title: Accelerated dosing frequency of a pulmonary formulation of tissue plasminogen activator is well-tolerated in mice.
abstract: 1. Tissue plasminogen activator (tPA) has both fibrinolytic and anti-inflammatory activity. These properties may be useful in treating inflammatory lung diseases, such as acute respiratory distress syndrome (ARDS). 2. We have previously demonstrated the feasibility of targeted pulmonary delivery of tPA. As part of our research to develop a clinically viable pulmonary formulation of tPA, we assessed the tolerability and incidence of haemorrhage associated with the administration of a pulmonary formulation of mouse tPA (pf-mtPA). 3. Intratracheal doses of nebulized pf-mtPA or sterile saline were administered with increasing frequency to male and female B6C3F1 mice. After dosing, the mice entered a recovery period, after which they were killed and their lungs were lavaged and harvested. Post-mortem gross necropsy was performed and all major organs were assessed histologically for haemorrhage. The bronchoalveolar lavage fluid was assessed for markers of lung injury. 4. Mouse tPA that was formulated to mimic a previously characterized human pf-tPA was well tolerated when given intratracheally with increasing dosing frequency. The administration of pf-mtPA did not result in any detectable haemorrhagic-related events or signs of lung injury. 5. The results of the present longitudinal study demonstrate that a maximally feasible dose of pf-mtPA (3 mg/kg) can be given frequently over a short period of time (12 h) without haemorrhagic complications. Although these data were generated in a healthy mouse model, they provide support for the continued evaluation of pf-tPA for the treatment of pulmonary diseases, such as ARDS.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA. stringek@umich.edu
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Stringer
authors.forename: Meghan
authors.initials: M
authors.lastname: Tobias
authors.forename: John S
authors.initials: JS
authors.lastname: Dunn
authors.forename: Jackie
authors.initials: J
authors.lastname: Campos
authors.forename: Zachary
authors.initials: Z
authors.lastname: Van Rheen
authors.forename: Mitra
authors.initials: M
authors.lastname: Mosharraf
authors.forename: Rajiv
authors.initials: R
authors.lastname: Nayar
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D008137:Longitudinal Studies; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D004304:Dosage Forms; D010959:Tissue Plasminogen Activator