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炎性细胞因子和趋化因子（包括TNFa、IL-2和IL-12）的产生和释放对肉芽肿形成的调节，因此治疗一直针对这些介质。尽管皮质类固醇强的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导致显著的发病率（如糖尿病、高血压、骨质疏松症），因此需要寻找替代或减少其使用的治疗方法。

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.