Phosphodiesterases as Therapeutic Targets: Translational

磷酸二酯酶作为治疗靶点：转化

• 批准号: 7321645
• 负责人: VINCENT MANGANIELLO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7321645
• 关键词: Phosphodiesterases; Therapeutic; Targets; Translational

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.

由于肺结节病的发病机制涉及单核细胞肺泡炎以及通过炎症细胞因子和趋化因子（包括 TNFa、IL-2 和 IL-12）的产生和释放来调节肉芽肿形成，因此治疗已针对这些介质。尽管皮质类固醇泼尼松仍然是目前治疗急性结节病的主要方法，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显着的发病率（例如糖尿病、高血压、骨质疏松症），因此可以替代或减少其治疗的疗法寻求使用。 由于已知 cAMP 可以抑制各种炎症反应，因此增加 cAMP 的药物（包括 PDE 抑制剂）可能可以替代或减少结节病中皮质类固醇的使用。己酮可可碱 (POF) 是一种黄嘌呤衍生物，是一种非特异性 PDE 抑制剂 (12)，多年来一直用于治疗外周血管疾病。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，一项开放标签临床试验已证明 POF 在治疗少数肺结节病患者中具有益处。由于本研究的设计并未排除 POF 的一些明显反应是由于结节病自发缓解所致的可能性，因此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 方案 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 是否可以作为泼尼松的替代品来治疗肺结节病。在这项试验中，泼尼松按照预设的时间表逐渐减量并停药。患者被随机分配接受 POF 或安慰剂，在入组时进行评估，并且在 10 个月的时间内大约每 4-6 周进行一次评估。主要终点定义为两项肺功能测试 (PFT) 参数显着改善，或一项 PFT 参数显着增加，同时呼吸困难严重程度改善。如果患者出现“耀斑”，？即，根据呼吸困难恶化、胸部 X 光检查或 PFT 的定义，泼尼松增加至 40 毫克/天，然后逐渐减少。 在这项试验中，共招募了 28 名患者；由于双臂的退出（30%），小样本量进一步减少。除一名患者外，POF 治疗组未达到主要终点，并且由于入组缓慢，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探索性分析，重点关注 POF 对耀斑发生率和泼尼松使用的影响。该分析表明，接受 POF 治疗的患者比接受安慰剂治疗的患者出现的症状更少。在研究的第 8 个月和 10 个月（不是第 6 个月），POF 治疗组的平均泼尼松使用量较低，并且 POF 组的泼尼松使用量显着减少。此外，根据方案设计，泼尼松逐渐减量并停用后，POF 组中出现了更长的类固醇保留期的趋势。然而，尽管副作用并不严重，但 POF 组中超过一半的患者报告出现恶心和腹泻，并且有两名接受 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 可能不适合治疗肺结节病。尽管该研究存在缺陷，但临时探索性分析还是产生了假设，因为它为研究新型选择性 PDE4 抑制剂或其他新型抗炎药物（如他汀类药物）在肺结节病中的作用提供了基础。它还表明，未来的研究可能最好针对利用减少耀斑和类固醇使用作为主要或次要终点。