Safety of prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in mice

摘要: Abstract Background Disruption of fibrinolytic homeostasis participates in the pathogenesis severe lung diseases like acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF) and plastic bronchitis. We have developed a formulation tissue plasminogen activator (pf-tPA) that withstands nebulization reaches lower airways. Objective Since treatment ARDS, IPF bronchitis will require repeated administration pf-tPA, purpose this study was to determine safety prolonged, pf-mouse tPA (pf-mtPA) lungs healthy mice. Methods Male female B6C3F1 mice received one two intratracheal (IT) doses either nebulized pf-mtPA or sterile saline twice daily for 28 days. Weekly blood samples were collected estimate hematocrit. Following dosing period, animals sacrificed gross necropsy, acquisition bronchoalveolar lavage fluid (BALF), histological assessment other major organs. Results The low dose well tolerated by both male However, high experienced 16% 8% incidence, respectively, fatal hemorrhage. Although had incidence bleeding, these events occurred at mean (±S.E.) (1.06±0.02 mg/kg/d) compared with females (1.48±0.03 mg/kg/d, p  Conclusion This established safe range demonstrated feasibility pf-tPA. High (≥1 mg/kg/d) associated hemorrhage may be due, part, accumulation drug lungs.