Phosphodiesterases as Therapeutic Targets: Translational

由于肺结节病的发病机制涉及单核细胞肺泡炎和通过产生和释放炎性细胞因子和趋化因子(包括TNFa、IL-2和IL-12)来调节肉芽肿的形成，因此针对这些介质的治疗一直是针对这些介质的。虽然激素泼尼松仍然是目前治疗急性结节病的主要药物，但长期治疗的益处尚不确定，而且由于长期使用皮质类固醇可能导致严重的并发症(如糖尿病、高血压、骨质疏松症)，因此人们寻求能够取代或减少其使用的治疗方法。 由于cAMP已知可以抑制各种炎症反应，增加cAMP的药物，包括PDE抑制剂，可能用于替代或减少皮质类固醇在结节病中的使用。己酮可可碱(POF)是一种黄嘌呤类化合物，是一种非特异性PDE抑制剂(12)，多年来一直用于周围血管疾病的治疗。据报道，POF还可以抑制从结节病或外源性过敏性肺泡炎患者分离的肺泡巨噬细胞释放TNFa。此外，一项开放标签的临床试验表明，POF在治疗少数肺结节病患者方面有好处。由于这项研究的设计不排除POF的一些明显反应是由于结节病的自发缓解的可能性，我们设计了一项随机、双盲、安慰剂对照试验来研究POF对肺结节病患者的影响(NHLBI协议99-H-0057：？用己酮可可碱治疗肺结节病？)。 临床试验的目的是确定POF是否可以替代泼尼松治疗肺结节病。在这项试验中，泼尼松逐渐减少，并按照预先设定的时间表停用。患者随机接受POF或安慰剂治疗，在登记时进行评估，大约每4-6周评估一次，为期10个月。主要终点被定义为两个肺功能测试(PFT)参数的显著改善，或一个PFT参数的显著增加，结合呼吸困难严重程度的改善。如果病人经历了耀斑，？即，根据加重的呼吸困难、胸部X光或PFTs的定义，强的松增加到40毫克/天，然后逐渐减少。 在这项试验中，28名患者入选；小样本量进一步减少了两组中的辍学率(30%)。除了一名患者外，POF治疗组没有达到主要终点，由于登记速度较慢，NHLBI数据安全和监测委员会建议终止试验。因此，对试验结果进行了事后的探索性分析，重点是POF对耀斑发生率和泼尼松使用的影响。这项分析表明，接受POF治疗的患者比接受安慰剂治疗的患者经历的闪光更少。在研究的8个月和10个月(而不是6个月)，POF组的平均泼尼松使用量较低，POF组的泼尼松使用量显著减少。此外，在按照方案设计逐渐减少和停用强的松后，POF组有延长类固醇节约期的趋势。然而，虽然副作用不严重，但POF组有超过一半的患者出现恶心和腹泻，2名接受POF治疗的患者因胃肠道副作用而退出。这表明，在所使用的剂量下，POF可能不适合于肺结节病的治疗。尽管这项研究存在缺陷，但这项特别的探索性分析是一种假设生成，因为它为研究新的选择性PDE4抑制剂或其他新型抗炎药，如他汀类药物，在肺结节病中的作用提供了基础。它还表明，今后的调查最好是利用减少照明弹和类固醇的使用作为主要或次要终点。

Since the pathogenesis of pulmonary sarcoidosis involves mononuclear cell alveolitis and regulation of granuloma formation by production and release of inflammatory cytokines and chemokines, including TNFa, IL-2 and IL-12, therapies have been directed against these mediators. Although the corticosteroid prednisone remains the current mainstay of therapy for acute sarcoidosis, the benefit of long term therapy is uncertain, and because significant morbidity (e.g., diabetes, hypertension, osteoporosis) can result from chronic corticosteroid use, therapies that can replace or reduce its usage are sought. Since cAMP is known to inhibit various inflammatory responses, agents that increase cAMP, including PDE inhibitors, could possibly serve to replace or reduce usage of corticosteroids in sarcoidosis. Pentoxifylline (POF), a xanthine derivative, is a non-specific PDE inhibitor (12), which has been used for many years in treatment of peripheral vascular disease. POF was reported also to inhibit TNFa release by alveolar macrophages isolated from patients with sarcoidosis or extrinsic allergic alveolitis. Furthermore, an open-label clinical trial had demonstrated benefit of POF in treatment of a small number of patients with pulmonary sarcoidosis. Since the design of this study did not exclude the possibility that some of the apparent responses to POF were due to spontaneous remission of sarcoidosis, we designed a randomized double-blind, placebo-controlled trial to study effects of POF in patients with pulmonary sarcoidosis (NHLBI Protocol 99-H-0057: ?Treatment of Pulmonary Sarcoidosis with Pentoxifylline?). The objective of the clinical trail was to determine whether POF could serve as an alternative to prednisone as therapy for pulmonary sarcoidosis. In this trial, prednisone was tapered and discontinued in accord with a preset schedule. Patients, randomized to receive POF or placebo, were evaluated at enrollment, and approximately every 4-6 weeks for a 10 month period. Primary endpoints were defined as a significant improvement in two Pulmonary Function Testing (PFT) parameters, or a significant increase in one PFT parameter, combined with an improvement in the severity of dyspnea. If patients experienced ?flares,? i.e., defined by worsening dyspnea, chest x-rays or PFTs, prednisone was increased to 40 mg/day and then tapered. In this trial, 28 patients were enrolled; the small sample size was further reduced by dropouts (30%) in both arms. Except for one patient, primary endpoints were not achieved in the POF-treated group, and because of slow enrollment, the NHLBI Data Safety and Monitoring Board recommended termination of the trial. Consequently, a post hoc, exploratory analysis of the trial results was performed, focusing on effects of POF on the incidence of flares and on prednisone usage. This analysis demonstrated that POF-treated patients experienced fewer flares than the placebo-treated group. The mean prednisone usage was lower in the POF-treated group at 8 and 10 months (not at 6 months) into the study, and there was a significantly less prednisone usage by the POF group. In addition, after prednisone was tapered and discontinued in accord with the protocol design, there was a trend toward a longer steroid sparing period in the POF arm. However, although the side effects were not severe, nausea and diarrhea were reported in over one half of patients in POF arm, and two POF-treated patients dropped out because of gastrointestinal side effects. This suggested that, at the dosages used, POF may not be suitable therapy for pulmonary sarcoidosis. Despite the shortcomings of the study, the ad hoc exploratory analysis was hypothesis generating, in that it provided a basis for studying the role of new selective PDE4 inhibitors or other novel anti-inflammatory agents, such as statins, in pulmonary sarcoidosis. It also served to suggest that future investigations might be best directed towards utilizing reduction in flares and steroid usage as primary or secondary endpoints.