反应的实验研究

目的　探讨双醋瑞因减轻小鼠角膜碱烧伤炎症反应的作用。方法　将174只小鼠角膜碱烧伤造模成功的小鼠随机分为三组:双醋瑞因组、地塞米松组和生理盐水组，分别给予双醋瑞因、地塞米松、生理盐水滴眼制剂滴眼，比较造模后2 d、3 d、4 d、5 d各组小鼠的角膜混浊度、病灶面积、上皮缺损面积及炎症细胞的浸润情况。结果　双醋瑞因组造模后4 d、5 d角膜临床评分明显较生理盐水组低（均为P<0.01），地塞米松组造模后3 d、4 d、5 d角膜临床评分较生理盐水组低（均为P<0.05）。对于角膜上皮缺损而言，双醋瑞因组碱烧伤后各时间点角膜上皮缺损面积均小于生理盐水组（均为P<0.05），地塞米松组与生理盐水组角膜上皮缺损无明显差异。对角膜中性粒细胞进行统计发现，双醋瑞因组碱烧伤后各时间点中性粒细胞计量明显少于生理盐水组（均为P<0.01）；地塞米松组造模后3 d、5 d中性粒细胞浸润少于生理盐水组（均为P<0.05）。对巨噬细胞进行统计发现，双醋瑞因组造模后3 d、5 d巨噬细胞均较生理盐水组浸润少（均为P<0.05）；造模后5 d地塞米松组浸润少于生理盐水组（P<0.05）。通过MPO活性测定发现，双醋瑞因组和地塞米松组造模后2 d、3 d、5 d MPO活性均较生理盐水组明显降低（均为P<0.01）。结论　双醋瑞因能够减轻小鼠角膜碱烧伤的炎症反应，改善角膜碱烧伤的预后。     

双醋瑞因联合甲氨喋呤治疗类风湿关节炎的临床研究

目的 探讨双醋瑞因(Diacerein)联合甲氨喋呤(MTX)及单用甲氨蝶呤治疗类风湿关节炎的疗效、细胞因子变化及安全性.方法 符合纳入及排除标准的类风湿关节炎120例随机数字表法分为单用甲氨喋呤(10 mg/周)组、双醋瑞因联合甲氨喋呤治疗组(Diacerein 50 mg/次,每日2次+MTX 10 mg/周),n=60.总疗程52周,在2、6、26、52周进行疗效、细胞因子变化及安全性评价,以ACR20作为主要疗效指标,ACR50作为次要疗效指标.结果 治疗2、6、26、52周2组达ACR 20%的患者比例,治疗组:20.3%(12/59)、40.7%(24/59)、81.4%(48/59)、91.5%(54/59),对照组:1.7%(1/59)、22.0%(13/59)、59.3%(35/59)、71.2%(42/59),治疗组明显高于对照组,差异有统计学意义(P<0.05);达ACR 50%的患者比例,治疗组:0%(0/59)、13.6%(8/59)、50.8%(30/59)、83.1%(49/59),对照组:0%(0/59)、0%(0/59)、39.0%(23/59)、59.3%(35/59),治疗组明显高于对照组,自第6周起差异有统计学意义(P<0.01,P<0.05).52周时双醋瑞因联合甲氨喋呤组疼痛、患者对自身健康状况的总体评估(PGA)、健康评价(HAQ)、血沉(ESR)、C反应蛋白(CRP)、IL-1、IL-6、TNF-α的改善和变化高于单用甲氨喋呤组(P<0.01, P<0.05).结论 双醋瑞因联合甲氨喋呤治疗类风湿关节炎能显著改善其症状及实验室指标,疗效明显优于单用甲氨蝶呤组,并且起效快、安全性好,不增加不良反应的发生率.     

2%双醋瑞因滴眼液结膜囊多次与单次给药的角膜药代动力学差异

目的：对比2%双醋瑞因滴眼液结膜囊多次给药与单次给药在角膜中的药代动力学差异,为临床医师治疗感染性角膜病时多次给药提供实验依据。

方法：以2%双醋瑞因为实验滴眼液,选取健康无眼疾的雄性昆明白小鼠,随机分为多次给药组和单次给药组,双眼结膜囊分别给予双醋瑞因滴眼液。多次给药组间隔2min给药一次,共给药3次; 单次给药组仅给药1次。用高效液相法测定角膜中双醋瑞因的代谢产物(大黄酸)的浓度,多次给药组和单次给药组的时间点均为5、15、30、60、120、180min。将小鼠角膜组织中的药物浓度经药物动力学程序(DAS2.1.1)进行拟合,并计算相关药动学参数。

结果：结膜囊多次给药组和单次给药组各个时间点角膜中均可检测到其活性代谢产物大黄酸; 多次给药组5、15、30、60、120、180min的浓度分别为318.678±40.88、210.02±25.66、188.83±31.74、112.24±11.70、90.28±22.01和57.67±13.71μg/g,单次给药组各时间点浓度分别为145.17±19.29、97.95±10.49、71.18±18.70、39.11±2.44、18.10±2.34和9.08±2.04μg/g。两组小鼠角膜中大黄酸的含量均于给药后5min最高,多次给药组浓度高于单次给药组浓度,差异具有统计学意义(P<0.01)。随时间延长大黄酸的浓度逐渐下降,3h后多次给药组浓度仍高于单次给药组,差异具有统计学意义(P<0.01)。单次给药组半衰期为0.89±0.31h。

结论：结膜囊多次给药与单次给药相比具有药物有效浓度高、维持时间长的优点,双醋瑞因作为一种新的抗菌药物,可以在感染性角膜炎的早期对病程的发展起到抑制作用。多次给药后可以对急性发展期起到较好的治疗效果,而且在夜晚也可维持较高浓度,在保证患者的睡眠休息质量同时又起到了对疾病的治疗作用。     

双醋瑞因联合独活寄生汤治疗中老年膝骨性关节炎

目的:评价双醋瑞因联合独活寄生汤治疗中老年膝骨性关节炎的临床疗效和安全性。方法:将确诊为膝骨性关节炎患者120例随机分为A,B,C 3组,A组为独活寄生汤组,B组为双醋瑞因组,C组为独活寄生汤联合双醋瑞因组,分别采用相应治疗。3组均以1个月为1个疗程,共观察、治疗3个疗程。以VAS评分、WOMAC评分、红细胞沉降率(ESR),C反应蛋白(CRP)治疗前后变化作为临床疗效判定指标,并对综合疗效评分做出评价,观察治疗过程中不良反应例数。结果:3个月治疗后,3组VAS评分,WOMAC评分,ESR,CRP均较治疗前有显著改善(P<0.01),C组临床疗效指标改善情况要优于药物单用的B和C组(P<0.05),且综合疗效评价效果较好(P<0.01),且具有较低的不良反应率(7.5%)。结论:双醋瑞因、独活寄生汤是治疗膝骨关节炎的有效药物,临床疗效良好,联合使用效果更为显著,且无明显不良反应,值得推广。     

微小RNA的辐射敏感性和生物标记作用的研究进展

目的 探讨复方玄驹胶囊联合双醋瑞因治疗膝骨性关节炎的临床疗效。方法 选取2019年5月—2021年4月在扬州大学医学院附属沭阳医院就诊的200例膝骨性关节炎患者作为研究对象,按照治疗方法将患者分为对照组和观察组,各100例。对照组口服双醋瑞因胶囊,50 mg/次,2次/d。观察组在对照组基础上口服复方玄驹胶囊,3粒/次,3次/d。患者连续治疗4周。观察两组的临床疗效,比较两组治疗前后的西安大略和麦马斯特大学骨关节炎指数（WOMAC）、膝关节的活动度评分（ROM）、膝关节功能评分（Lysholm）以及血清人类软骨寡聚蛋白（COMP）、基质金属蛋白酶-3（MMP-3）、白细胞介素-17（IL-17）水平。结果 治疗后,观察组的总有效率为91.00%,明显高于对照组的80.00%,差异有统计学意义（P<0.05）。治疗后,两组的疼痛、僵硬、日常生活评分、WOMAC总分显著降低（P<0.05）;治疗后,观察组的疼痛、僵硬、日常生活评分、WOMAC总分显著低于对照组,差异有统计学意义（P<0.05）。治疗后,两组ROM评分、Lysholm评分均显著升高（P<0.05）,且观察组ROM评分、Lysholm评分显著高于对照组（P<0.05）。治疗后,两组的COMP、MMP-3、IL-17水平均显著降低（P<0.05）;且观察组COMP、MMP-3和IL-17水平显著低于对照组,差异有统计学意义（P<0.05）。结论 复方玄驹胶囊联合双醋瑞因治疗膝骨性关节炎的疗效确切,可改善膝关节功能和活动度,控制病情,可能与调节炎症因子有关,安全性良好。     

Influence of renal function on the pharmacokinetics of diacerein after a single oral dose

Summary— The pharmacokinetics of diacerein (a new anti-inflammatory analgesic antipyretic drug) following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of eight patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC_0-∞ was multiplied by a factor of ca 2: 40.5 mg h/l versus 21.3 in healthy subjects, P = 0.04; and t_1/2 was prolonged by the same factor: 9.6 h versus 4.3 in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% ( P = 0.01) and 0.13 l/h ( P = 0.008) in healthy subjects. Amounts of glucuro and sulfo conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag-time, C_max, t_max, V_ss/F, urinary glucuro- to sulphoconjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the maintenance dosage of diacerein should be considered in severe renal failure.     

Stability-indicating spectrophotometric and spectrodensitometric methods for the determination of diacerein in the presence of its degradation product

Three sensitive, selective, and precise stability-indicating methods for the determination of the novel osteoarthritis drug, diacerein (DIA) in the presence of its alkaline degradation product (active metabolite, rhein) and in pharmaceutical formulation were developed and validated. The first method is a first derivative (D(1) ) spectrophotometric one, which allows the determination of DIA in the presence of its degradate at 322 nm (corresponding to zero crossing of the degradate) over a concentration range of 4-40 μg/mL with mean percentage recovery 100.21 ± 0.833. The second method is the first derivative of the ratio spectra (DD(1) ) by measuring the peak amplitude at 352 nm over the same concentration range as (D(1) ) spectrophotometric method, with mean percentage recovery 100.09 ± 0.912. The third method is a TLC-densitometric one, where DIA was separated from its degradate on silica gel plates using ethyl acetate:methanol:chloroform (8:1.5:0.5 v:v:v) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of DIA at 340 nm over a concentration range of 1-10 μg/spot, with mean percentage recovery 100.24 ± 1.412. The selectivity of the proposed methods was tested using laboratory-prepared mixtures. The proposed methods have been successfully applied to the analysis of DIA in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with reference method.     

双醋瑞因对破骨细胞性骨破坏的抑制作用及机制

目的考察双醋瑞因对破骨细胞生成及骨破坏功能是否具有抑制作用，以及双醋瑞因抑制破骨细胞的作用是否与影响成骨细胞中OPG及RANKL的表达有关。方法MC3T3-E1细胞与骨髓前体细胞共培养生成破骨细胞，将TRAP染色阳性、细胞核数目≥3个的细胞作为破骨细胞，计数生成的破骨细胞。计数IL-1β作用前后典型的骨吸收陷窝以观察破骨细胞的活性。应用Western blotting法、流式细胞术及RT-PCR法在蛋白水平及基因水平观察MC3T3-E1细胞中RANKL及OPG的表达。结果双醋瑞因可显著抑制IL-1β作用下破骨细胞的生成及其骨陷窝形成功能，sRANKL的加入可逆转双醋瑞因的上述作用。双醋瑞因可在基因及蛋白水平上调MC3T3-T1细胞中OPG/RANKL的比例。结论双醋瑞因具有抑制IL-1β诱导的破骨细胞性骨破坏的作用，这一作用可能与其抑制MC3T3-E1细胞中RANKL表达同时促进OPG表达有关。