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首页> 外文期刊>Pulmonary pharmacology & therapeutics >Safety of prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in mice.
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Safety of prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in mice.

机译：在小鼠中长期重复施用组织纤溶酶原激活物的肺部制剂的安全性。

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BACKGROUND: Disruption of fibrinolytic homeostasis participates in the pathogenesis of severe lung diseases like acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF) and plastic bronchitis. We have developed a pulmonary formulation of tissue plasminogen activator (pf-tPA) that withstands nebulization and reaches the lower airways. OBJECTIVE: Since treatment of ARDS, IPF and plastic bronchitis will require repeated administration of pf-tPA, the purpose of this study was to determine the safety of prolonged, repeated administration of pf-mouse tPA (pf-mtPA) to the lungs of healthy mice. METHODS: Male and female B6C3F1 mice received one of two intratracheal (IT) doses of either nebulized pf-mtPA or sterile saline twice daily for 28 days. Weekly blood samples were collected to estimate hematocrit. Following the dosing period, animals were sacrificed for gross necropsy, the acquisition of bronchoalveolar lavage fluid (BALF), and histological assessment of the lungs and other major organs. RESULTS: The low dose of pf-mtPA was well tolerated by both female and male mice. However, female and male mice that received the high dose experienced a 16% and 8% incidence, respectively, of fatal pulmonary hemorrhage. Although male mice had a lower incidence of bleeding, these events occurred at lower mean (+/-S.E.) doses (1.06+/-0.02mg/kg/d) of pf-mtPA compared with females (1.48+/-0.03mg/kg/d, p<0.001). In addition, male mice had higher BALF mtPA concentrations. Bleeding occurred six and 12 days in male and female mice, respectively, after the initiation of dosing suggesting that mtPA accumulated in the lungs. CONCLUSION: This study established a safe dose range and demonstrated the feasibility of prolonged, repeated dosing of pf-tPA. High doses (> or =1mg/kg/d) were associated with pulmonary hemorrhage that may be due, in part, to accumulation of drug in the lungs.
机译：背景：溶纤蛋白稳态的破坏参与了严重的肺部疾病的发病机理，如急性呼吸窘迫综合征（ARDS），特发性肺纤维化（IPF）和可塑性支气管炎。我们已经开发了一种组织纤溶酶原激活物（pf-tPA）的肺部制剂，它可以承受雾化并到达下呼吸道。目的：由于ARDS，IPF和塑料性支气管炎的治疗需要重复使用pf-tPA，因此本研究的目的是确定长期，重复使用pf-小鼠tPA（pf-mtPA）对健康人肺的安全性老鼠。方法：雄性和雌性B6C3F1小鼠每天两次两次接受气管内（IT）雾化pf-mtPA或无菌生理盐水剂量之一，两次，共28天。每周收集血样以估计血细胞比容。在给药期间之后，处死动物以进行大体尸检，获取支气管肺泡灌洗液（BALF）以及对肺和其他主要器官的组织学评估。结果：雌性和雄性小鼠均对低剂量的pf-mtPA有良好的耐受性。但是，接受高剂量的雌性和雄性小鼠致命肺出血的发生率分别为16％和8％。尽管雄性小鼠的出血发生率较低，但与雌性小鼠（1.48 +/- 0.03mg / d）相比，这些事件发生在pf-mtPA的平均剂量（+/- SE）较低（1.06 +/- 0.02mg / kg / d）时kg / d，p ＜0.001）。此外，雄性小鼠的BALF mtPA浓度较高。开始给药后，雄性和雌性小鼠分别发生出血6天和12天，这表明mtPA积累在肺中。结论：本研究确定了安全剂量范围，并证明了延长，重复给药pf-tPA的可行性。高剂量（>或= 1mg / kg / d）与肺出血有关，这可能部分是由于药物在肺中积聚所致。

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