银屑病生物学治疗药物新进展

综述了近年来银屑病生物治疗药物的进展.根据作用靶位的不同,生物学治疗药物可分类为细胞因子调节剂、协同刺激分子结合抑制剂、细胞因子制剂及抗淋巴细胞单克隆抗体.生物治疗药物具有高效、作用位点明确、无严重不良反应的特点,是银屑病治疗的新选择.     

银屑病治疗的小分子药物研究进展

银屑病是一种复杂的炎性皮肤疾病,其发病机制尚不完全清楚,且反复发作,治疗难度很大,严重影响了患者的生活和工作,这给新药研究和筛选带来一定的困难。尽管如此,抗银屑病新药一直是皮肤病药物治疗学研究的一个热点。国际上在寻找新的抗银屑病药物方面一直在做不懈努力,拟用于治疗的新候选药物不断出现,旨在继续提高疗效和降低毒副作用。目前,可用于治疗银屑病药物的作用靶点较多,主要集中在核激素受体的配体、免疫信号转导通路中的相关细胞因子和酶,以及作用于表皮的天然药用药材。针对治疗银屑病效果较佳、作用机制较明确的小分子药物进行总结,为开发抗银屑病的新药提供研究思路。     

抗细胞因子抗体治疗的研究进展

美国Tufts药物发展研究中心成立于1976年，其药物数据库包括了在研究中和临床所用的涉及单克隆抗体(mAb)、重组蛋白质和小分子药物。该数据库收录了1980～2003年进人临床试验的311种治疗性单克隆抗体，其中包括30种抗细胞因子单克隆抗体。这30种单克隆抗体主要以γ-干扰素(INF)，白介素(IL)-4，IL-5，IL-6，IL-8，IL-10，IL-12，IL-15，IL-18，转化生长因子(TGF)β1，TGFβ2，肿瘤坏死因子(TNF)-α和血管内皮生长因子(VEGF)等细胞因子作为作用靶标。这些抗细胞因子抗体中，有16种用于治疗自身免疫性疾病，如类风湿性关节炎、克罗恩病、银屑病、系统性红斑狼疮、多发性硬化症、过敏性鼻炎、哮喘。     

生物制剂与银屑病治疗

银屑病是一种T淋巴细胞介导的慢性炎症性疾病，致病的记忆-效应T淋巴细胞集聚于病变皮肤并产生I型细胞因子是发病机制的中心环节。基于银屑病发病机制中细胞免疫的关键步骤，研究开发了一些具有靶位特异性的生物制剂，这类药物无特定脏器毒性，具有安全、易耐受和使用方便的特点，为银屑病的长期治疗提供了安全有效的方案。根据作用靶点，可将药物分为抑制抗原呈递和共刺激、抑制T淋巴细胞活化和白细胞结合、直接杀伤活化T淋巴细胞、抑制炎症介质的活性和调节细胞因子平衡5类。     

贝伐珠单抗注射液在改善银屑病小鼠模型中的作用及机制

目的：研究贝伐珠单抗注射液（安维汀）在改善银屑病小鼠模型中所发挥的作用及作用机制。方法：通过对银屑病小鼠模型的构建,安维汀药物处理,小鼠病情等级评定,细胞因子检测,mRNA定量,蛋白免疫印迹的生物学方法,研究安维汀用药后,银屑病小鼠病情,体内细胞因子和血管生成因子mRNA含量及蛋白含量变化。结果：小鼠病情级别评定结果显示,安维汀能减轻银屑病的症状;mRNA定量结果和免疫蛋白印迹结果均显示,安维汀可以改变银屑病小鼠体内炎症细胞因子含量和血管生成因子含量,从而缓解银屑病的症状。结论：安维汀通过影响Th1类细胞因子IFN-γ,Th17类细胞因子IL-17A,Th2类细胞因子IL-4及Treg细胞因子IL-10及血管生成相关因子的含量,抑制炎症和血管的生成,从而改善银屑病症状。     

银屑病治疗靶点及其药物研发进展

银屑病的发病机制未能完全阐明,近年来大量的实验和临床研究证实,银屑病可能是T细胞介导的自身免疫性疾病。这一发病过程涉及了很多靶点的激活,T细胞增殖和细胞因子的作用。目前,基于这些靶点研发治疗银屑病的新药已取得了长足的进展,本文就近年来银屑病靶向药物研究进展作一综述,为开发新的靶向药物提供参考。     

银屑病生物制剂治疗进展

银屑病是一种与免疫相关的慢性炎症疾病,其中肿瘤坏死因子-α（TNF-α）、白细胞介素-23(IL-23)、白细胞介素-17A(IL-17A等炎症细胞因子在免疫反应中起到重要作用,能促进角质形成细胞过度增殖和免疫细胞浸润,而这些细胞因子目前已经成为银屑病治疗的靶点,文章总结了近年来银屑病生物治疗新靶点及相关药物,为研发针对性更强、疗效更佳的生物制剂提供思路。     

银屑病的免疫治疗进展

银屑病的病因目前仍不明确,临床治疗困难。近年来,银屑病免疫治疗日益受到重视。本文介绍了治疗银屑病的一些新的免疫治疗药物(环孢素A、他克莫司、辣椒辣素、抗角蛋白抗体、转移因子、抗α-肿瘤坏死因子),临床应用中取得了一定的疗效,免疫治疗银屑病疗效肯定。     

窄谱中波紫外线治疗寻常型银屑病疗效观察及对血清TNF-α水平的影响

<正>研究表明,银屑病是多基因遗传背景下T细胞异常的免疫性疾病。研究发现其发病与CD8+T细胞、CD4+T细胞和细胞因子网络直接相关[1],其中,Th1型及Th2型细胞因子均参与了银屑病的发病,但以Th1型细胞因子如白细胞介素(IL)-2,干扰素(IFN)-γ等为主。此外,前炎症因子如IL-1、IL-8,肿瘤坏死因子TNF-α等也参与了皮损形成。TNF-α的活化在银屑病的发病机制中起重要的作用,     

抗银屑病蛇床子素贴剂体外药物释放的研究

目的研究抗银屑病蛇床子素贴剂处方组成对体外药物释放的影响。方法以丙烯酸树脂为贴剂的主要组分，配以交联剂(琥珀酸)、增塑剂(柠檬酸三乙酯)及松香，制备不同浓度抗银屑病蛇床子素贴剂，考察其体外药物释放情况。结果贴剂初粘性好，药物在压敏胶中分布均匀，有较低的玻璃化温度，有利于药物的渗透和释放。但当各组分相容性不好、压敏胶基质的玻璃化温度较高时，药物在压敏胶中分布不均匀，药物的释放相对缓慢。结论贴剂的压敏性能对体外药物释放有较大的影响，贴剂处方除具备适当的压敏性能，还要考虑贴剂对皮肤的贴敷性能和生物相容性。     

Interleukin-10: an important immunoregulatory cytokine with major impact on psoriasis

Interleukin (IL)-10 is a pluripotent cytokine with effects on numerous cell populations, in particular circulating and resident immune cells as well as epithelial cells. With its potent immunoregulatory capacities its main biological function seems to be the limitation and termination of inflammatory responses. Thus its low level expression found in psoriasis may have pathophysiological relevance for this immune disease. Remarkably, induction of IL-10 expression was found by conventional antipsoriatic therapies, supporting the hypothesis that IL-10 may be a key cytokine in psoriasis and that application of this cytokine itself may have therapeutic effects. In first clinical trials in patients with established psoriasis IL-10 showed moderate antipsoriatic effects and was well tolerated. Moreover, long term application in psoriatic patients remission showed that IL-10 therapy decreases the incidence of relapse and prolongs the disease free interval. The immunological effects observed during these clinical studies together with in vitro observations suggests that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen presenting cells and T-cells (lasting type 1/ type 2 cytokine balance shift), but not through direct effects on keratinocytes. In conclusion IL-10 seems to have major importance in psoriasis. Further investigations, in particular multicenter, placebo-controlled, double blind trials are required to fully determine whether IL-10 application will become a successful antipsoriatic therapy.     

CC-10004

CC-10004, a phosphodiesterase 4 inhibitor and selective cytokine inhibitor, is under development by Celgene for the potential treatment of asthma, chronic obstructive pulmonary disease, inflammation and psoriasis. By October 2004, phase II trials in psoriasis had commenced.     

Biological Products for the Treatment of Psoriasis: Therapeutic Targets,Pharmacodynamics and Disease-Drug-Drug Interaction Implications

Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.Key words: disease-drug-drug interactions (Disease-DDI), inflammatory disease, IL-6, interleukin-6, proinflammatory cytokines, psoriasis     

Exacerbation of paranoid schizophrenia in a psoriatic patient after treatment with cyclosporine A, but not with etanercept

Psoriasis may be frequently associated with psychiatric diseases. We present a 44-year-old man undergoing cyclosporine therapy for treatment of generalized plaque psoriasis which exacerbated his symptoms of paranoid schizophrenia, and disappeared a few days after discontinuation of cyclosporine. Replacement therapy with etanercept achieved clinical remission of psoriasis without any psychiatric side effects. Systemic medications, such as cyclosporine and etanercept, induce modifications of the cytokine network. This is pathogenetically significant in both psoriasis and psychiatric disorders. This case report suggests that dermatologists need to become more familiar with the risk-benefit of drug-induced cytokines dysregulation in psoriatic patients with comorbid psychiatric disorders.     

银屑1号对银屑病样动物模型细胞因子网络及其信号通路的调控

目的 研究中药复方银屑1号对银屑病样动物模型细胞因子网络及其信号通路的影响。方法建立小鼠阴道上皮模型和鼠尾鳞片表皮模型,设生理盐水组、银屑1号小、中、大剂量组和雷公藤多甙片治疗组共五组,观察各组对小鼠阴道上皮细胞有丝分裂的影响和促进小鼠尾部鳞片颗粒层形成的能力;并比较各组中六个细胞因子IL-2、IL-4、IL-6、IL-10、TNF-α,IFN-γ荧光强度的变化及“JAKs—STATS”信号通路中STAT3,P—STAT3,STAT5,P—STAT5的变化。结果银屑1号的小、中、大剂量组均可以显著抑制雌激素期小鼠阴道上皮有丝分裂（P〈0．01）。银屑1号中、大剂量组均可以显著提高小鼠尾部鳞片颗粒层形成数（P〈0．01）。银屑1号的中、大剂量组均可降低IFN-γ的水平（P〈0．05）银屑1号的大剂量组可升高IL-4的水平（P〈0．05）。各组STAT3、P—STAT3、STAT5、P—STAT5比较均无统计学意义（P〉0．05）。结论银屑1号具有抑制表皮细胞的过度增生和改善表皮角化不全的作用,可能通过抑制IFN-γ的合成及促进IL-4的合成,调节细胞因子网络平衡,参与抗炎与免疫调节过程而发挥治疗作用。     

光量子血疗对寻常型银屑病患者血清TNF—α、IL-6及IL-8的影响

目的观察光量子血疗治疗寻常型银屑病的疗效及对寻常型银屑病患者血清中细胞因子水平的影响。方法光量子血疗治疗前后对银屑病患者皮损进行PASI评分。采用ELISA法检测银屑病患者治疗前后和正常对照者血清中TNF-α、IL-6及IL-8的表达水平变化。结果光量子血疗治疗110例寻常型银屑病患者有效率为80．35％,治疗后PASI评分显著下降（P〈0．01）,患者血清中TNF-α、IL-6及IL-8水平明显高于正常对照组（P〈0．01）,治疗后其表达水平较治疗前明显下降（P〈0．01）,患者体内TNF-α、IL-6及IL-8表达水平与PASI积分呈正相关（P〈0．01）。结论光量子血疗对寻常型银屑病有良好的治疗作用,血清TNF-α、IL-6及IL-8在银屑病的发病中有重要意义。     

寻常型银屑病患者的外周血T淋巴细胞亚群和血清肿瘤坏死因子α的变化及临床意义

目的了解寻常型银屑病患者的外周血T淋巴细胞亚群和肿瘤坏死因子α(TNF-α)水平的变化和临床意义。方法采用流式细胞术测定了50例银屑病患者和32例正常对照组的T淋巴细胞亚群。用酶联免疫吸附试验测定血清中TNF-α的含量。结果寻常型银屑病组的CD4+百分率和CD4+/CD8+比值均低于对照组(P<0.01和P<0.05)。血清TNF-α含量与正常对照组相比较有显著增高(P<0.01)。结论银屑病患者T细胞免疫功能发生紊。TNF-α是一种与银屑病免疫炎性反应密切相关的细胞因子,T淋巴细胞亚群和TNF-α在银屑病的发生、发展及维持中起着重要的作用。     

The successful use of etanercept in combination therapy for treatment of acrodermatitis continua of hallopeau

Acrodermatitis continua of Hallopeau (ACH) is a rare form of pustular psoriasis which poses a challenge to treat and causes considerable pain and suffering for those afflicted. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine involved in the pathogenesis of ACH and other forms of psoriasis. Inhibition of TNF-alpha has been shown to provide benefit in such inflammatory conditions as rheumatoid arthritis, psoriatic arthritis, and, most recently, plaque psoriasis. In this report, we present the case of a 65-year-old man with a 9-year history of recalcitrant ACH who demonstrated significant and sustained clinical improvement when etanercept, a competitive inhibitor of TNF-alpha, was added to his treatment regimen of acitretin and topical corticosteroids over a 12-week period.     

The potential of interleukin 12 inhibition in the treatment of psoriasis

Interleukin 12 (IL-12) is an important cytokine produced by a variety of immune effector cells that leads to a type 1 helper T cell (Th1) response. IL-12 also directs T cells to the skin via induction of cutaneous lymphocyte antigen (CLA) expression. In this article we report the current understanding of the immunobiology of IL-12, reviewing its structure, receptor, and function. We also discuss the role of IL-12 in the pathogenesis of psoriasis. Some effective conventional psoriasis treatments alter IL-12 levels. Importantly, specific antibodies directed against IL-12 may prove useful against psoriasis but may also act by targeting IL-23 in addition to IL-12.     

A pathogenetic approach to autoimmune skin disease therapy: psoriasis and biological drugs, unresolved issues, and future directions

Psoriasis is a chronic inflammatory disease with a complex pathophysiology and a multigenic background. Autoimmunity and genetic hallmarks couple to confer the disease, which is characterized by chronic plaques (85-90% of all cases) and/or psoriasis arthritis (PsA), and involve the peripheral and sacro-iliac joints, nails, and skeleton. Dissecting the ethiopathogenetic mechanisms of psoriasis and PsA is a major basic research challenge. One important question is whether a single inflammatory mediator can be responsible for the interactive network that forms between immune cells and cytokines in this disease. Despite much progress, no research has yet been able to define a single model to explain the multifaceted pathogenesis of psoriasis and PsA. It is known that both the innate and adaptive immune systems are involved, antigen presenting cells and T lymphocytes play a prominent role, and that the deregulation of the T helper (Th)- 1/Th-2/Th-17/Th-23 axis is directly implicated in disease pathogenesis. Pharmacological therapy for psoriasis has evolved with the development of human knowledge of the disease pathophysiology. Thus, the first "ethiopathogenetic" drugs (e.g., methotrexate, cyclosporin, and alefacept) inhibited T-cell activation directly or targeted co-accessory molecules implicated in T-cell activation. When the mechanism underlying psoriatic inflammation was accepted as a cytokine network disorder, more specific biologics were studied in murine models and were later used clinically. Tumor necrosis factor was the first successful target of cytokine inhibition therapy for psoriasis and PsA (e.g., infliximab, adalimumab, and etanercept). With the recently discovered role for Th-17 in autoimmunity, drugs targeting interleukin-23 (ustekinumab) have become accepted for the pharmacological treatment of psoriasis. The expansion of pharmacological treatment options for psoriasis is not complete. As the knowledge of pathogenetic mechanisms increases, it may be possible to design therapeutic approaches that selectively target the ethiopathogenetic cells or cytokines while sparing the others. In this way, using a more targeted drug therapy may preserve the integrity of the immune system. Thus, one great struggle in treating this complex disease is the challenge to synthesize the "perfect" drug.