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OBJECTIVES: Although numerous studies have identified damage to the cochlear and vestibular end organs as the primary site of aminoglycoside-induced ototoxicity, the effect on the saccule remains poorly understood, possibly due to lack of monitoring saccular function in experimental animals. Therefore, this study applied three kinds of aminoglycosides into the tympanic space of guinea pigs to examine their toxic impact on the saccule by way of click-evoked myogenic potential test coupled with morphologic assessment. DESIGN: Albino guinea pigs were treated with saline, gentamicin, tobramycin, or amikacin, with 10 animals assigned to each group. Each compound was injected directly overlying but not through the round window membrane on the left ear, with the right ear serving as a control. One week after injection, each animal underwent auditory brain stem response, caloric test, and click-evoked myogenic potential test. Animals were then killed for morphologic assessment through the use of light and electron microscopic examinations. RESULTS: The animals treated with saline, gentamicin, tobramycin, or amikacin exhibited abnormal auditory brain stem response in 0%, 30%, 100%, and 30% of cases; abnormal caloric responses were found in 0%, 100%, 40%, and 40% of cases; absent click-evoked myogenic potentials were found in 0%, 100%, 30%, and 40% of cases, respectively. Gentamicin and other groups differed significantly in abnormal rates of caloric responses and click-evoked myogenic potentials. Morphologic study of the gentamicin-treated animals confirmed that the absence of click-evoked myogenic potential originated from the lesion in the saccular macula. CONCLUSIONS: Gentamicin represents the dominant susceptibility of aminoglycoside-induced vestibulotoxicity for eliminating both semicircular canal and saccular functions. This study further confirms the findings of human studies in which the caloric and vestibular evoked myogenic potentials responses were monitored to assess the abolition of vestibular function in patients treated with intratympanic gentamicin injection.

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A key factor in the well-known interaction between ethacrynic acid (EA) and aminoglycoside antibiotics (AABs) is disruption of the blood-labyrinth barrier (BLB), leading to rapid entry of EA and AABs into the cochlear fluids. The idea that the blood-labyrinthine fluid concentration gradient might be utilized in a protective manner was tested in the current experiment. We hypothesized that administering EA when gentamicin (GM) levels are higher in the cochlea than in the blood might actually reduce cochlear damage by permitting efflux of GM from the cochlear fluids into the bloodstream, down a concentration gradient and across a temporarily disrupted BLB. Guinea pigs received 1, 11, 14 or 20 injections of GM (125 mg/kg i.m.). Approximately half of the animals also received a single injection of EA (40 mg/kg i.v.) either concurrently or 12-18 h after the last GM injection. Concurrent injection of EA significantly increased GM concentration in serum and perilymph at all time points sampled (2.5, 5-8, and 12 h post injection). Compared to animals that received GM only, animals that received a delayed injection of EA had a significantly lower GM concentration in perilymph, lower thresholds of the compound action potential, and less outer hair cell loss. Collectively, the evidence suggests that EA can reduce GM ototoxicity if it is administered 12-18 h after GM, but the mechanism remains to be elucidated. The results may have implications for the clinical management of aminoglycoside ototoxicity in humans, as well as for understanding the mechanisms underlying AAB/EA interactions.

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The availability of genetic information, transgenic and knock-out animals make the mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for kanamycin ototoxicity in adult CBA/J, C57BL/6 and BALB/c mouse strains and a comparison to Sprague-Dawley rats. Five-week-old mice were injected subcutaneously twice daily with 400-900 mg kanamycin base/kg body weight for 15 days. Kanamycin induced dose-dependent auditory threshold shifts of up to 70 dB at 24 kHz as measured by auditory brain stem-evoked responses. Vestibular function was also affected in all strains. The functional deficits were accompanied by hair cell loss in both cochlear and vestibular neurosensory epithelia. Concomitant administration of the antioxidant 2,3-dihydroxybenzoate significantly attenuated the kanamycin-induced threshold shifts. In adult male Sprague-Dawley rats, doses of 1 x 500 mg or 2 x 300 mg kanamycin base/kg body weight/day x 14 days induced threshold shifts of approximately 50 dB at 20 kHz. These were accompanied by loss of outer hair cells. The order of susceptibility, BALB>CBA>C57, was not due to differences in the pharmacokinetics of kanamycin. It also did not correlate with the presence of Ahl/Ahl2 genes which predispose C57 and BALB strains, respectively, to accelerated age-related hearing loss. Pigmentation, however, paralleled this rank order suggesting an influence of melanin on cochlear antioxidant status.

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Although patient symptoms and an audiogram can typically identify the affected ear or ears in Ménière's disease, there are some cases where this differentiation is problematic. This paper concentrates on the sole use of vestibular test data to discriminate between unilateral and bilateral Ménière's disease. Patients that were known to have peripheral unilateral vestibular hypofunction (n = 104) were used as learning groups to define a region in multidimensional measurement space consisting of four vestibular test scores which summarized data from electronystagmography, sinusoidal harmonic acceleration, and computerized dynamic posturography tests. A multivariate boundary was created from the unilateral learning group that determined thresholds for identifying bilateral vestibular hypofunction. Patients with bilateral Ménière's disease (n = 23) and with bilateral ototoxicity (n = 19) were then used as test subjects to determine the sensitivity of the multivariate boundary. Results showed up to a increase in estimated test sensitivity (specificity = 95%) from 67%(current method)to 82%(new method)in identifying bilateral vestibular hypofunction.

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Antimicrobial therapy in hemodialysis patients is made possible by pharmacokinetic dosage modifications. The problem is that overdosage produces side effects whereas therapeutic drug action is missed by underdosage. The dose should be calculated to achieve identical peak levels (for bactericidal drugs) as in normal renal function or identity of AUC (for bacteriostatic drugs). Antimicrobial therapy is started with a loading dose which usually equals the dose in patients with normal renal function. The maintenance dose is reduced in renal failure and adjusted to the increase in the dominant elimination half-life. The effect of hemodialysis must be taken into account and replacement of the removed fraction by a supplementary dose is needed to assure therapeutic drug action.

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Beta 2-microglobulin (beta 2-m) is a low molecular weight protein of importance in the evaluation of the reabsorptive capacity of the proximal kidney tubule. This is based on the properties of beta 2-m: the daily production is constant and it leaves the body almost exclusively by glomerular filtration; 99.9% of the filtered amount is reabsorbed by the proximal tubule. The urinary excretion of beta 2-m is elevated (greater than 370 micrograms/day) in patients suffering from proximal tubular dysfunction with disturbance of tubular reabsorption. It is of great value as a marker of tubular involvement in toxic nephropathies, interstitial nephritis and the non-invasive method of choice to distinguish between renal and lower urinary tract infections.

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A series of nephrotoxic compounds dissolved in 0.9% NaCl was given to groups of five male Wistar rats in a single i.p. injection. Mercuric acetate and mercuric trifluoroacetate at 1 mg Hg/kg induced a sharp increase in urinary gamma-glutamyl transferase (GGT) activity on day 1, followed by a decrease below control values on day 3. Sodium ethylmercurithiosalicylate induced a relatively small urinary GGT increase, explained by its low Hg-bioavailability. An increased urinary GGT activity was noted after treatment with the aminoglycoside antibiotics kanamycin, neomycin, paramomycin, and streptomycin (100 and 800 mg/kg), ammonium fluoride (18.5 and 37 mg/kg), potassium bichromate (7.5 and 30 mg/kg), sodium tetrathionate (62.5 and 125 mg/kg), and cis-diamminedichloroplatinum (2 and 4 mg/kg). This was lower than for the mercury compounds, but clearly different from the controls. The urinargy GGT increase was an acute phenomenon. It is concluded that the measurement of urinary GGT can be used as an indicator of acute nephrotoxicity.

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