Targeted delivery of hyaluronic acid-coated solid lipid nanoparticles for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders.     

Successful administration of BI 695501, an adalimumab biosimilar,using an autoinjector (AI): results from a Phase II open-label clinical study (VOLTAIRE®-RL)

Background: This study examined the patient handling experience and self-injection success of patients with rheumatoid arthritis (RA) administering BI 695501 using an AI.

Methods: This Phase II, 7-week, open-label, interventional study (NCT02636907) included adult patients with moderately to severely active RA not adequately controlled by DMARDs, with no experience of self-injecting with AI/pen. Patients self-injected BI 695501 via AI every 2 weeks in the AI Assessment Period (AAP). Training was given on first injection; AI handling events were recorded. Percentage of self-injection success was the primary end point. Patients could enter a 42-week pre-filled syringe (PFS) safety extension.

Results: The AAP was completed by 73/77 patients. In total, 216/218 (99.1%) self-injections on Days 15, 29, and 43, were successful. Nine (11.7%) patients had drug-related adverse events (AEs). Two patients reported four serious AEs (SAEs), none drug-related. Overall (in the AAP and PFS extension), 28 (36.4%) patients had drug-related AEs; nine patients had SAEs, one was considered drug-related. Five (6.5%) patients reported injection-site reactions in the AAP; 13 (18.1%) in the PFS extension.

Conclusions: After training, almost all patients were successfully able to self-administer BI 695501 using an AI. BI 695501 via AI (and via PFS in the extension) was well tolerated.

Clinical Trial Registration: NCT02636907     

他克莫司与甲氨蝶呤联合治疗难治性类风湿关节炎效果观察

摘 要 目的：探讨他克莫司与甲氨蝶呤联合治疗难治性类风湿关节炎的临床效果。方法：80例难治性类风湿关节炎患者随机分为观察组和对照组,每组40例。观察组给予他克莫司与甲氨蝶呤联合治疗,对照组给予环磷酰胺与甲氨蝶呤联合治疗,两组均治疗24周。观察两组患者治疗前后关节疼痛指数、关节肿胀指数及晨僵时间的变化,采用视觉模拟评分（VAS ）对患者疼痛情况进行评估;评价两组临床疗效;比较两组患者治疗前后红细胞沉降率（ESR）、C 反应蛋白（CRP）、肿瘤坏死因子α（TNF α）、血管内皮生长因子（VEGF）等指标变化。结果：观察组总缓解率为100.00%,显著高于对照组的67.50%（P<0.05）。治疗后两组关节疼痛指数、关节肿胀指数、晨僵时间及VAS 评分均较治疗前显著降低（P<0.05）,且观察组各项指标均明显低于对照组（P<0.05）。两组治疗后ESR、CRP、TNF α、VEGF均较治疗前显著降低（P<0.05）,且观察组明显低于对照组（P<0.05）。结论：他克莫司与甲氨蝶呤联合治疗难治性类风湿关节炎临床疗效好,安全性高,其作用机制可能与降低患者体内炎症反应及下调VEGF水平有关。     

类风湿关节炎合并心血管疾病的研究进展

类风湿关节炎(RA)患者心血管疾病(CVD)的风险高于年龄和性别相匹配的一般人群的1.5～2.0倍.因全身慢性炎症导致的心血管风险增高是RA的特征之一.RA最优化心血管风险管理的挑战包括改进预测心血管风险的方法和确定目标危险因素以减少心血管风险.从RA研究中吸取经验教训,对于一般人群同样收益,因为炎症在动脉粥样硬化的发病机制中有着重要作用.     

Drug safety evaluation of certolizumab pegol

Introduction: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents.

Areas covered: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy.

Expert opinion: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta.     

Adalimumab: a review of side effects

Adalimumab (Humira^®) is a human monoclonal TNF-α antibody that blocks the effects of TNF-α. It is administered by subcutaneous injection. It has been approved alone or in combination with methotrexate for the treatment of rheumatoid arthritis in the EU and US. Approval for its use for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis is expected in the near future. Its side effect profile is favourable when compared with traditional systemic treatments for these diseases. It does not require laboratory monitoring. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. There is a two-fold risk of serious infections with the use of adalimumab, as reported in the Premier trial. This risk should not be minimised in this way. It should not be used during periods of active infection. Its most notable infectious complication is the reactivation of tuberculosis. Tuberculosis screening should be according to country standards and may or may not include purified protein derivative test or chest X-ray. Deep fungal and other serious and atypical infection can also be promoted by adalimumab. It has been associated infrequently with skin rashes. Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease. There has been reported pancytopenia and elevated transamines with the use of adalimumab, which suggest that laboratory monitoring blood counts and liver functions, at least intermittently, are useful. In patients with any of the foregoing problems, its use should be extremely carefully considered. Adalimumab is a useful medication which can be safely used if its side effects are recognised.     

Surface modification of poly (l-lactic acid) microspheres for site-specific delivery of ketoprofen for chronic inflammatory disease

The purpose of this research was to investigate the potential of surface modified Poly (l-lactic acid) (PLA) microspheres as a carrier for site-specific delivery of anti-inflammatory drug, ketoprofen, for the treatment of rheumatoid arthritis. Microspheres were prepared by solvent evaporation method using 20% w/w PLA in methylene chloride and 100 mL of a 2.5% poly vinyl alcohol (PVA) solution. Formulations were optimized for several processing parameters like drug to polymer ratio, stirring rate and volume of preparation medium etc. The surface of PLA microspheres was modified with gelatin to impart fibronectin recognition. The microspheres were characterized by surface morphology, size distribution, encapsulation efficiency, and by in vitro drug release studies. The prepared microspheres were light yellow, discrete, and spherical. Formulation with optimum drug to polymer ratio exhibited smallest vesicle size (43.02), high drug encapsulation efficiency (81.11) and better process yield (83.45). The release of drug was extended up to 24 h with Higuchi pattern of drug release. The in vivo results showed that the gelatin modified formulation reduced paw edema at greater extent than pure drug and PLA microspheres and it could be a promising carrier system for controlled and site-specific delivery of ketoprofen with possible clinical applications.     

红花寄生对尿酸钠诱导急性痛风性关节炎大鼠的干预作用

目的：探究红花寄生对尿酸钠诱导急性痛风性关节炎大鼠的干预作用。方法：36只SD大鼠随机分为正常组（生理盐水）、模型组（生理盐水）、苯溴马隆组（阳性对照,4.2 mg·kg-1）和红花寄生高、中、低量组（4.0、2.0、1.0 g·kg-1）,连续灌胃给药10天（苯溴马隆组2天）,灌胃体积为10 mL·kg-1,每天给药1次。末次给药1 h后,除正常组外其余各组大鼠用微晶型尿酸钠（MSU）诱发急性痛风性关节炎。于造模后0、2、4、8、12、24、48、72、96 h测量右侧踝关节周长;于造模后96 h测定大鼠血清白细胞介素-1β（IL-1β）、白细胞介素-8（IL-8）、肿瘤坏死因子-α（TNF-α）、尿酸（UA）及黄嘌呤氧化酶（XOD）水平。结果：MSU注射大鼠右侧踝关节腔成功诱发急性踝关节肿胀和急性痛风性关节炎。各剂量红花寄生提取物能不同程度显著抑制大鼠踝关节肿胀,并能显著降低血清IL-1β、IL-8、TNF-α、UA与XOD水平（P < 0.05,P < 0.01,P < 0.001）。结论：红花寄生提取物对急性痛风性关节炎大鼠有干预作用,可能与其抑制炎症反应、抑制XOD活力及促进尿酸排泄有关。     

电针“大椎”“命门”对佐剂性关节炎大鼠应激相关因子影响的实验研究

目的:通过观察电针“大椎”“命门”穴后下丘脑CRH、血浆ACTH、血清Cort、TNF-α含量的关系,分析电针不同穴位对应激相关因子的影响。方法:以佐剂性关节炎大鼠(AA)作为研究对象,随机分正常组、模型组、电针“大椎”组、电针“命门”组。观察电针对关节炎症局部及下丘脑CRH、血浆ACTH、血清Cort、TNF-α含量的影响。结果:“大椎”组、“命门”组经治疗右后足足爪肿胀率与模型对照组比较极明显降低(P<0.01),“大椎”组下丘脑CRH含量、血清Cort、TNF-α含量,“命门”组血清Cort含量与模型对照组比较明显降低(P<0.05)。结论:电针具有一定的抗炎作用,并且这种作用可能是通过对CRH、Cort等应激相关因子的调节,减轻疾病应激程度而实现的。     

温阳补肾法对高原类风湿关节炎患者血清25羟维生素D3水平的影响

目的:观察温阳补肾法对高原类风湿关节炎患者血清25羟维生素D3水平的影响。方法:选取2015年7月至2017年8月青海省中医院收治的高原类风湿关节炎患者132例作为研究对象,随机分为对照组和观察组,每组66例。对照组应用常规西医治疗,观察组在对照组治疗基础上应用温阳补肾法治疗,2组均连续治疗3个月。比较2组治疗后临床疗效,统计2组治疗前后主要临床症状与体征、健康状况评定量表(HAQ)评分和DAS28评分,检测2组治疗前后实验室检查指标、血清25羟维生素D3以及血液流变学指标水平。结果:治疗后,观察组临床治疗总有效率显著高于对照组(P 0. 05); 2组关节肿胀指数、关节疼痛指数、关节压痛指数、晨僵时间、关节功能分级和20 m步行时间均较治疗前显著降低(P 0. 05),且观察组均显著低于对照组(P 0. 05); 2组HAQ评分、DAS28评分、类风湿因子(RF)、C反应蛋白(CRP)和红细胞沉降率(ESR)水平均较治疗前显著降低(P 0. 05),且观察组均显著低于对照组(P 0. 05); 2组血清25羟维生素D3水平均较治疗前显著升高(P 0. 05),且观察组显著高于对照组(P 0. 05); 2组红细胞电泳指数、红细胞压积、血浆黏度、全血低切黏度、全血高切黏度水平均较治疗前显著降低(P 0. 05),且观察组均显著低于对照组(P 0. 05)。结论:温阳补肾法治疗高原类风湿关节炎,疗效满意,同时能明显增加血清25羟维生素D3水平。