Formulation and characterization of lornoxicam-loaded cellulosic-microsponge gel for possible applications in arthritis

Rheumatoid arthritis (RA) is an autoimmune disease associated with severe joint pain. Herein, we report lornoxicam loaded cellulosic microsponge gel formulation with sustained anti-inflammatory effects that are required to manage arthritic pain. The microsponges were formulated using quasi emulsion-solvent diffusion method employing four different surfactant systems, namely polyvinyl alcohol (PVA), Tween80, Gelucire 48/16 and Gelucire 50/13. All the lornoxicam loaded microsponge formulations were extensively characterized with a variety of analytical tools. The optimized microsponge formulation was then converted into gel formulation. The lornoxicam loaded microsponge gel formulation had adequate viscosity and sufficient pharmaceutical properties as confirmed by the texture analysis and the drug release followed Super case II transport. It is noteworthy that we described the preparation of a new cellulosic polymers based microsponge system for delivery of lornoxicam to provide quick as well as lasting (sustained) anti-inflammatory effects in rats using carrageenan induced rat paw edema model. We were able to demonstrate a 72% reduction in inflammation within 4 h using the optimize transdermal gel formulation utilizing Transcutol P as permeation enhancer and with the aid of skin micro-piercing by microneedles, hence, demonstrating the potential of this microsponge gel formulation in arthritis management.     

Design and development of an injectable in situ forming drug delivery system of methotrexate for the treatment of rheumatoid arthritis

Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA). At present there exists a lacuna in delivering methotrexate in suitable dosage form to maintain optimum plasma concentration to achieve therapeutic efficacy during the treatment period. Exposure of MTX at higher concentrations resulted in severe side effects. Moreover, the treatment modality (initial and maintenance dose) of RA is not clinically uniform. Biodegradable injectable in situ gels offer versatility in delivering drug at predetermined rates, and maintaining plasma concentration with a possibility of dose adjustment. They can be developed to optimize the therapeutic properties of a drug product, render them safe, effective and reliable during therapy. The aim of the present study was to formulate a biodegradable injectable in situ gel system for methotrexate sodium in the treatment of rheumatoid arthritis. The formulations were prepared by "cold technique" using thermosensitive polymer, Pluronic F-127 (20 %) and varying concentration of co-polymers, Pluronic F-68 (2–6 %) and Carbopol 934 (1.0-1.5 %). The prepared in situ gels were evaluated in vitro for drug interactions by FT-IR, sterility, gelation characteristics, content uniformity, viscosity, syringeability and in vitro drug release. MTX was evenly distributed in all formulations, which were sterile and syringeable through an 18 gauze needle. The gels were thermosensitive and thermoresponsive, and were dependent on the concentration of co-polymers. Drug release from in situ gels was sustained for 96 h to 120 h, and influenced by the type and concentration of co-polymers employed. Drug release was significantly higher in dynamic diffusion state in comparison with static state as ascertained by student t-test. The drug release was by non-fickian diffusion mechanism and followed first-order kinetics. These findings suggested that in situ gels can be effectively used to achieve controlled drug release; are easy to administer, are effective with reduced frequency of dosage, and result in increased patient compliance and comfort. It may be concluded that methotrexate in situ gels are ideally suitable in the treatment of RA.     

喷昔洛韦眼用温度敏感原位凝胶的制备及评价（英文）

目的研制以普朗尼克F127为主要基质的喷昔洛韦制剂,以提高其眼部生物利用度。方法通过将HPMC K4M或卡波姆934P与普朗尼克F127复合使用,制备了喷昔洛韦的温度敏感原位凝胶。以胶凝温度、流变学、药物释放特性、药代动力学及眼部刺激性等为指标进行筛选,得到最优化处方。结果使用HPMC K4M或者卡波姆934P均能降低凝胶的胶凝温度,略微增加其粘度,延缓体系中药物的释放速率;药物释放为非Fick扩散;所有处方均未表现出眼部刺激或对角膜的损伤;含卡波姆934P和普朗尼克F127的凝胶体系的眼部生物利用度最高。结论含普朗尼克F127的喷昔洛韦制剂能够以滴眼液的形式给药,而达到眼部温度时可形成凝胶;体内外评价结果表明,含有HPMC K4M或卡波姆934P以及低浓度普朗尼克F127（12%）的喷昔洛韦制剂,提高了药物在眼部的生物利用度,是一种很有前景的眼部给药系统。     

Methotrexate treatment suppresses local cytokine and chemokine production in rat adjuvant arthritis

Rheumatoid arthritis (RA) is a disease that is still insufficiently controlled by current treatments. Methotrexate (M7X), a small molecular weight compound, has been the gold standard in the treatment of RA. It has several anti-inflammatory activities, but their contribution to its antiarthritic effects has not yet been established. We conducted a rat adjuvant arthritis study, in which we investigated the effect of MTX on local cytokine and chemokine production in arthritic paws. Our data demonstrate that MTX was able to significantly suppress cytokine and chemokine release in the inflamed joints in a dose-dependent fashion, accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores. These findings prompt further studies to clarify whether these suppressive effects of MTX on local cytokine and chemokine release are direct or whether they are a result of other preceding anti-inflammatory activities of the compound.     

Efficacy of biologicals in the treatment of rheumatoid arthritis. a meta-analysis

Rheumatoid arthritis (RA) is a chronic multisystem disease. A characteristic feature of RA is persistent inflammatory synovitis, usually involving the peripheral joints in a symmetric distribution. The prevalence of RA is approximately 0.8% of the population (range: 0.3-2.1%); women are affected approximately 3 times more often than men. The current therapeutic approach is to start a disease-modifying agent early in the illness to prevent eventual joint damage. Older disease-modifying anti-rheumatic drugs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporin are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents, which block certain key molecules involved in the pathogenesis of the illness. They include tumour-necrosis-factor-alpha-blocking agents such as infliximab, etanercept and adalimumab, the anti-CD-20 agent, rituximab, and CTLA-4 Ig abatacept. The present study was planned with the aim of evaluating the efficacy of such newer biological therapies in refractory RA at various time points. Databases including Medline, Embase and the Cochrane Library were searched for all relevant studies up to January 2007. A total of 26 studies were included in present meta-analysis. The method of DerSimonian and Laird [Control Clin Trials 1986;7:177-188] was used to calculated a pooled odds ratio (OR) for the American College of Rheumatology (ACR) criteria 20, 50 and 70, at 24, 54 and 96 weeks. The overall pooled OR were found to be significantly more than the placebo at all 3 time points for all 3 criteria (ACR 20, 50 70). In conclusion, biologicals as a group are highly effective in the treatment of RA. Biologicals were efficacious both in treatment na?ve and methotrexate-refractory patients.     

Integrated nanomaterials for non-invasive photothermal therapy of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that causes swelling, redness, and arthralgia of multiple joints. Despite significant research and development on the treatment modalities for RA, there is still no established effective treatment option for eradicating joint damage and inflammation. In recent years, photothermal therapy (PTT) has emerged as a practical approach to treat RA. In this review, we outline various factors that affect the effective treatment of RA. Moreover, we discuss various PTT-based nanomaterials that can be used to treat RA.     

一种新的治疗类风湿关节炎的潜在靶点IL-18

类风湿关节炎（RA）是一种以关节滑膜炎为特征、以对称性多关节炎为主要临床表现的异质性、系统性、慢性炎症性疾病，严重影响了健康和生活质量，但其发病机制目前还不甚清楚，临床尚缺乏理想的治疗方法。白细胞介素-18（IL-18）是近年来新发现的一种前炎性细胞因子，属于IL-1家族，研究表明其在RA的发病中发挥了重要作用，是临床治疗RA的潜在靶点。现就I-．18的生物学特性及其与RA的关系作一综述。     

甲氨蝶呤联合羟氯喹或雷公藤多苷治疗抗环瓜氨酸肽抗体阳性的早期类风湿关节炎的临床研究

目的观察甲氨蝶呤(MTX)联合羟氯喹(HCQ)或雷公藤多苷(TG)治疗抗环瓜氨酸肽抗体(抗CCP)阳性的早期类风湿关节炎疗效及安全性。方法 96例患者随机分为2组。48例接受MTX联合HCQ治疗(MTX 10mg/次,1次/周:HCQ 200mg/次,2次/d)。48例接受MTX联合TG治疗(MTX 10mg/次,1次/周;TG 20mg/次,3次/d)。24周内各药的剂量保持不变。治疗24周时与治疗前比较美国风湿病学会RA缓解标准(ACR50)指标改善情况,同时观察2组不良反应发生率。结果 2组ACR50改善率分别为73%(35/48)和50%(24/48),差异有统计学意义(P<0.05)。2组药物不良反应发生率差异无统计学意义(P>0.05)。结论 MTX联合HCQ在治疗抗CCP阳性的早期RA患者,较MTX联合TG起效更快,更能有效缓解病情,改善关节功能,并且不增加不良反应的发生率。     

类风湿关节炎与心血管疾病风险

类风湿关节炎(RA)病人心血管(CV)疾病的发病率和病死率增加.RA病人CV风险的增加除了与传统危险因素相关外,还与炎症负荷的增加和抗风湿药物的心脏毒性有关.尽管人们对RA病人CV疾病有一定的认知,但最佳管理RA病人仍是一项艰巨的任务.严格控制疾病活动、管理传统危险因素、改变生活方式,从而改善RA病人CV疾病结局.该文就目前有关RA与CV风险相关的文献、指南做一综述.     

Management of early rheumatoid arthritis

Rheumatoid arthritis (RA) affects 1% of the adult population and is a chronic disease lasting for many decades. RA often results, despite therapy, in progressive joint destruction, deformity and disability, causing a major economic loss for the patients and the society. Most common the onset of the disease is between the 4th and 5th decade: RA affects 3 times more women than men. Both, the diagnostic as well as the therapeutic opportunities, have greatly improved over the last years. Nevertheless, there are still deficiencies in the care of patients with early RA (ERA). Consequently, the "German Society for Rheumatology" has set up recommendations for "The management of early RA", which are introduced in this article.     

Cytokine balance in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common, frequently severe, chronic inflammatory disease. Although the cause of RA remains unknown, recent advances in understanding its pathogenesis have been substantial. Despite the use of a variety of medications, the treatment of RA is not fully effective in most patients. A T-helper type 1 (Th1)/T-helper type 2 (Th2) cytokine imbalance has been suggested to be of pathogenic importance in several diseases. In this review, the information of cytokine balance in both the experimental model of arthritis and patients with arthritis were summarized. Furthermore, to characterize the cytokine balance at a single cell level, we analyzed the subtypes of cytokine-secreting cells in an experimental model of arthritis using a dual color enzyme-linked immunospot assay (Stardust assay) which we newly developed. These information including our findings might provide us the clue for diagnosis and therapy of arthritis.     

实验性关节炎动物模型建立及病理机制研究进展

类风湿关节炎(rheumatoid arthritis,RA)是一种慢性系统性的免疫性炎症疾病,病因和发病机制尚未完全清楚。胶原性关节炎大鼠、小鼠模型,佐剂性关节炎大鼠模型,多聚糖蛋白诱导的关节炎小鼠模型,链球菌细胞壁诱导的关节炎大鼠、小鼠模型和转基因小鼠模型与人RA发病机制和病理变化等有着相似特点,是研究RA、筛选抗炎免疫药物较理想的实验性病理模型。探讨RA动物模型的发病机制及其与临床的关系,对进一步了解RA病理、生理、免疫等特点及寻找安全有效的治疗RA的药物十分重要。该文将对几种常用的实验性关节炎模型的建立、造模特点、发病机制、与RA的异同等方面进行综述。     

An intra‐articular injectable phospholipids‐based gel for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy with a high deformity rate. Despite numerous studies and clinical trials, no curative treatment is available for large weight-bearing joints. Intra-articular (IA) injections could deliver high concentrations of drug to the afflicted joint and improve the drug efficacy while reducing systemic toxicity. However, free drugs are rapidly cleared from synovial fluid and do not significantly halt the progression of joint disease. Herein, a phospholipids-based controlled-release gel was prepared for sustained IA delivery of celastrol (CEL) and the therapeutic efficiency was evaluated in a rheumatoid arthritis rabbit model. The CEL-loaded gel (CEL-gel) contained up to 70% phospholipids yet was easy to inject. After injecting into the joint cavity, CEL-gel achieved sol to gel phase transition without special stimuli and gelling agent. In vitro release and in vivo pharmacokinetic studies evidenced the stable and sustained release action of CEL-gel. A single IA injection of CEL-gel could maintain therapeutic efficiency for about 25 d and showed much better anti-arthritic efficacy compared to repeated injections of free drug solution (CEL-sol). Furthermore, the IA injection of CEL-gel greatly reduced the systemic toxicity of CEL. With good biocompatibility and biodegradability, CEL-gel might be a promising IA drug delivery system.     

类风湿性关节炎动物模型研究进展

类风湿性关节炎（rheumatoid arthritis,RA）是一种自身免疫性疾病,其病理机制不确定,目前治疗方法较多,但是多有副作用。关于RA的研究,构建和应用合适的动物模型是重要的一个环节,尤其是获得与人RA发病相似的动物模型尤为重要。目前研究表明,各种类风湿性关节炎模型的发病因素不同,病理特点有别,有必要对动物模型进行总结。     

中药治疗类风湿关节炎有效成分提取研究进展

类风湿性关节炎(RA)是一种全身性、自身免疫性疾病,是临床难治疾病之一,中药对类风湿性关节炎的治疗疗效确切、安全、副作用少,优势独特,具有广泛的应用前景和重要的开发价值.近年来,国内外针对中药的抗RA作用开展了大量的研究工作.很多中药的活性成分和作用机制得到初步阐明.本文主要针对中药治疗RA有效成分提取的研究进展进行阐述.     

基因芯片技术用于中医药治疗类风湿性关节炎的研究进展

类风湿性关节炎(rheumatoid arthritis,RA)是一种致残率极高、临床治愈率低的自身免疫性疾病,被认为是一种多因素参与、多基因改变协同作用的结果.如何有效治疗RA值得医药界研究人员的探讨.随着中医药技术的发展,基因芯片技术已从基础研究逐步应用于新药研发和临床诊断,为进一步研究治疗RA提供了新的思路及方法...     

Folate-Conjugated Superoxide Dismutase Adsorbed Over Antioxidant Mimicking Nanomatrix Frameworks for Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease occurring in larger population, characterized by synovial inflammation followed by destruction of joint. Major concerned factor for cause of RA has been related to oxidative stress due to environmental toxicity and immune imbalance. Reactive oxygen species generated from macrophages communes series of oxidation at cellular and genetic level and leads to generation of inflammatory cytokines for provoking inflammation in RA. Superoxide dismutase and catalase are supposed to be potential antioxidant enzymes to scavange free radicals. However, many clinical studies report reduced potency of enzyme due to lack of its targeting efficacy. Therefore, the aim of the work involves development of nanomatrix mimicking as catalase over which folate-linked superoxide dismutase was adsorbed for a macrophage targeting. The developed formulation was optimized, characterized for morphological studies, enzyme loading efficiency, protein activity, and in vitro drug release. Quantification of interleukin 6 was performed by indirect enzyme linked immunosborent assay over macrophage cell lines to determine in vitro treatment efficacy. It is concluded that the prepared system can act as enzyme reservoir to deliver acid labile enzymes in controlled form to efficiently treat RA.     

The role of T-cells in rheumatoid arthritis and the use of immunomodulating drugs

Rheumatoid arthritis (RA) is a chronic inflammatory process of unknown etiology affecting 1% of the population worldwide. It results in excess morbidity in a majority of cases and early mortality in patients with aggressive disease. Early immunohistologic studies of the rheumatoid synovium demonstrate that T-cells, especially cluster of differentiation (CD)4(+) cells, are a major component of the infiltrating inflammatory cells. It has also been demonstrated that RA patients share a common major histocompatibility complex (MHC) class II molecule, HLA-DR4. Immune activation by T-cells requires the formation of the antigen recognition complex composed of the T-cell receptor, the MHC II molecule, and antigen. Many treatment modalities for RA have targeted the T-cell and/or the antigen recognition complex. These have varied from relatively crude methods such as leukopheresis to very specific monoclonal antibodies directed toward specific T-cell antigens such as the CD4 molecule itself. Not only have these therapies been effective, but also they have provided some interesting data on the pathogenesis of RA. Unfortunately, some have been associated with harmful side effects. To date, the safest and most effective modality has been immunomodulatory drugs such as cyclosporin and FK506, either alone or in combination with other agents. It appears that the earlier these treatments are started in the course of RA, the more effective they are, not only in controlling disease but also in achieving a potential remission.     

桡骨远端不稳定型骨折的远期疗效分析

小儿脑性瘫痪(Cerebral Palsy)是以慢性、非进行性运动功能障碍为特征的一组症候群,患儿常伴有不同程度的认知障碍.我国的小儿脑性瘫痪定义为:以妊娠到新生儿之间的各种原因所致的脑的非进行性病变为基础,形成永存的,但可以变化的运动和姿势异常,其症状在2岁之前出现.随着早产儿存活率的升高,脑瘫的发病率也上升至人口总数的0.06%~0.59%.我国此类患儿不少于250万,且每年新增患儿约20万左右.脑性瘫痪是目前小儿时期最主要的运动功能伤残疾病,而且多数伴发有智力低下及语言功能障碍.     

Ⅱ型胶原诱导的小鼠关节炎动物模型的建立及影响因素

类风湿性关节炎(RA)是一种顽固性、致畸性自身免疫性疾病。Ⅱ型胶原诱导的小鼠关节炎(CIA)表现为严重的多关节性炎,并能引起慢性、破坏性关节损伤,与RA有很多相似之处,目前国际上广泛用于RA发病机制的研究以及创新药物的研发。该文就CIA实验动物模型的建立以及CIA发生病变的主要影响因素进行综述。