磷酸二酯酶4抑制剂临床及安全性研究进展

磷酸二酯酶4 (phosphodiesterase 4, PDE4)是磷酸二酯酶家族中重要成员之一,可特异性水解环磷酸腺苷(cyclic adenosine monophosphate, cAMP),通过改变cAMP浓度引发下游磷酸化级联反应,与多种疾病密切相关。靶向PDE4的抑制剂临床研究包括呼吸系统疾病、自身免疫性疾病、中枢神经系统疾病及皮肤病等多种疾病领域。但是在已上市的PDE4抑制剂临床研究中发现,大多数药物的恶心、呕吐等胃肠道不良反应发生率较高,限制了其临床应用。因此本综述总结了已上市PDE4抑制剂的临床进展及安全性问题,结合PDE4蛋白结构分析、PDE4抑制剂的作用机制及相关不良反应机制研究,阐述了PDE4抑制剂产生不良反应的主要原因,旨在为开发安全有效的PDE4抑制剂提供参考。     

沙利度胺治疗葡聚糖硫酸钠诱导小鼠炎症性肠病及其机制研究

目的考察沙利度胺对葡聚糖硫酸钠诱导小鼠炎症性肠病的治疗作用,并探讨其可能的作用机制。方法 60只Balb/c小鼠按体质量随机分为对照组、模型组、柳氮磺吡啶(200 mg/kg)组以及沙利度胺30、60、120 mg/kg剂量组,每组10只。试验当天为第1天,试验期间葡聚糖硫酸钠诱导组饮用2.5%葡聚糖硫酸钠饮用水,对照组则饮用纯净水。从试验第5天开始,各给药组开始ig给予相应药物,给药容积10 m L/kg,1次/d,对照组和模型组则给予相应体积的0.5%MC,直至第12天结束试验。试验期间,每天记录各动物体质量变化。试验结束后,测量各动物结肠长度,观察各组结肠组织病理学改变和评分,ELISA法检测结肠组织肿瘤坏死因子-α(TNF-α)含量。结果沙利度胺在120 mg/kg剂量下改善葡聚糖硫酸钠诱导小鼠体质量下降症状,改善小鼠的结肠缩短,降低结肠组织TNF-α含量,减少炎症细胞对结肠组织的浸润。结论沙利度胺对葡聚糖硫酸钠诱导小鼠炎症性肠病呈现较好治疗作用,该作用可能与沙利度胺对TNF-α的调节作用有关。     

免疫抑制剂治疗炎症性肠病的研究进展

炎症性肠病在临床较为常见,具有慢性、复发性高等特点,可进一步导致肠道黏膜损伤、出血、穿孔等病症,严重影响患者生活质量。临床认为,炎症性肠病的发生发展与肠道微生态、肠道上皮屏障、免疫功能三者互相作用有关。在治疗方面,硫唑嘌呤、甲氨蝶呤以及环孢素A等免疫抑制剂是目前临床上常用的治疗炎症性肠病的药物,但长期用药可能导致不良反应,影响治疗效果及用药安全性。本文针对炎症性肠病的发病机制及免疫抑制剂治疗效果进行综述,以期为临床规范用药提供参考。     

免疫抑制剂在炎症性肠病中的治疗新进展

炎症性肠病的药物治疗在过去20年里变化巨大。一项丹麦的研究显示,2003-2011年与1995-2002年相比,在克罗恩病的治疗中,美沙拉嗪的使用逐渐下降,而硫唑嘌呤和生物制剂[抗肿瘤坏死因子（TNF—α）抗体]的使用明显上升,糖皮质激素的使用没有显著变化。同期,克罗恩病的手术率也明显下降。药物治疗的变化对于患者的自然病程产生重要的影响,其中免疫抑制剂在克罗恩病治疗中的意义不容忽视。     

磷酸二酯酶及其抑制剂的研究进展

磷酸二酯酶(PDEs)是一类可水解细胞内第二信使环磷酸腺苷(cyclic adenosine monophosphate,cAMP)和环磷酸鸟苷(cyclic guanosine monophosphate,cGMP)的酶类,可调节细胞内的多种信号传递和生理活动。PDEs由11种不同的家族组成,且各家族包含不同的亚型,各个亚型在细胞内分布、表达、调节方式以及对抑制剂的敏感性均不同,参与了炎症、哮喘、抑郁、勃起功能障碍等多种病理过程的发生发展,这些特点使得PDE作为新的药物靶点得到了越来越多的关注。该文将从PDE各家族生物学特点、生理病理学意义及其抑制剂的应用作一简单综述。     

磷酸二酯酶4抑制剂治疗银屑病的研究进展

银屑病是一种遗传和环境共同作用诱发的、免疫介导的慢性炎症性皮肤病.环磷酸腺苷(cAMP)/蛋白激酶A(PKA)通路与银屑病的发病机制密切相关,而磷酸二酯酶4是可以专一水解cAMP的酶,因此磷酸二酯酶4成为银屑病治疗的期望小分子靶点.磷酸二酯酶4抑制剂类药物通过竞争性阻断磷酸二酯酶4对cAMP的降解作用,使T辅助细胞1(...     

大鼠急性肺损伤模型肺组织中磷酸二酯酶4活性的变化

目的观察磷酸二酯酶4(PDE4)、肿瘤坏死因子-α(TNF-α)和炎症细胞浸润在急性肺损伤过程中的变化规律,以及它们之间的相关性。方法脂多糖(LPS)诱导大鼠急性肺损伤(ALI),高效液相法(HPLC)测定肺组织PDE4活性、ELISA法检测TNF-α含量,常规细胞形态学检测中性粒细胞在支气管肺泡灌洗液(BALF)和肺组织中的浸润变化。结果气道内滴入LPS,1 h后肺组织中PDE4活性开始增加,6 h达到峰值,与对照组相比(P<0.01),24 h后开始回落。支气管肺泡灌洗液(BALF)的白细胞总数和中性粒细胞数的变化与PDE4活性变化相关(r=0.83,P<0.05),2 h后开始增加,6 h达到峰值,48 h后回落接近滴入LPS前。肺组织匀浆的TNF-α含量在LPS滴入后迅速上升,2 h达到峰值,24 h后开始回落,其上升先于前两者。在LPS滴入6 h测定抗超氧阴离子自由基(O.2)和中性粒细胞髓过氧化酶(MPO)水平也明显上升。给予PDE4抑制剂RP73-401(piclamilast)后,肺组织中PDE4活性与TNF-α含量均下降,肺部炎症也得到改善,与损伤后6 h相比差异有显著性(P<0.01)。结论气道内滴入LPS后肺组织中PDE4活性迅速上升,并与TNF-α上升有一定的相关性,运用PDE4抑制剂后,二者水平均明显降低。PDE4和TNF-α升高可能诱导中性粒细胞聚集和过氧化反应的因素,提示PDE4抑制剂可能是一个治疗ALI的重要靶点。     

磷酸二酯酶4研究进展

环腺苷酸(cAMP)和环鸟苷酸(cGMP)对于细胞的许多功能有重要作用。磷酸二酯酶(PDEs)催化cAMP和cGMP水解开环分别生成AMP和GMP,这是细胞内降解cAMP和cGMP的唯一途径。PDEs可分为11个家族,其中有8个家族可以水解cAMP,包括能专一性地水解cAMP的PDE家族(如PDE4),和既可水解cAMP又可水解cGMP的PDE家族。PDE4同工酶主要存于在炎症细胞中。PDE4可分为A、B、C、D 4个亚家族,根据其N端的特殊结构,有长、短和超短三种形式。PDE4催化区三维结构的阐明有助于它们功能的研究和相关药物的设计。PDE4通过与其它蛋白如抑制蛋白、A激-酶锚定蛋白(AKAP)以及活化的C激酶1受体(RACK1)等相互作用使cAMP浓度区域化,选择性地调节各种细胞功能。PDE4作为一个治疗靶点,研究其选择性抑制剂具有重要的意义,可以用于治疗由炎症引起的疾病,如哮喘、慢性阻塞性肺疾病(COPD)、阿尔采末病(AD)、帕金森病(PD)和中风等由潜在的炎症引起神经元受损造成的中枢神经系统疾病。     

生物制剂治疗炎症性肠病的进展

近年来,随着炎症性肠病的病因和发病机制方面研究取得了重大进展,生物制剂的应用使其病情进展和疾病转归得到了新转折。抗肿瘤坏死因子α已成为治疗中重度炎症性肠病的一线用药。近年来,抗黏附因子也成为治疗炎症性肠病的重要药物,维多珠单抗(Vedolizumab)常被用于抗肿瘤坏死因子α失应答和对其他治疗方法不耐受的情况。而更多的生物制剂正处于临床试验的各个开发阶段,包括抗IL-12/23的乌司奴单抗(Ustekinumab)、JAK抑制剂—托法替尼(Tofacitinib)和抗黏附分子—Etrolizumab。本文主要介绍目前新出现的主要的治疗炎症性肠病的生物制剂的有效性和安全性。     

Real-world incidence of inflammatory bowel disease among patients with other chronic inflammatory diseases treated with interleukin-17a or phosphodiesterase 4 inhibitors

Objectives: (1) To assess the real-world incidence of inflammatory bowel disease (IBD) in patients with or without other chronic inflammatory diseases (CIDs), and (2) to understand whether IBD incidence differs in CID patients receiving interleukin-17a signaling antagonists (anti-IL-17a) or phosphodiesterase 4 inhibitors (PDE4i) versus patients using a biologic not indicated for IBD or biologic-naïve patients.

Methods: The MarketScan Research Databases (January 2010–July 2017) were used. A CID population was created from patients with ankylosing spondylitis, psoriatic arthritis, psoriasis or rheumatoid arthritis (RA). The CID population was stratified into different cohorts based on the baseline treatments received: (1) anti-IL-17a, (2) PDE4i, (3) biologic-naïve, and (4) non-IBD-indicated biologic (i.e. biologics not indicated for the treatment of IBD and excluding anti-IL-17a and PDE4i); a non-CID cohort was also created. The 1?year incidence rate (IR) of IBD was compared between cohorts using a logistic regression model adjusting for baseline characteristics.

Results: CID cohorts included older patients than the non-CID cohort (mean age range: 48.4–54.4 versus 46.3?years). The 1?year IR of IBD was 1.41% in the anti-IL-17a cohort (N?=?355), 0.68% in the PDE4i cohort (N?=?2195), 0.47% in the biologic-naïve cohort (N?=?424,767), 0.51% in the non-IBD-indicated biologic cohort (N?=?56,317) cohort and 0.25% in the non-CID cohort (N?=?1,008,436). After 1?year of follow-up, the odds of having IBD were 2.85 (p?=?.0213) and 1.42 (p?=?.1891) times higher in the anti-IL-17a and PDE4i cohorts, respectively, compared to the biologic-naïve cohort, and 2.86 (p?=?.0253) and 1.21 (p?=?.4978) times higher compared to the non-IBD-indicated biologic cohort. Similar results were observed in sensitivity analyses where patients with RA only were excluded (since anti-IL-17a and PDE4i agents are not indicated for RA).

Conclusions: Anti-IL-17a treatment was associated with a nearly three-fold higher risk of IBD in CID patients. Treatment decisions for patients with CIDs should take into account the risk of developing of IBD.     

Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies

Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti-inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas (?)), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose-response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid.     

治疗炎症性肠病的纳米颗粒研究进展

炎症性肠病是一组慢性非特异性肠道炎症性疾病,目前临床上常用的传统非靶向药物可以缓解患者症状,但不能终止黏膜炎症活动、疾病发展,且严重的不良反应限制了这些药物的应用。纳米颗粒由于其独特的大小和物理特性,能够通过黏液层将负载药物传递到肠道细胞,也可以通过内吞作用被巨噬细胞吞噬,从而调节肠道的免疫环境,此外,纳米颗粒还具有改变药物特性的潜力。总结了治疗炎症性肠病的合成纳米颗粒、天然纳米颗粒的研究情况,以期为炎症性肠病的治疗带来新的机遇。     

Type 4 phosphodiesterase inhibitors and their potential in the treatment of inflammatory disease

Although symptomatologic treatment of inflammatory diseases is widely available, agents that slow or halt disease progression are limited in both number and efficacy. Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations, for example, through inhibition of its degradation by phosphodiesterase (PDE) enzymes, has been shown to inhibit inflammation in a variety of preclinical models. Here we evaluate the data which have been generated to assess the therapeutic potential of inhibitors of Type 4 phosphodiesterase (PDE4) in a variety of diseases, but most particularly in asthma, rheumatoid arthritis (RA) and atopic dermatitis (AD).     

Therapeutic potential of phosphodiesterase 4 inhibitors in allergic diseases

Cyclic adenosine monophosphate (cAMP) is thought to be associated with inflammatory cell activity: high levels tend to decrease proliferation and cytokine secretion, whereas low concentrations have the opposite effect (1). Since many phosphodiesterases (PDEs) degrade cAMP, inhibitors of this enzyme decrease inflammatory cell activity. Theophylline, which has nonselective PDE inhibitor activity in addition to its other mechanisms of action, has been used in the treatment of asthma for many years. Unfortunately, because of the important role of PDEs in the cell, nonspecific inhibition of these enzymes causes many undesirable side effects. The discovery of PDE isoenzyme families (PDE1-PDE10), their subtypes (HPDE4 and LPDE4) and their differential distribution among the cell types, as well as their specific functions in controlling cell processes, has led to the development of new, specific PDE4 inhibitors. This review details the rationale for the use of PDE4 inhibitors in the treatment of allergic disease. In addition, the effects of PDE4 inhibitors in vitro, in preclinical animal models and in the clinic are covered. Finally, up-to-date information on the most recently developed inhibitors, such as SB-207499, CDP-840, AWD-12-281 and D-4418, is provided.     

Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease

Crohn's disease and ulcerative colitis (UC) are common, chronic inflammatory bowel diseases (IBDs) characterized by episodes of life-altering symptoms such as diarrhea, bleeding, fecal urgency and incontinence, abdominal pain and cramps, and fever lasting weeks to months at a time. Existing treatments are 5-aminosalicyclates or immunosuppressants, but long-term control of IBD is a major problem for a large number of patients. Phosphodiesterase 4 (PDE4) is a key enzyme in cell homeostasis and inflammation and its inhibition has been useful in diseases such as asthma and chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. This review focuses on the role of oxidative stress in IBD and the PDE4 inhibitor OPC-6535 (tetomilast), an investigational agent for the treatment of UC. The authors detail the clinical development of the compound and report and provide insight into some of the unpublished data from the recently completed multicenter Phase III trials in UC.     

cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases

Introduction: PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body.

Areas covered: Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels. Clearly, such enzymes represent ideal drug targets for the pharmacological treatment of many pathologies. The discovery and development of small molecules targeting cAMP-specific PDEs reported in the last 5 years is the focus of the present review.

Expert opinion: The first PDE4 inhibitors recently reached the market, having avoided, by different strategies, their dose-limiting side effects (after more than two decades of drug development). Meanwhile, new cAMP-specific PDE7 and PDE8 inhibitors emerged as effective and safe drugs for severe unmet diseases. The therapeutic potential of these inhibitors will be tested in the near future, as many of these drug candidates are ready to start clinical trials.     

蜂胶在炎症性肠病中相关作用的研究进展

炎症性肠病（inflammatory bowel disease,IBD）包括克罗恩病和溃疡性结肠炎,以慢性复发性肠炎为主要特征。其发病原因目前尚未完全明确,并且缺乏有效的靶向药物,治愈难度很大。蜂胶（propolis）是一种具有多种生物学活性及药理学功效的天然混合物。相关研究表明,富含多酚的蜂胶提取物表现出显著的抗炎...