Department of Drug Discovery, Celgene Corporation, Summit, NJ 07901, USA.
Br J Pharmacol. 2010 Feb;159(4):842-55. doi: 10.1111/j.1476-5381.2009.00559.x. Epub 2009 Dec 24.
Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.
Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed.
Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin.
Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.
阿普米司特是一种口服磷酸二酯酶-4 抑制剂，目前正在进行银屑病和其他慢性炎症性疾病的 2 期临床研究。本研究旨在探讨阿普米司特对人外周血单个核细胞（PBMC）、多形核细胞、自然杀伤（NK）细胞和表皮角质形成细胞的促炎反应的体外和银屑病临床前模型中的抑制作用。
体外试验中，检测了阿普米司特对脂多糖和超抗原刺激的 PBMC、细菌肽和酵母聚糖刺激的多形核细胞、免疫球蛋白和细胞因子刺激的 NK 细胞以及紫外线 B 光激活的角质形成细胞的作用。阿普米司特对 beige-严重联合免疫缺陷小鼠进行了口服给药，该小鼠移植了正常的人类皮肤，并被人类银屑病 NK 细胞触发。分析了表皮皮肤厚度、增殖指数和炎症标志物。
阿普米司特抑制 PBMC 产生趋化因子 CXCL9 和 CXCL10、细胞因子干扰素-γ和肿瘤坏死因子（TNF）-α以及白细胞介素（IL）-2、IL-12 和 IL-23。NK 细胞和角质形成细胞产生的 TNF-α也被抑制。在体内，阿普米司特显著降低表皮厚度和增殖，减少银屑病样特征的一般组织病理学表现，并降低病变皮肤中 TNF-α、人类白细胞抗原-DR 和细胞间黏附分子-1 的表达。
阿普米司特在多种细胞类型中表现出广泛的抗炎活性，并降低了体内银屑病样反应的发生率和严重程度。这种磷酸二酯酶-4 抑制剂抑制 TNF-α、IL-12 和 IL-23 的产生以及 NK 和角质形成细胞的反应，提示了治疗银屑病的一种新方法。
