title: Inhibition of proteases in Pseudomonas otitis media in chinchillas.
abstract: The treatment of chronic suppurative otitis media caused by Pseudomonas aeruginosa remains a challenging problem. The virulence of Pseudomonas is related to its secretion of two matrix metalloproteinases, alkaline protease and elastase. This experiment examines the effects of a synthetic inhibitor of matrix metalloproteinases GM 6001, or N-(2(R)-2(hydroxyamido carbonylmethyl)-4-methylpentanoyl)-L-tryptophane methylamide), in a chinchilla Pseudomonas otitis media model. Thirty chinchillas underwent bilateral subtotal tympanic membrane perforations. Twenty-four chinchillas underwent bilateral middle ear inoculation with P. aeruginosa. Chinchillas were divided into four groups of six animals after the establishment of otitis media. Animals in one group were controls; the other three groups received either gentamicin, GM 6001, or gentamicin plus GM 6001 into the external auditory canal three times daily for 4 weeks. Clearance of Pseudomonas infection occurred in three ears of three animals, all in gentamicin groups, with or without GM 6001. Otorrhea (p = 0.0014) and external canal erythema (p = 0.025) were mild in the two gentamicin groups and moderate in the GM 6001 group when compared with bacterial controls. Animals in the GM 6001 group had the highest survival rate, less severe facial paralysis, and less vestibular toxicity than the gentamicin, gentamicin plus GM 6001, or control groups, although these differences were not statistically significant. This pilot study showed encouraging results for a role of ototopical protease inhibitors in the treatment of Pseudomonas otitis media.
authors.affiliation: Department of Otolaryngology, University of Florida, Gainesville, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Cotter
authors.forename: M A
authors.initials: MA
authors.lastname: Avidano
authors.forename: S P
authors.initials: SP
authors.lastname: Stringer
authors.forename: G S
authors.initials: GS
authors.lastname: Schultz
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002682:Chinchilla; D004151:Dipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005839:Gentamicins / Q000627:therapeutic use; D010033:Otitis Media / Q000188:drug therapy* / Q000382:microbiology; D010865:Pilot Projects; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; D005839:Gentamicins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors