The Laryngoscope · 2015
Circadian variation of gentamicin toxicity in rats.
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McKinney William, Yonovitz Al, Smolensky Michael H
Аннотация
OBJECTIVES/HYPOTHESIS: Two undesired effects of the aminoglycoside antibiotic gentamicin are ototoxicity and nephrotoxicity. This study investigated if these adverse effects vary according to the circadian time of its administration.
STUDY DESIGN: This study entails laboratory animal research.
METHODS: Four groups of Sprague-Dawley rats were synchronized to a 12:12 light/dark schedule. Each group receiving the antibiotic (100 mg/kg gentamicin sulfate) at a different circadian time. Auditory brainstem response was obtained at pretreatment and at 2, 4, and 6 weeks.
RESULTS: At all measured frequencies, hearing losses were significantly (P < .001) greater when gentamicin was administered during the diurnal rest span than the nighttime activity span. At 4 weeks, the average total hearing loss, quantified by elevation of threshold values over the tested auditory frequencies, was 31.3 and 25.6 dB for the 2 hours after lights on (HALO) and 8 HALO groups, respectively. The loss progressed at 6 weeks to 42.5 (2 HALO) and 37.5 (8 HALO) dB. At 6 weeks, the 14 and 20 HALO groups had losses of 17.5 and 26.3 dB, respectively. Trough serum gentamicin concentration significantly (P < .01) increased during treatment, being the highest at 4 weeks. Urine urea nitrogen 24-hour levels of the 2 and 8 HALO groups differed significantly (P < .01) from the 14 and 20 HALO groups.
CONCLUSIONS: Ototoxicity was greater when gentamicin was administered during their diurnal rest than during nocturnal activity. A dosing paradigm may be used to deliver a lower therapeutic antimicrobial concentration during the nighttime rest period when the studied adverse effects are of highest risk.
STUDY DESIGN: This study entails laboratory animal research.
METHODS: Four groups of Sprague-Dawley rats were synchronized to a 12:12 light/dark schedule. Each group receiving the antibiotic (100 mg/kg gentamicin sulfate) at a different circadian time. Auditory brainstem response was obtained at pretreatment and at 2, 4, and 6 weeks.
RESULTS: At all measured frequencies, hearing losses were significantly (P < .001) greater when gentamicin was administered during the diurnal rest span than the nighttime activity span. At 4 weeks, the average total hearing loss, quantified by elevation of threshold values over the tested auditory frequencies, was 31.3 and 25.6 dB for the 2 hours after lights on (HALO) and 8 HALO groups, respectively. The loss progressed at 6 weeks to 42.5 (2 HALO) and 37.5 (8 HALO) dB. At 6 weeks, the 14 and 20 HALO groups had losses of 17.5 and 26.3 dB, respectively. Trough serum gentamicin concentration significantly (P < .01) increased during treatment, being the highest at 4 weeks. Urine urea nitrogen 24-hour levels of the 2 and 8 HALO groups differed significantly (P < .01) from the 14 and 20 HALO groups.
CONCLUSIONS: Ototoxicity was greater when gentamicin was administered during their diurnal rest than during nocturnal activity. A dosing paradigm may be used to deliver a lower therapeutic antimicrobial concentration during the nighttime rest period when the studied adverse effects are of highest risk.