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2623142 
Journal Article 
Abstract 
Chronic inhalation of denufosol tetrasodium aerosol is non-inflammatory in rodent and canine respiratory tract tissues 
Cowlen, MS; Verhoeven, RS 
2010 
Yes 
American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 
181 
A1846 
English 
WOS:000208771001054 
is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans
Rationale: Denufosol tetrasodium (INS37217, denufosol) is a P2Y receptor-mediated chloride channel activator in Phase 3 development 2 for the treatment of cystic fibrosis (CF) lung disease. This study was performed to assess the effect of denufosol on background inflammation in the lung following chronic inhalation in rats and dogs at doses intended to exceed the human clinical dose.

Methods: Denufosol was administered as an isotonic, aerosol formulation using Pari eFlow nebulizers. Aerosol particle size was monitored, and denufosol concentration, respiratory minute volume, daily exposure time, and lung weight at necropsy were used to calculate daily pulmonary-deposited dose. Rats were treated daily for 2 years at doses up to 2.36 mg/g lung weight/day; dogs were treated daily for 1 year at doses up to 7.27 mg/g lung weight/day. Control animals were treated with nebulized isotonic saline. Bronchial alveolar lavage fluid and/or plasma denufosol levels were determined to verify exposure. The potential for denufosol to induce inflammatory responses in respiratory tract tissues was assessed histopathologically by board-certified veterinary pathologists.

Results: Rats and dogs treated with saline exhibited a variety of background inflammatory lesions in the lung, including macrophage accumulation, inflammatory cell infiltration, interstitial inflammation and edema. No increase in background inflammation was observed in denufosol-treated animals when compared to placebo in either species up to the highest doses tested (6 to 18 times the human dose to children normalized to lung weight).

Conclusion: These results demonstrate that denufosol does not increase background levels of pulmonary inflammation when compared to placebo following chronic inhalation in rats and dogs at significant multiples above the human clinical dose under investigation for the treatment of CF lung disease. 
American Thoracic Society 2010 International Conference 
New Orleans, LA 
May 14-19, 2010