Potentiating Effects of Cisplatin and Ethacrynic Acid in Ototoxicity

Abstract

\s=b\ Seven milligrams per kilogram of body weight of cisplatin and 50 mg/kg of body weight of ethacrynic acid were given intravenously to guinea pigs. The threshold for Preyer's reflex, the cochlear microphonics (CM), and the endocochlear dc potential (EP) were measured during a four-day period after the injection. The changes in Preyer's reflex audiometry and the CM were more severe than that of the EP. These changes are greater than those that occur with the administration of each agent independently. The ototoxic interaction seemingly has a greater effect on the hair cells than on the stria vascularis.Baseline and periodic audiometry should be performed when both of these drugs are administered clinically. (Arch Otolaryngol 1981;107:594-597) The ototoxic effect of cisplatin has been reported in man and labora¬ tory animals.13 In our study of the pathophysiology of the ototoxic effect of cisplatin, 12.5 mg/kg of body weight of cisplatin produced a perma¬ nent loss of hearing and a profound depression of the endocochlear dc potential (EP) and the cochlear micro¬ phonics (CM).4 Likewise, the loop diu¬ retics, such as ethacrynic acid, have been demonstrated to have a toxic PA 19104 (Dr Snow). effect on the inner ear of man and animals."" The toxic effects of these drugs on the inner ear are different. Cisplatin mainly affects the outer hair cells of Corti's organ, and ethacrynic acid mainly affects the stria vascular¬ is. Clinically, aminoglycoside antibiot¬ ics, such as kanamycin sulfate, often are used in combination with diuret¬ ics, especially the effective loop di¬ uretics. Although diuretics can be expected to reduce the nephrotoxicity of aminoglycosides, West et al·' and Prazma et al1" demonstrated that the combination of kanamycin and etha¬ crynic acid potentiates their individu¬ al ototoxic effects. Otani et al" dem¬onstrated that the daily administra¬ tion of kanamycin and furosemide induced more severe damage to the outer hair cells in rabbits than did kanamycin alone. Nakai and Morimo¬ to12 observed that a single injection of 3',4'-dideoxykanamycin B, 400 mg/kg of body weight, followed in two hours by an injection of 100 mg/kg of body weight of furosemide damages the hair cells in guinea pigs. In short-and long-term experiments in guinea pigs, Brummett et al13 demonstrated that the administration of kanamycin and furosemide induced an ototoxic inter¬ action that resulted in depressed coch¬ lear potentials and permanent hear¬ ing losses. These interactions mainly involved the hair cells except in the study of Prazma et al,'°i n which the interaction involved the stria vascu¬ laris more than the hair cells.Cisplatin is an antineoplastic agent that has a severe nephrotoxic effect.If ethacrynic acid was used to reduce the nephrotoxic effect of cisplatin, it may increase the ototoxic effect of cisplatin. Therefore, a study was carried out in guinea pigs to deter¬ mine if cisplatin and ethacrynic acid potentiate their individual ototoxic effects. After receiving these agents individually and in combinat...

Comparative Ototoxicity of Cisplatin during Acute and Chronic Treatment

“…Furthermore, the stria vascularis was affected in this study only by the acute treatment. Previous reports concerning the effect of CDDP on endo cochlear potentials have shown that while large doses of CDDP reduce the endocochlear potential [8,16], small consecutive doses of CDDP resulted in hearing loss with out a reduction in the endocochlear potential [7,8,17]. These electrophysiological data are in agreement with present morphological data on the stria vascularis.…”

Reduction of Cisplatin Ototoxicity by Fosfomycin in Animal Model

“…The present study on the ototoxic effect of CDDP in rats confirms the findings of pre vious studies in monkeys [Stadnicki et al, 1975], guinea pigs [Estrem et al, 1981;Komune and Snow, 1981;Nakai et al, 1982;Tange el al., 1982] and rabbits [Aikawa et al, 1982]. The outer hair cell damage due to CDDP was most pronounced in the basal turn with greatest severity in the first row as seen in the damage due to aminoglycoside antibiotics.…”

Ototoxicity of ethacrynic acid

“…We have recently found that glutathione depletion by the selective inhibitor of glutathione synthesis, buthionine sulfoximine, markedly enhances the threshold shift in ABR, auditory brain stem evoked response and outer hair cell loss in chinchillas pretreated with ethacrynic acid-kanamycin combination (Hoffman era/., 1986). These findings may explain the clinical (Mathog and Klein, 1969) and experimental observations of marked potentiation of ototoxicity when aminoglycosides , (West et ai, 1973 or cisplatinum (Komune and Snow, 1981) are combined with loop diuretics such as ethacrynic acid. The above case should serve as a reminder that clinicians need to be vigilant for ototoxicity in patients being treated with ethacrynic acid, particularly in patients with renal failure who may be receiving concomitant treatment with aminoglycosides or cisplatinum.…”