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. Copyright 2009 Elsevier Ltd. All rights reserved.
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-mousetPA (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. Copyright 2009 Elsevier Ltd. All rights reserved.
Authors: Stephan Urs Sixt; Martin Beiderlinden; Herbert Peter Jennissen; Jürgen Peters Journal: Am J Physiol Lung Cell Mol Physiol Date: 2007-01-12 Impact factor: 5.464
Authors: Michelle A Carey; Jeffrey W Card; James W Voltz; Dori R Germolec; Kenneth S Korach; Darryl C Zeldin Journal: Am J Physiol Lung Cell Mol Physiol Date: 2007-06-15 Impact factor: 5.464
Authors: R Phillip Dellinger; Mitchell M Levy; Jean M Carlet; Julian Bion; Margaret M Parker; Roman Jaeschke; Konrad Reinhart; Derek C Angus; Christian Brun-Buisson; Richard Beale; Thierry Calandra; Jean-Francois Dhainaut; Herwig Gerlach; Maurene Harvey; John J Marini; John Marshall; Marco Ranieri; Graham Ramsay; Jonathan Sevransky; B Taylor Thompson; Sean Townsend; Jeffrey S Vender; Janice L Zimmerman; Jean-Louis Vincent Journal: Crit Care Med Date: 2008-01 Impact factor: 7.598
Authors: Soraya Hengsawas Surasarang; Sawittree Sahakijpijarn; Galina Florova; Andrey A Komissarov; Christina L Nelson; Enkhbaatar Perenlei; Satoshi Fukuda; Marla R Wolfson; Thomas H Shaffer; Steven Idell; Robert O Williams Journal: J Drug Deliv Sci Technol Date: 2018-04-30 Impact factor: 3.981
Authors: Lauren Heath; Shelley Ling; Jennifer Racz; Gerta Mane; Lindsay Schmidt; Jeffrey L Myers; Wan C Tsai; Regine L Caruthers; Jennifer C Hirsch; Kathleen A Stringer Journal: Pediatr Cardiol Date: 2011-07-24 Impact factor: 1.655
Authors: Swan Lin; Jennifer Racz; Melissa F Tai; Kristina M Brooks; Phillip Rzeczycki; Lauren J Heath; Michael W Newstead; Theodore J Standiford; Gus R Rosania; Kathleen A Stringer Journal: Pharm Res Date: 2015-08-01 Impact factor: 4.200
Authors: Satoshi Fukuda; Perenlei Enkhbaatar; Christina Nelson; Robert A Cox; Marla R Wolfson; Thomas H Shaffer; Robert O Williams; Soraya Hengsawas Surasarang; Sahakijpijarn Sawittree; Galina Florova; Andrey A Komissarov; Kathleen Koenig; Krishna Sarva; Harrison T Ndetan; Karan P Singh; Steven Idell Journal: Clin Transl Med Date: 2018-06-18
Authors: Massimo Colaneri; Andrea Quarti; Marco Pozzi; Stefano Gasparini; Ines Carloni; Fernando Maria de Benedictis Journal: Ital J Pediatr Date: 2014-02-13 Impact factor: 2.638