title: HIV protease inhibitors in pulmonary hypertension: rationale and design of a pilot trial in idiopathic pulmonary arterial hypertension.
abstract: 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.).
authors.affiliation: Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, People's Republic of China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Zai-Xin
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Cai
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, People's Republic of China ; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
authors.affiliation: Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China; State Key Laboratory of Medical Genetics, Central South University, Changsha, People's Republic of China; and Center of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Lv
authors.affiliation: Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Zi-Ying
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Huang
authors.affiliation: Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Cardiology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
keywords: HIV protease inhibitors; clinical trial; inflammation; pulmonary hypertension