Circadian Rhythm Dependent Kanamycin-induced Hearing Loss in Rodents Assessed by Auditory Brainstem Responses

Abstract

An antimicrobial agent, kanamycin, has been shown to produce as an untoward effect, ototoxicity. The purpose of this study was to investigate differential effects of kanamycin ototoxicity as a function of Rx timing with regard to circadian rhythms. Four groups of comparable weight Sprague-Dawley rats received a daily subcutaneous dosage of 225 mg/kg kanamycin sulfate with each receiving the antibiotic at a different time: 8 AM (8A), 2 PM (2P), 8 PM (8P), and 2 AM (2A). The rats were housed in separate cages, in a room on a light-dark (12:12) illumination cycle with light between 6 AM and 6 PM. Hearing loss was assessed with the auditory brainstem response (ABR) using pure tone stimuli at 8, 16, 24, and 32 kHz. ABR measures were obtained before dosing began and 2, 4, and 6 weeks after the initial dosing. Kanamycin produced a hearing loss which reflected the total dosage given to each group. Significant differences in physiologic thresholds were observed for both timing of the daily dosage (p less than 0.05), and the 2, 4 and 6 week testings (p less than 0.001). After 2 weeks, the 8A group showed an average hearing loss of 11.5 dB at 32 kHz, with the other timed treatment groups exhibiting minimal effects (3.0-6.5 dB). For the 8A group at this frequency, the loss progressed at 4 (19.5 dB) and 6 (22.5 dB) weeks. The 2P group after 4 weeks exhibited similar losses as the 8A group for this frequency, with the loss at 6 weeks being even greater (34.0 dB). The 8P and 2A groups exhibited only slight losses over all frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptive resistance following single doses of gentamicin in a dynamic in vitro model

“…Concentration-dependent initial killing and the postantibi2nd exposure otic effect (9) both support the use of larger initial doses of + v ++_ aminoglycosides given less frequently. Chronotoxicity studies with animals favor single doses given at the time of day that causes the least toxicity (39,42). The phenomenon of adaptive resistance further supports the use of less frequent doses of aminoglycosides.…”

Gentamicin-induced ototoxicity and nephrotoxicity vary with circadian time of treatment and entail separate mechanisms

“…This research proposes to simultaneously examine the relationship between damage to auditory and kidney function induced by gentamicin according to the circadian time of greatest and lowest risk for its toxic effects, respectively, beginning of the rest and activity span, based on the findings of experiments previously conducted by us and others (Beauchamp & Labrecque, 2007; McKinney et al, 2015; Yonovitz & Fisch, 1991). Gentamicin can cause damage to the outer hair cells of the cochlea, resulting in permanent sensorineural hearing loss, and also the nephrons of the renal cortex, resulting in compromised kidney function.…”

“…Gentamicin can cause damage to the outer hair cells of the cochlea, resulting in permanent sensorineural hearing loss, and also the nephrons of the renal cortex, resulting in compromised kidney function. In animal models, ABR is the most effective method of assessing auditory function (Evans et al, 1983; Yonovitz & Fisch, 1991), and urine testing for N-acetyl-β-glucosaminidase (NAG) enzyme activity has been substantiated to be a sensitive means of assessing renal injury that correlates well with microscopic renal cortical tissue indices (Wellwood et al, 1976). …”

“…Various methods have been implemented to investigate ototoxicity, including behavioral and electrophysiological ones. The auditory brainstem evoked response (ABR) is the most effective and accurate means of assessing hearing loss in animals, and it does not require animal training or reliance on motor responses that may be impaired (Evans et al, 1983; Yonovitz & Fisch, 1991). Many different methods have been utilized in the past to assess nephrotoxicity, for example, urinary excretion of creatinine, urea, and enzymes indicative of renal tissue injury.…”

“…Several investigations demonstrate the extent of beneficial and/or adverse effects of aminoglycoside antibiotics (Beauchamp & Labrecque, 2007; McKinney et al, 2015; Yonovitz & Fisch, 1991) and many other types of medications, including BP-lowering ones (Ayala et al, 2013; Crespo et al, 2013; Hermida et al, 2013a, 2013b, 2013c; Moyá et al, 2013; Reinberg & Smolensky, 1983; Smolensky et al, 2010), differ sometimes markedly according to circadian time of dosing. Such differences in medication effects can be explained by rhythm dependencies of their pharmacokinetics (PK), i.e., chronopharmacokinetics (dosing-time differences in drug absorption, distribution, metabolism, and elimination due to circadian variation in gastrointestinal motility; gastric pH, transport, and emptying; biliary function and hepatic enzyme activity; renal glomerular filtration; and organ blood flow, e.g., of the duodenum, liver, and kidney), and/or chronopharmacodynamics (administration-time differences, independent of drug chronopharmacokinetics, in desired and undesired effects due to circadian patterning, e.g., in blood drug-free fraction, number/conformation of receptors, second messengers, and signaling pathways of drug-targeted cells, tissues, and organs) (Smolensky & Peppas, 2007).…”