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 anima l. 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 oto toxic insults. Subjects and Design: Guinea pigs were fed either a full -protein (18.5% protein) or a low-protein (7% protein) diet. Gentamici n sulfate was given as a single inj ection (100 mg/kg of body weight s ubcutaneously), followed 90 minutes later by varying concentrations of ethacrynic acid intravenously. Auditory function was assessed by audi tory brain-stem response and morphologic characteristics in surface pr eparations of the organ of Corti. Results: In animals fed a full-prote in diet, 35 mg of ethacrynic acid per kilogram of body weight was requ ired 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 lo ss in the organ of Corti paralleled the pathophysiological findings. C onclusions: A metabolically challenged animal may better represent the situation of a severely ill patient undergoing drug therapy. Therefor e, studies in diet-restricted animals may be more appropriate than stu dies in healthy animals for an assessment of potential adverse therape utic side effects.