Protease inhibitors alpha1-antitrypsin and ilomastat are not ototoxic in the chinchilla.
OBJECTIVE
Proteases of both the serine and the metalloprotease families have been shown to play a role in the pathogenesis of otitis media. Inhibitors of proteases from each of these families have been shown to beneficially impact disease progression in a number of related chronic inflammatory conditions. The purpose of this study was to assess the safety of protease inhibitors when instilled into the middle ear, with a view to their potential use in the treatment of human otitis media.


METHODS
Prospective, randomized, controlled trial in the chinchilla model.


METHODS
After completing baseline auditory testing and bilateral transpalatal obstruction of the Eustachian tube, chinchillas received weekly transbullar injections of protease inhibitor (alpha1-antitrypsin, ilomastat, or both), vehicle, or saline. After 1 month, hearing was tested and the animals were sacrificed. Temporal bone histopathologic examination was performed.


RESULTS
All treatment groups demonstrated a statistically insignificant average loss in long-term hearing (0 dB) for all measures using clicks and tones (P >.15 for all conditions). All treatment groups were statistically insignificantly different from one another (P =.5625). Histopathologic examination revealed no significant inner ear changes.


CONCLUSIONS
Protease inhibitors that are currently under study in animal models and humans for the treatment of inflammatory diseases that are related to imbalances between protease and protease inhibitor have no significant toxic effect on the inner ear of chinchillas. These findings support the safety of further clinical trials using these inhibitors to treat middle ear inflammation.
Antonelli
Patrick J
PJ
Department of Otolaryngology, University of Florida, Box 100264, 1600 SW Archer Road, Gainesville, FL 32610-0264, USA. antonpj@ent.ufl.edu
Schultz
Gregory S
GS
Sundin
David J
DJ
Pemberton
Philip A
PA
Barr
Philip J
PJ
D000818:Animals; D002682:Chinchilla; D004195:Disease Models, Animal; D005260:Female; D006309:Hearing / Q000187:drug effects*; D006877:Hydroxamic Acids; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007322:Instillation, Drug; D008297:Male; D010033:Otitis Media / Q000188:drug therapy; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013701:Temporal Bone / Q000473:pathology; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D006877:Hydroxamic Acids; D007211:Indoles; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; C119203:ilomastat