A sensitive animal model to assess acute and chronic ototoxic effects.
BACKGROUND
Ototoxic side effects of aminoglycosides or cisplatin are strongly influenced by the nutritional state of the experimental animal. We previously demonstrated that guinea pigs fed a low-protein diet are a sensitive model to investigate chronic ototoxic effects of drugs. We now demonstrate that this model is equally sensitive to acute ototoxic insults.


METHODS
Guinea pigs were fed either a full-protein (18.5% protein) or a low-protein (7% protein) diet. Gentamicin sulfate was given as a single injection (100 mg/kg of body weight subcutaneously), followed 90 minutes later by varying concentrations of ethacrynic acid intravenously. Auditory function was assessed by auditory brain-stem response and morphologic characteristics in surface preparations of the organ of Corti.


RESULTS
In animals fed a full-protein diet, 35 mg of ethacrynic acid per kilogram of body weight was required for a significant threshold shift at all frequencies tested (3, 8, and 18 kHz). In animals fed a low-protein diet, 15 mg of ethacrynic acid per kilogram significantly elevated threshold at all frequencies, and 20 mg/kg caused a profound threshold shift (> 90 dB). Hair cell loss in the organ of Corti paralleled the pathophysiological findings.


CONCLUSIONS
A metabolically challenged animal may better represent the situation of a severely ill patient undergoing drug therapy. Therefore, studies in diet-restricted animals may be more appropriated than studies in healthy animals for an assessment of potential adverse therapeutic side effects.
Lautermann
J
J
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, USA.
Schacht
J
J
D000208:Acute Disease; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001309:Auditory Threshold; D018753:Diet, Protein-Restricted; D004195:Disease Models, Animal; D004232:Diuretics / Q000633:toxicity; D004976:Ethacrynic Acid / Q000633:toxicity; D016057:Evoked Potentials, Auditory, Brain Stem; D005839:Gentamicins / Q000633:toxicity; D006168:Guinea Pigs; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009925:Organ of Corti / Q000473:pathology
D000900:Anti-Bacterial Agents; D004232:Diuretics; D005839:Gentamicins; D004976:Ethacrynic Acid