ORL 37: 27-34 (1975)
Aspirin Ototoxicity in the Guinea Pig1 S. Crifd2 Department of Otorhinolaryngology, University of Rome, Rome
Key Words. Ototoxicity ■Aspirin ■Shiver audiometry Abstract. Aspirin ototoxicity has been studied on guinea pigs by shiver-audiometry and histological investigation of the cochlear duct. One dose of 350 mg/kg has provoked, after 7 h, a mean hearing loss of 18-24 dB at 0.25-8 kHz, followed by complete recovery in 3 days. The difference between the administration of 50 mg/kg/day and 350 mg/kg/day con sists of a wide extension of the frequencies involved, and in about 10 dB a greater hearing loss. In both cases, no appreciable recovery of hearing was observed after 22 days (the histological investigations were negative). The biochemical pathogenesis of aspirin ototoxi city is discussed and periodical audiometric controls before and during salicylate treatment are recommended.
Aspirin ototoxicity has been observed both in experimental animals (cat, monkey) and in man. The very wide use of salicylates and the occurrence of acute forms, following accidental or suicidal consumption, and of chronic forms, particularly in rheumatic patients treated with salicylates, has encouraged re search in this field. It has been shown that salicylates cross the cochlear barrier and can be estimated in the labyrinthine fluids in relation to serum levels (Siherstein etal., 1967). In the guinea pig, moreover, tritiated salicylic acid is capable of penetrat ing quickly into the inner ear (Ishii et al., 1967). It is concentrated mainly in the 1 Paper read at the 12th International Congress of Audiology in Paris, France, on April 23, 1974. 2 I wish to thank Dr. D. Difeliceantonio, Dr. G. Di Francesco and Dr. A. Sidoli for their cooperation. This research was financed in part by the Ministero Pubblica Istruzione, L.286, 1972-3.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Received: May 24, 1974; accepted: August 5, 1974.
Crifo
28
vascular stria and in the spiral ligament but may diffuse into the organ of Corti. However, in the Saimiri monkey (Myers and Bernstein, 1965) ultrastructural investigations of the inner ear 24 h after the administration of 500- 600 mg/kg of salicylate have proved negative, although avoidance-conditioned audiometry has shown a hearing loss of 17-36 dB at 0.25-8 kHz. In the cat, Silverstein et al. (1967) have noted a marked depression of cochlear microphonics and action potentials after a dose of 350 mg/kg, coupled with a significant decrease of malic-dehydrogenase activity in the perilymph and endolymph, indicating an impairment of cochlear intermediate metabolism. In man (Graham and Parker, 1948) the critical ototoxic salicylaemic level seems to be around 35 mg%. It is likely that individual sensitivity to the drug varies. The ototoxic syndrome caused by salicylates (i.e., aspirin) is characterized by tinnitus and hypacusia (Falbe-Hansen, 1941; Graham and Parker, 1948; McCabe and Day, 1965) and after very high doses by vertigo {Falbe-Hansen, 1941; Waltner, 1955\ McCabe andDey, 1965). Audiometric studies have demonstrated that hypacusia is sensorineural in character and may be associated with recruitment (Falbe-Hansen, 1941; Waltner, 1955; Myers and Bernstein, 1965). In the normal subject the provoked deficit was often pantonal {Myers and Bernstein, 1965; Bernstein and fVeiss, 1967) or there was a prevalent or exclusive loss of high frequencies {Falbe-Hansen, 1941; McCabe and Dey, 1965). The acute syndrome is characterized by its sudden onset and reversibility within 1—10 days {Falbe-Hansen, 1941; Jager and A lway, 1946; Waltner, 1955; Myers and Bernstein, 1965). This seems to indicate a biochemical impairment of the inner eat {Myers and Bernstein, 1965; McCabe and Dey, 1965; Silverstein et al., 1967; Ishii et al., 1967), seen also by the absence of any morphological lesion in the temporal bones of two rheumatic patients suffering from deafness probably caused by salicylates {Bernstein and Weiss, 1967). The purpose of the present study has been the assessment of the hearing pattern of guinea pigs during acute and chronic aspirin intoxication.
In the ‘acute experiment’ ten albino guinea pigs of about 250 g (Morini, Bologna, Italy) with normal hearing (0.25-8 kHz) on shiver-audiometry according to the technique pre viously reported (Crifo, 1973, 1974) and with a normal pinna reflex, were treated endoperitoneally with lisine acetyl-salicylate (Flectadol, Maggioni, Italy), corresponding to 350 mg of aspirin per kg. This dose may produce a salicylaemia - micro method of Trinder (1954) - of 38-58 mg% after about 2 h, and of 9 -3 7 % after about 7 h. Shiver audiometry and pinna reflex tests were performed after 2, 7, 24 and 72 h. In the ‘chronic experiments’ ten similar albino guinea pigs were divided into two groups: (a) six animals were treated daily for 20 days endoperitoneally with lisine acetylsalicylate corresponding to 50 mg of aspirin per kg (3.5 g for man); (b) four animals were
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Materials and Methods
Aspirin Ototoxicity in the Guinea Pig
29
treated for 20 days with a daily dose lisine acetyl-salicylate corresponding to 350 mg of aspirin per kg (24.5 g for man). The shiver-audiometric and pinna-reflex controls were performed every 5 days during the experiments, and 10 and 22 days after their completion. The corresponding threshold values were correlated with the pretreatment values adjusted to zero. During the experiments, some animals of group (a) and one of group (b) were sacri ficed to examine the middle ear for otitis and, following fixation in glutaraldehydc-osmic acid and embedded in Epon, to study the cochlear duct (I—III turns) on serial semi-thin sections stained with toluidin blue.
Results
Fig. 1. a~d Individual threshold values and average hearing curve obtained with shiveraudiometry in albino guinea pigs, 2, 7, 24 and 72 h after one endoperitoneal dose of 350 mg of soluble aspirin (acetyl-salicylate of lisine) per kg body weight, a After 2 h no modifica tions appear, b After 7 h a hearing loss resulted at 6- 8 kHz. c This deficit persists after 24 h, followed by d after 72 h, with a complete recovery.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Figure 1 presents the audiometric results of the ‘acute experiment’. While non-evident hearing variation was observed after 2 h (a), a significant hearing deficit of 18-24 dB was observed after 7 h (b). The curve falls slightly because
Crifd
30
the mean hearing loss is more marked for the frequencies 6 and 8 kHz. Indi vidual variations may occur. After 24 h (c), hearing loss was about the same, but the curve becomes flat because of a slight recovery for high frequencies. After 3 days ('¿/A there was complete recovery of the hearing of all animals. Figure 2 shows the individual threshold values and the corresponding mean curve obtained by means of periodical audiometric controls of the guinea pigs of the group (a) (50 mg/kg/day). After 5 —10 days (a -b ) the mean curve indicates a significant hearing deficit at 6 and 8 kHz, though marked individual variations were present. After 15 days (c) hearing deteriorated at 4 kHz. Eventually, after 20 days (d) the animals showed a mean pantonal hearing loss of 20-37 dB, a little more marked at
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Fig. 2. a d Individual threshold values and average hearing curve obtained in albino guinea pigs during treatment with aspirin (50 mg/kg/day). The curves at the bottom of a and d were obtained with Preyer’s reflex, a b After 5 10 days a similar hearing deficit result at 6 -8 kHz. c After 15 days the 4 kHz frequency is also involved, d After 20 days of treat ment a mean hearing loss of 27 37 dB was demonstrated with descendent average hearing curve. The behaviour of Preyer’s reflex indicates damage of the receptors.
Aspirin Ototoxicity in the Guinea Pig
31
4—8 kHz. As to the pinna reflex, it showed an improvement on the fifteenth day and this seems to indicate the cochlear character of the hearing loss caused by aspirin. There was no evidence of otitis media, and morphological studies of the cochlear duct of animals treated for 5 and 10 days failed to reveal any micro scopical change. Figure 3 presents the results obtained in the 350 mg/kg/day treated guinea pigs (group b). After 5 and 10 days an evident hearing deficit at 1.5-8 kHz was observed. After 15 days (c) all frequencies, particularly the high ones, were compromised. Finally, after 20 days (d) the deficit was more marked, ranging between 28 and 50 dB with a falling curve. The curve obtained with the pinna reflex shows, after 15 days, an improvement from 2 kHz onwards. The postmortem examination of
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Fig. 3. a d Individual threshold values and average hearing curve observed during ‘chronic’ test with a high dose of aspirin (350 mg/kg/day). a b After 5 10 days, hearing loss is present at 1.5- 8 kHz. c After 15 days all frequencies are involved, d After 20 days of treatment the medium hearing loss is 28-50 dB. The behaviour of Preyer’s reflex indicates damage of the receptors.
Crifo
32
the animal sacrificed after 10 days did not show otitis media and the cochlear duct appeared to be normal on microscopical examination.
The results obtained with the ‘acute experiment’ suggest that in normal hearing albino guinea pigs, one dose of 350 mg of aspirin per kg is capable of causing, within a few hours and in relation to the diffusion of the drug from the blood into the tissues, a high tone hypacusia of cochlear character as indicated by the normal pinna reflex. This is in agreement with the findings in the cat and monkey by means of different techniques. Furthermore, as observed in man, the hearing deficit is transient. This fact, together with the rapid onset and the absence of histological lesions of the cochlea, suggests a biochemical effect of the drug, which is usually reversible. A hypothesis proposed by Silverstein et al. (1967), based on the fact that salicylate is capable of blocking oxidative phos phorylation, of inhibiting some transaminase and dehydrogenase systems, and of acting indirectly on the transfer of hydrogen by competitive inhibition with DPN, is supported by the finding of a reduced malic dehydrogenase activity in the labyrinthine fluids. Another hypothesis by Ishii et al. (1967) suggests that aspirin inhibits the cholinesterase activity of the efferent nerve endings of the organ of Corti. The consequent functional effect may be very selective and without morphological equivalents. This hypothesis, based on the fact that lim ited doses of salicylate cause a non-competitive and transient inhibition of ace tylcholinesterase activity, preventing in .this way the synaptic transmission, is of great interest and worthy of further investigation. The results of the ‘chronic’ experiment indicate that, in normal-hearing albino guinea pigs, the parenteral administration of aspirin in a dose of 50mg/kg/day causes after 5 and 10 days a hearing loss of the same degree, progressing only slightly on further administration of the drug. The difference between the hearing loss caused by the administration of 50 mg/kg/day and 350 mg/kg/day is caused by a wide extension of the frequencies involved, and in a greater deficit of about 10 dB. The lack of a real correlation between dosage and the degree of hypacusia has been observed in rheumatoid patients treated with 6 -8 g/day of salicylate until they manifested hypacusia and tinnitus (Myers and Bernstein, 1965): they had a sensorineural hypacusia, sometimes with re cruitment, for a salicylaemia of 40 mg%, but the hypacusia did not get worse with a further increase of salicylaemia. Our experimental data on chronic aspirin intoxication resemble those in rheumatic patients treated for long periods or with high doses of salicylates. It is important that salicylate-treated patients should have preliminary and periodical audiometric tests together with regular blood tests and careful clinical examination for the detection of tinnitus and hypacusia.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Conclusions
Aspirin Ototoxicity in the Guinea Pig
33
Zusammenfassung ln der vorliegenden Arbeit wird die ototoxische Wirkung des Aspirins beim Meer schweinchen mittels Audiometrie und morphologischer Kontrolle des Innenohres unter sucht. Eine Dosis von 350 mg/kg/Tag ruft nach 7 Stunden eine durchschnittliche Gehörsab nahme von 18-24 dB zwischen 0,25 und 8 kHz hervor, welche sich jedoch innert 3 Tagen vollständig zuriickbildet. Eine Gruppe von Versuchstieren wurde mit 50 mg/kg/Tag täglich behandelt, eine zweite mit 350 mg/kg/Tag. Der Unterschied zwischen den beiden Gruppen besteht darin, dass bei den Versuchstieren der 350-mg-Gruppe ein Hörverlust festgestellt werden kann, der nicht nur 10 dB grösser ist, sondern auch mehr Frequenzen umfasst. Bei beiden Gruppen konnte jedoch nach 22 Tagen noch keine sichere Rückbildung der Schwer hörigkeit beobachtet werden. Die histologische Untersuchung der Schneckenorgane fiel je doch negativ aus. Die biochemische Pathogenese der Aspirin-Ototoxizität wird diskutiert, und es wird auf die Notwendigkeit einer periodischen audiometrischen Kontrolle vor und während einer Behandlung mit Salizylaten hingewiesen.
Résumé L’ototoxicité à l’aspirine a été étudiée chez le cobaye par la frisson-audiométrie et le contrôle morphologique du canal cochléaire. Une seule dose de 350 mg/kg provoquait au bout de 7 h une diminution de l’ouïe (en moyenne 18-24 dB à 0,25-8 kHz), mais après 3 jours on a observé une récupération presque complète. Les différences entre le traitement à 50 mg/kg/jour et celui à 350 mg/kg/jour pour 5 -2 0 jours étaient dans le second groupe (350 mg/kg/jour) représentées par une extension plus étendue dans la gamme des fréquences analysées et par une hypoacousie de 10 dB plus haute. Dans les deux groupes, aucune récupération appréciable n’a pu être observée 22 jours après la fin du traitement. Le con trôle morphologique a été toujours négatif. La pathogénèse biochimique de l’ototoxicité à l’aspirine est discutée et l’importance du contrôle audiométrique périodique avant et pen dant le traitement aux salicylates est souügnée.
Bernstein, J.M. and Weiss, A.D.: Further observations on salicylate ototoxicity. J. Laryng. 81: 915-925 (1967). Crifo, S.: Shiver-audiometry in the conditioned guinea pig (simplified Anderson-Wedenberg test). Acta Oto-laryng. 75: 38 - 44 (19 7 3). Crifo, S.: Identification of ototoxic drugs by guinea pig shiver-audiometry. Audiology 13: 302-310 (1974). Falbe-Hansen, J.: Clinical and experimental histological studies on effects of salicylate and quinine on the ear. Acta oto-laryng. 44: 1-216 (1941). Graham, J.D.P. and Parker, W.A.: The toxic manifestations of sodium salicylate therapy. Quart. J. Med. 153-163 (1948). Ishii, T.: Bernstein, J.M., and Balogh, K.: Distribution of tritium-labelled salicylate in the cochlea. Ann. Otol. 76: 368-376 (1967). Jager, B.V. and Alwey, R.: The treatment of acute rheumatic fever with large doses of sodium salicylate. Amer. J. med. Sci. 211: 273-285 (1946).
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References
Crifd
34
Request reprints from: Prof. Stelio Crifd, Cattedra Audiologia, Department of Oto rhinolaryngology, Policlinico Umberto 1°, I - 00186, Roma (Italy)
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McCabe, P. and Dey, F.: The effect of aspirin upon auditory sensitivy. Ann. Otol. 74: 312-324 (1965). Myers, E.N. and Bernstein, J.M.: Salicylate ototoxicity. A clinical and experimental study. Arch, oto-laryng. 82: 483-493 (1965). Silverstein, H.: Bernstein, J.M., and Davies, D.G.: Salicylate ototoxicity. A biochemical and electrophysiological study. Ann. Otol. 76: 118-128(196 7). Trinder, P.: Rapid determination of salicylate in biological fluids. Biochem. J. 57: 301 303 (1954). Waltner, J.: The effects of salicylate on the inner ear. Ann. Otol. 64: 617-622 (1955).
Aspirin Ototoxicity in the Guinea Pig1 S. Crifd2 Department of Otorhinolaryngology, University of Rome, Rome
Key Words. Ototoxicity ■Aspirin ■Shiver audiometry Abstract. Aspirin ototoxicity has been studied on guinea pigs by shiver-audiometry and histological investigation of the cochlear duct. One dose of 350 mg/kg has provoked, after 7 h, a mean hearing loss of 18-24 dB at 0.25-8 kHz, followed by complete recovery in 3 days. The difference between the administration of 50 mg/kg/day and 350 mg/kg/day con sists of a wide extension of the frequencies involved, and in about 10 dB a greater hearing loss. In both cases, no appreciable recovery of hearing was observed after 22 days (the histological investigations were negative). The biochemical pathogenesis of aspirin ototoxi city is discussed and periodical audiometric controls before and during salicylate treatment are recommended.
Aspirin ototoxicity has been observed both in experimental animals (cat, monkey) and in man. The very wide use of salicylates and the occurrence of acute forms, following accidental or suicidal consumption, and of chronic forms, particularly in rheumatic patients treated with salicylates, has encouraged re search in this field. It has been shown that salicylates cross the cochlear barrier and can be estimated in the labyrinthine fluids in relation to serum levels (Siherstein etal., 1967). In the guinea pig, moreover, tritiated salicylic acid is capable of penetrat ing quickly into the inner ear (Ishii et al., 1967). It is concentrated mainly in the 1 Paper read at the 12th International Congress of Audiology in Paris, France, on April 23, 1974. 2 I wish to thank Dr. D. Difeliceantonio, Dr. G. Di Francesco and Dr. A. Sidoli for their cooperation. This research was financed in part by the Ministero Pubblica Istruzione, L.286, 1972-3.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Received: May 24, 1974; accepted: August 5, 1974.
Crifo
28
vascular stria and in the spiral ligament but may diffuse into the organ of Corti. However, in the Saimiri monkey (Myers and Bernstein, 1965) ultrastructural investigations of the inner ear 24 h after the administration of 500- 600 mg/kg of salicylate have proved negative, although avoidance-conditioned audiometry has shown a hearing loss of 17-36 dB at 0.25-8 kHz. In the cat, Silverstein et al. (1967) have noted a marked depression of cochlear microphonics and action potentials after a dose of 350 mg/kg, coupled with a significant decrease of malic-dehydrogenase activity in the perilymph and endolymph, indicating an impairment of cochlear intermediate metabolism. In man (Graham and Parker, 1948) the critical ototoxic salicylaemic level seems to be around 35 mg%. It is likely that individual sensitivity to the drug varies. The ototoxic syndrome caused by salicylates (i.e., aspirin) is characterized by tinnitus and hypacusia (Falbe-Hansen, 1941; Graham and Parker, 1948; McCabe and Day, 1965) and after very high doses by vertigo {Falbe-Hansen, 1941; Waltner, 1955\ McCabe andDey, 1965). Audiometric studies have demonstrated that hypacusia is sensorineural in character and may be associated with recruitment (Falbe-Hansen, 1941; Waltner, 1955; Myers and Bernstein, 1965). In the normal subject the provoked deficit was often pantonal {Myers and Bernstein, 1965; Bernstein and fVeiss, 1967) or there was a prevalent or exclusive loss of high frequencies {Falbe-Hansen, 1941; McCabe and Dey, 1965). The acute syndrome is characterized by its sudden onset and reversibility within 1—10 days {Falbe-Hansen, 1941; Jager and A lway, 1946; Waltner, 1955; Myers and Bernstein, 1965). This seems to indicate a biochemical impairment of the inner eat {Myers and Bernstein, 1965; McCabe and Dey, 1965; Silverstein et al., 1967; Ishii et al., 1967), seen also by the absence of any morphological lesion in the temporal bones of two rheumatic patients suffering from deafness probably caused by salicylates {Bernstein and Weiss, 1967). The purpose of the present study has been the assessment of the hearing pattern of guinea pigs during acute and chronic aspirin intoxication.
In the ‘acute experiment’ ten albino guinea pigs of about 250 g (Morini, Bologna, Italy) with normal hearing (0.25-8 kHz) on shiver-audiometry according to the technique pre viously reported (Crifo, 1973, 1974) and with a normal pinna reflex, were treated endoperitoneally with lisine acetyl-salicylate (Flectadol, Maggioni, Italy), corresponding to 350 mg of aspirin per kg. This dose may produce a salicylaemia - micro method of Trinder (1954) - of 38-58 mg% after about 2 h, and of 9 -3 7 % after about 7 h. Shiver audiometry and pinna reflex tests were performed after 2, 7, 24 and 72 h. In the ‘chronic experiments’ ten similar albino guinea pigs were divided into two groups: (a) six animals were treated daily for 20 days endoperitoneally with lisine acetylsalicylate corresponding to 50 mg of aspirin per kg (3.5 g for man); (b) four animals were
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Materials and Methods
Aspirin Ototoxicity in the Guinea Pig
29
treated for 20 days with a daily dose lisine acetyl-salicylate corresponding to 350 mg of aspirin per kg (24.5 g for man). The shiver-audiometric and pinna-reflex controls were performed every 5 days during the experiments, and 10 and 22 days after their completion. The corresponding threshold values were correlated with the pretreatment values adjusted to zero. During the experiments, some animals of group (a) and one of group (b) were sacri ficed to examine the middle ear for otitis and, following fixation in glutaraldehydc-osmic acid and embedded in Epon, to study the cochlear duct (I—III turns) on serial semi-thin sections stained with toluidin blue.
Results
Fig. 1. a~d Individual threshold values and average hearing curve obtained with shiveraudiometry in albino guinea pigs, 2, 7, 24 and 72 h after one endoperitoneal dose of 350 mg of soluble aspirin (acetyl-salicylate of lisine) per kg body weight, a After 2 h no modifica tions appear, b After 7 h a hearing loss resulted at 6- 8 kHz. c This deficit persists after 24 h, followed by d after 72 h, with a complete recovery.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Figure 1 presents the audiometric results of the ‘acute experiment’. While non-evident hearing variation was observed after 2 h (a), a significant hearing deficit of 18-24 dB was observed after 7 h (b). The curve falls slightly because
Crifd
30
the mean hearing loss is more marked for the frequencies 6 and 8 kHz. Indi vidual variations may occur. After 24 h (c), hearing loss was about the same, but the curve becomes flat because of a slight recovery for high frequencies. After 3 days ('¿/A there was complete recovery of the hearing of all animals. Figure 2 shows the individual threshold values and the corresponding mean curve obtained by means of periodical audiometric controls of the guinea pigs of the group (a) (50 mg/kg/day). After 5 —10 days (a -b ) the mean curve indicates a significant hearing deficit at 6 and 8 kHz, though marked individual variations were present. After 15 days (c) hearing deteriorated at 4 kHz. Eventually, after 20 days (d) the animals showed a mean pantonal hearing loss of 20-37 dB, a little more marked at
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Fig. 2. a d Individual threshold values and average hearing curve obtained in albino guinea pigs during treatment with aspirin (50 mg/kg/day). The curves at the bottom of a and d were obtained with Preyer’s reflex, a b After 5 10 days a similar hearing deficit result at 6 -8 kHz. c After 15 days the 4 kHz frequency is also involved, d After 20 days of treat ment a mean hearing loss of 27 37 dB was demonstrated with descendent average hearing curve. The behaviour of Preyer’s reflex indicates damage of the receptors.
Aspirin Ototoxicity in the Guinea Pig
31
4—8 kHz. As to the pinna reflex, it showed an improvement on the fifteenth day and this seems to indicate the cochlear character of the hearing loss caused by aspirin. There was no evidence of otitis media, and morphological studies of the cochlear duct of animals treated for 5 and 10 days failed to reveal any micro scopical change. Figure 3 presents the results obtained in the 350 mg/kg/day treated guinea pigs (group b). After 5 and 10 days an evident hearing deficit at 1.5-8 kHz was observed. After 15 days (c) all frequencies, particularly the high ones, were compromised. Finally, after 20 days (d) the deficit was more marked, ranging between 28 and 50 dB with a falling curve. The curve obtained with the pinna reflex shows, after 15 days, an improvement from 2 kHz onwards. The postmortem examination of
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Fig. 3. a d Individual threshold values and average hearing curve observed during ‘chronic’ test with a high dose of aspirin (350 mg/kg/day). a b After 5 10 days, hearing loss is present at 1.5- 8 kHz. c After 15 days all frequencies are involved, d After 20 days of treatment the medium hearing loss is 28-50 dB. The behaviour of Preyer’s reflex indicates damage of the receptors.
Crifo
32
the animal sacrificed after 10 days did not show otitis media and the cochlear duct appeared to be normal on microscopical examination.
The results obtained with the ‘acute experiment’ suggest that in normal hearing albino guinea pigs, one dose of 350 mg of aspirin per kg is capable of causing, within a few hours and in relation to the diffusion of the drug from the blood into the tissues, a high tone hypacusia of cochlear character as indicated by the normal pinna reflex. This is in agreement with the findings in the cat and monkey by means of different techniques. Furthermore, as observed in man, the hearing deficit is transient. This fact, together with the rapid onset and the absence of histological lesions of the cochlea, suggests a biochemical effect of the drug, which is usually reversible. A hypothesis proposed by Silverstein et al. (1967), based on the fact that salicylate is capable of blocking oxidative phos phorylation, of inhibiting some transaminase and dehydrogenase systems, and of acting indirectly on the transfer of hydrogen by competitive inhibition with DPN, is supported by the finding of a reduced malic dehydrogenase activity in the labyrinthine fluids. Another hypothesis by Ishii et al. (1967) suggests that aspirin inhibits the cholinesterase activity of the efferent nerve endings of the organ of Corti. The consequent functional effect may be very selective and without morphological equivalents. This hypothesis, based on the fact that lim ited doses of salicylate cause a non-competitive and transient inhibition of ace tylcholinesterase activity, preventing in .this way the synaptic transmission, is of great interest and worthy of further investigation. The results of the ‘chronic’ experiment indicate that, in normal-hearing albino guinea pigs, the parenteral administration of aspirin in a dose of 50mg/kg/day causes after 5 and 10 days a hearing loss of the same degree, progressing only slightly on further administration of the drug. The difference between the hearing loss caused by the administration of 50 mg/kg/day and 350 mg/kg/day is caused by a wide extension of the frequencies involved, and in a greater deficit of about 10 dB. The lack of a real correlation between dosage and the degree of hypacusia has been observed in rheumatoid patients treated with 6 -8 g/day of salicylate until they manifested hypacusia and tinnitus (Myers and Bernstein, 1965): they had a sensorineural hypacusia, sometimes with re cruitment, for a salicylaemia of 40 mg%, but the hypacusia did not get worse with a further increase of salicylaemia. Our experimental data on chronic aspirin intoxication resemble those in rheumatic patients treated for long periods or with high doses of salicylates. It is important that salicylate-treated patients should have preliminary and periodical audiometric tests together with regular blood tests and careful clinical examination for the detection of tinnitus and hypacusia.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
Conclusions
Aspirin Ototoxicity in the Guinea Pig
33
Zusammenfassung ln der vorliegenden Arbeit wird die ototoxische Wirkung des Aspirins beim Meer schweinchen mittels Audiometrie und morphologischer Kontrolle des Innenohres unter sucht. Eine Dosis von 350 mg/kg/Tag ruft nach 7 Stunden eine durchschnittliche Gehörsab nahme von 18-24 dB zwischen 0,25 und 8 kHz hervor, welche sich jedoch innert 3 Tagen vollständig zuriickbildet. Eine Gruppe von Versuchstieren wurde mit 50 mg/kg/Tag täglich behandelt, eine zweite mit 350 mg/kg/Tag. Der Unterschied zwischen den beiden Gruppen besteht darin, dass bei den Versuchstieren der 350-mg-Gruppe ein Hörverlust festgestellt werden kann, der nicht nur 10 dB grösser ist, sondern auch mehr Frequenzen umfasst. Bei beiden Gruppen konnte jedoch nach 22 Tagen noch keine sichere Rückbildung der Schwer hörigkeit beobachtet werden. Die histologische Untersuchung der Schneckenorgane fiel je doch negativ aus. Die biochemische Pathogenese der Aspirin-Ototoxizität wird diskutiert, und es wird auf die Notwendigkeit einer periodischen audiometrischen Kontrolle vor und während einer Behandlung mit Salizylaten hingewiesen.
Résumé L’ototoxicité à l’aspirine a été étudiée chez le cobaye par la frisson-audiométrie et le contrôle morphologique du canal cochléaire. Une seule dose de 350 mg/kg provoquait au bout de 7 h une diminution de l’ouïe (en moyenne 18-24 dB à 0,25-8 kHz), mais après 3 jours on a observé une récupération presque complète. Les différences entre le traitement à 50 mg/kg/jour et celui à 350 mg/kg/jour pour 5 -2 0 jours étaient dans le second groupe (350 mg/kg/jour) représentées par une extension plus étendue dans la gamme des fréquences analysées et par une hypoacousie de 10 dB plus haute. Dans les deux groupes, aucune récupération appréciable n’a pu être observée 22 jours après la fin du traitement. Le con trôle morphologique a été toujours négatif. La pathogénèse biochimique de l’ototoxicité à l’aspirine est discutée et l’importance du contrôle audiométrique périodique avant et pen dant le traitement aux salicylates est souügnée.
Bernstein, J.M. and Weiss, A.D.: Further observations on salicylate ototoxicity. J. Laryng. 81: 915-925 (1967). Crifo, S.: Shiver-audiometry in the conditioned guinea pig (simplified Anderson-Wedenberg test). Acta Oto-laryng. 75: 38 - 44 (19 7 3). Crifo, S.: Identification of ototoxic drugs by guinea pig shiver-audiometry. Audiology 13: 302-310 (1974). Falbe-Hansen, J.: Clinical and experimental histological studies on effects of salicylate and quinine on the ear. Acta oto-laryng. 44: 1-216 (1941). Graham, J.D.P. and Parker, W.A.: The toxic manifestations of sodium salicylate therapy. Quart. J. Med. 153-163 (1948). Ishii, T.: Bernstein, J.M., and Balogh, K.: Distribution of tritium-labelled salicylate in the cochlea. Ann. Otol. 76: 368-376 (1967). Jager, B.V. and Alwey, R.: The treatment of acute rheumatic fever with large doses of sodium salicylate. Amer. J. med. Sci. 211: 273-285 (1946).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/15/2018 12:00:09 PM
References
Crifd
34
Request reprints from: Prof. Stelio Crifd, Cattedra Audiologia, Department of Oto rhinolaryngology, Policlinico Umberto 1°, I - 00186, Roma (Italy)
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McCabe, P. and Dey, F.: The effect of aspirin upon auditory sensitivy. Ann. Otol. 74: 312-324 (1965). Myers, E.N. and Bernstein, J.M.: Salicylate ototoxicity. A clinical and experimental study. Arch, oto-laryng. 82: 483-493 (1965). Silverstein, H.: Bernstein, J.M., and Davies, D.G.: Salicylate ototoxicity. A biochemical and electrophysiological study. Ann. Otol. 76: 118-128(196 7). Trinder, P.: Rapid determination of salicylate in biological fluids. Biochem. J. 57: 301 303 (1954). Waltner, J.: The effects of salicylate on the inner ear. Ann. Otol. 64: 617-622 (1955).
