Drug Design, Development and Therapy (Nov 2018)
Efficacy evaluation of reteplase in a novel canine acute pulmonary thromboembolism model developed by minimally invasive surgery and digital subtraction angiography
Abstract
Yinbing Zhang,1,2 Haifeng Liu,3 Yingqian Zhang,4 Qiong Wu,1 Yanyan Zhang,1,2 Jie Zhang,1,2 Xiangshan Zhou,3 He Jiao,5 Feng Fan,6 Qi Xue,7 Xin Wang,1,2 Zhihui Zhong1,2 1Laboratory of Nonhuman Primate Disease Modeling Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; 2Sichuan Kangcheng Biomed Co., Ltd., Chengdu, China; 3Angde Biotech Pharmaceutical Co., Ltd., Liaocheng, China; 4Department of Physiology, Southwest Medical University, Luzhou, China; 5Department of Interventional therapy, West China Hospital, Sichuan University, Chengdu, China; 6Department of Neurointervention, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 7Food and Drug Administration of Shibei District Government, Qingdao, China Purpose: In order to evaluate the thrombolytic effects of reteplase in pulmonary thromboembolism (PTE), we developed a novel canine PTE model. The efficacy of reteplase against PTE in comparison to alteplase was clarified for the first time, and this PTE model could be further applied to studies of novel thrombolytic therapies. Patients and methods: Twenty-four dogs were divided into four groups: sham operation, vehicle, alteplase, and reteplase. Autologous thrombi/saline were injected into the pulmonary artery, and thrombolytic agents were administrated. Thrombus formation and dissolution were monitored by real-time digital subtraction angiography (DSA), and pulmonary pressures were measured simultaneously. Blood coagulation, blood gas, hematology, and histopathologic examinations were used as subsidiary methods. Results: The canine PTE model was established with a significant decrease of blood flow and ~75% blocking area. Administration of reteplase (0.6 mg/kg) resulted in effective thrombus dissolution with a recovery of over 80% blood flow, as effective as alteplase (1.6 mg/kg). Correspondingly, the elevated pulmonary systolic, diastolic, and mean arterial pressures declined to the normal level. Blood coagulation was changed by reteplase, with a dramatic elongation of prothrombin time, activated partial thromboplastin time, and thrombin time, even longer than alteplase. In contrast to the vehicle group, no obvious pathological changes were found in the two thrombolytic groups. Hematological, blood biochemical, and blood gas results also indicated that reteplase had no adverse reactions in this PTE model. Conclusion: Reteplase proved to be an effective and safe therapy for PTE for the first time, and a small dosage of reteplase exerted an efficacy comparable to the routine dosage of alteplase. Our findings indicated the potential of reteplase as clinical treatment against PTE. This technically innovative, stability- and validity-proved canine PTE model developed by minimally invasive surgery and DSA resembled major clinical features. This may further facilitate our understanding of thrombotic disorders and development of prophylactic and therapeutic approaches. Keywords: reteplase, canine pulmonary thromboembolism model, thrombolytic therapy
