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首页> 外文期刊>Pulmonary Circulation >HIV Protease Inhibitors in Pulmonary Hypertension: Rationale and Design of a Pilot Trial in Idiopathic Pulmonary Arterial Hypertension:
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HIV Protease Inhibitors in Pulmonary Hypertension: Rationale and Design of a Pilot Trial in Idiopathic Pulmonary Arterial Hypertension:

机译：肺动脉高压中的HIV蛋白酶抑制剂：特发性肺动脉高压的基本原理和试验设计：

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We propose an exploratory clinical study, the first of its kind to our knowledge, to determine the safety and potential clinical benefit of the combination of the HIV protease inhibitors (HIV-PIs) saquinavir and ritonavir (SQV+RIT) in patients with idiopathic pulmonary arterial hypertension (IPAH). This study is based on evidence that (1) HIV-PIs can improve pulmonary hemodynamics in experimental models; (2) both Toll-like receptor 4 and high-mobility group box 1 (HMGB1) participate in the pathogenesis of experimental pulmonary hypertension; and (3) a high-throughput screen for inhibitors of HMGB1-induced macrophage activation yielded HIV-PIs as potent inhibitors of HMGB1-induced cytokine production. In this proposed open-label, pre-post study, micro, low, and standard doses of SQV+RIT will be given to IPAH patients for 14 days. Patients will receive follow-up for the next 14 days. The primary outcome to be evaluated is change in HMGB1 level from baseline at 14 days. The secondary outcome is changes in tumor necrosis factor α, interleukin 1β, interleukin 6, C-reactive protein, pulmonary arterial pressure based on echocardiography parameters and New York Heart Association/World Health Organization functional class, and Brog dyspnea scale index from baseline at 14 days. Other secondary measurements will include N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, and 6-minute walk distance. We propose that SQV+RIT treatment will improve inflammatory disorders and pulmonary hemodynamics in IPAH patients. If the data support a potentially useful therapeutic effect and suggest that SQV+RIT is safe in IPAH patients, the study will warrant further investigation. (ClinicalTrials.gov identifier: NCT02023450.)
机译：我们提出了一项探索性临床研究，这是我们所了解的第一个此类研究，目的是确定沙特那韦与HIV蛋白酶抑制剂（HIV-PIs）联合利托那韦（SQV + RIT）联合治疗在特发性肺部疾病中的安全性和潜在的临床益处动脉高压（IPAH）。这项研究基于以下证据：（1）HIV-PIs可以改善实验模型中的肺血流动力学; （2）Toll样受体4和高迁移率族框1（HMGB1）均参与实验性肺动脉高压的发病机制; （3）高通量筛选HMGB1诱导的巨噬细胞活化的抑制剂可产生HIV-PIs，作为HMGB1诱导的细胞因子产生的有效抑制剂。在这项拟议的开放标签，事后研究中，将为IPAH患者提供14天的微剂量，低剂量和标准剂量的SQV + RIT。患者将在接下来的14天接受随访。要评估的主要结果是14天基线时HMGB1水平的变化。次要结果是基于超声心动图参数和纽约心脏协会/世界卫生组织功能分类的肿瘤坏死因子α，白介素1β，白介素6，C反应蛋白，肺动脉压以及从基线开始的Brog呼吸困难量表指数的变化天。其他辅助测量将包括N端脑钠肽，心钠素和6分钟步行距离。我们建议SQV + RIT治疗将改善IPAH患者的炎症性疾病和肺血流动力学。如果数据支持可能有用的治疗效果，并提示SQV + RIT在IPAH患者中是安全的，则该研究值得进一步研究。 （ClinicalTrials.gov标识符：NCT02023450。）

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