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In normal adult guinea pigs, evoked potentials recorded at the ipsilateral auditory cortex to monaural high-frequency acoustic stimuli present higher thresholds and lower amplitudes than at the contralateral cortex; in the inferior colliculus, such ipsi-contralateral differences (ICDs) are smaller than in the auditory cortex. Changes in the ICDs were studied after opposite ear injury. Following quasi-complete hair cell destruction induced by sisomicin injection into the contralateral inner ear, threshold ICDs almost disappeared after about two to six days and ipsilateral amplitudes progressively increased in two to three weeks. The occurrence of ICDs at higher auditory centers revealed in this study, indicates peculiar processing of high frequency stimuli in normal guinea pigs. The alteration of ICDs after opposite ear impairment provides a new possibility to study the auditory plasticity in adult animals.

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This paper reports on a dynamic study of the morphological changes within the cochlear and vestibular ganglia of the guinea pig after local application of Sisomicin in the inner ear. The treatment leads to a rapid, complete and irreversible destruction of the sensory cells in the cochlear and vestibular neuroepithelia. A progressive degeneration of the type I and type II afferent neurons, presenting a decreasing gradient from the base towards the apex of the cochlea, is rapidly observed and becomes almost complete as early as 15 days after the peripheral injury. Five months after the treatment the spiral ganglion cells have almost completely disappeared. At this time the vestibular ganglion cell density appears normal but the neurons exhibit important signs of alteration. Such damage to the cochlear and vestibular afferent neurons may result from either retrograde neuronal degeneration and/or direct neurotoxic effect of the drug. Thus the combination of the two mechanisms could lead to neuronal losses in spiral and Scarpa's ganglia after the local aminoglycoside intoxication of the inner ear. The difference in the time course of degeneration for these two afferent ganglia could be due to their specific susceptibilities or to their different anatomical locations.

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Three aminoglycosidic antibiotics: tobramycin, amikacin and sisomicin were administered to rats. There was an increase in the activity of N-acetyl-beta-D-glucosaminidase (NAG) excreted in the urine and this was characterized by a change in the isoenzyme profiles eluted from DEAE--cellulose. The largest increase in NAG activity was observed following sisomicin administration due mainly to an increase in the B-form of NAG with a concomitant fall in the intermediate (I-form). Separation of urinary proteins by SDS-polyacrylamide gel electrophoresis demonstrated a mixed tubular and glomerular proteinuria following administration of sisomicin. It is concluded that the separation of NAG isoenzymes and urinary proteins provides valuable additional information on the nature and severity of antibiotic nephrotoxicity.

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The central auditory toxicity of sisomicin was studied in guineapigs administered sisomicin (135 mg/kg body weight) sc for 10 days. Total lipids, phospholipids and cholesterol were estimated in the pons, inferior colliculus, medial geniculate body and auditory cortex. While the total lipids were increased in a non-preferential manner in all the regions studied, phospholipids and cholesterol levels registered no change. This study suggests the possible central auditory toxicity following sisomicin administration.

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Treatment of the pregnant rat with aminoglycosides provokes nephrotoxicity in the newborn. This study compares the effects of three antibiotics belonging to this group: gentamicin (same day dose administered in one or two injections according to the groups), sisomicin and dibekacin, all administered during the last phase of gestation. Newborns were tested the day after birth, creatinine clearance was measured and then the kidneys were removed for histopathological examination. Functional variations (diuresis, creatinine clearance) and histological alterations of glomerula and tubules were observed. Slight differences suggest that, depending on the antibiotic used, intra-cellular nephrotoxic mechanisms are not completely identical. The modifications which occur after the administration of aminoglycosides, lead us to believe that further studies on the possible fetal nephrotoxic effects of drugs taken by mothers during gestation should be undertaken.

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The action of cefazolin on the pharmacokinetics and nephrotoxic effect of sisomicin was studied on Wistar rats. Sisomicin in doses of 12.5 and 25 mg/kg alone or in combination with cefazolin in doses of 90 and 360 mg/kg was administered intramuscularly to the animals daily for 16 days. It was shown that in both the doses cefazolin had no noticeable action on the level of the functional and morphological changes in the kidneys. Consequently, there were no significant changes in the levels of sisomicin in serum and the site of the nephrotoxic effect (cortical layer of the kidneys) and in the half-life of the aminoglycoside in the kidney cortical layer under the action of cefazolin. At the same time there was observed a marked individual variability of the levels of urea nitrogen and sisomicin in serum of the rats treated with the aminoglycoside alone or in combination with cefazolin. Analysis of the dependence of the nephrotoxic effect on concentration of sisomicin in serum after its use alone or in combination with cefazolin revealed that the changes in the individual intensity of the effect in all the cases were mainly induced by the changes in the sisomicin blood levels. Therefore, control of the blood levels of the aminoglycoside should provide prevention of the development of its nephrotoxic effect not only in monotherapy but also in the use of aminoglycosides in combination with cefazolin.

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To elucidate the possibility of predicting the level of aminoglycoside antibiotic penetration into the fluids of the internal ear by the antibiotic blood levels, the pharmacokinetics of sisomicin in the perilymph and blood serum was studied on guinea pigs. The antibiotic was administered to the animals subcutaneously in doses of 50, 100 and 200 mg/kg. On the basis of the comparison of the sisomicin concentrations in the perilymph normalized against the dose it was concluded that the pharmacokinetics of sisomicin in the perilymph and blood serum of the animals was linear. Comparison of the areas under the curves of the antibiotic concentration versus time in the perilymph (AUCp) and blood serum (AUCs) showed that the tissue availability of the antibiotic in this study characterized by its penetration into the perilymph and defined by the ratio of the AUCp to AUCs amounted to 55 per cent. In a two-compartment model it was not possible to predict the antibiotic levels in the perilymph by concentrations in the blood. However, by the antibiotic blood levels it was possible to characterize in a complex the pharmacokinetic behaviour of the antibiotic in the perilymph by predicting the areas under the respective curves of the antibiotic concentration versus time. The proportional relation between the values of the AUCp and AUCs suggested that the level of the antibiotic penetration into the internal ear and consequently the intensity of the potential ototoxic effect could be more reliably predicted not by separate values of the antibiotic concentration but by the areas under curves of aminoglycoside concentrations versus time.

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The effect of cephalothin on the nephrotoxicity and pharmacokinetics of sisomicin was studied on Wistar rats. Sisomicin was injected intramuscularly in doses of 12.5 and 25 mg/kg alone or in combination with cephalothin in a dose of 360 mg/kg once a day for 16 days. It was shown that the combined use of sisomicin and cephalothin resulted in less pronounced functional and morphological changes in the kidneys as compared to the use of sisomicin alone. The decrease in the nephrotoxic effect was accompanied by a decrease in the sisomicin concentration in the blood serum and the site of the nephrotoxic effect (the kidney cortical layer) and the period of the aminoglycoside half-life in the kidney cortical layer under the action of cephalothin. The analysis of the relation between the nephrotoxic effect and the concentration of sisomicin in the kidney cortical layer and blood serum demonstrates that the nephrotoxicity of the sisomicin combination with cephalothin is mainly due to a decrease in the aminoglycoside concentration in the zone of the nephrotoxic effect.

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General toxic and organotropic properties of sisomicin sulfate were studied in chronic experiments on different animal species with the use of doses equivalent to therapeutic ones in humans or exceeding them by several times. When sisomicin was injected intramuscularly for 4 weeks in a dose equivalent by the body surface to the average daily dose for humans, no significant effect on the macroorganism was observed. When the dose was 2--4 times higher, a significant increase in the blood serum levels of the urea nitrogen, creatinine, bilirubin and aspartate aminotransferase was shown. Histological examinations revealed focal adiposis of epithelial cells of the convoluted tubules of the kidney and small areas of parenchymal necrosis. Impairment of vestibular and auditory functions was detected in some animals.

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Degeneration of the cochlear nerve was produced in guinea pigs after treatment with high doses of ototoxic antibiotics completely destroying the cochlear receptor. An effective electric stimulation of the inner ear inducing evoked potentials at the auditory cortex was applied over a period of 3.5 months in half of the animals, while the other half was kept for control. The artificial stimulation had no effect on the sensitivity of the inner ear to electric stimulation and did not modify the extent of degeneration of the cochlear nerve.

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Nephrotoxicity and pharmacokinetics of gentamicin were studied on rats treated with the antibiotic for 30 days in doses of 6.25, 12.5 and 25 mg/kg administered daily. The pharmacokinetics of gentamicin and the time course of changes in the urea nitrogen levels of the blood serum were studied after the 1st, 5th, 8th and 30th injection. The analysis of the respective curves was used for calculation of the average integral values of the concentrations of the antibiotic (C) and urea nitrogen (E). After that the average integral values of these parameters ((CAVG and EAVG respectively) within the whole treatment couse with the use of every dose were calculated in the same way by using the curves of the dynamics of C and E changing. Comparison of the diagrams of E dependence on C for gentamicin and sisomycin showed that nephrotoxicity of sisomycin was 1.48 times higher than that of gentamicin.

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The kinetics of the urea nitrogen in serum was studied on anesthetized cats with constant concentrations of sisomycin in the blood. A correlation between the nephrotoxic effect of sisomycin and its concentration in the blood serum was found. High nephrotoxicity of sisomycin as compared to that of gentamicin, kanamycin or streptomycin under conditions of their equal levels in the blood was revealed on the basis of the above correlation. Still, when the antibiotic concentrations in the blood serum were maintained at the respective therapeutic levels, the nephrotoxic effects of sisomycin and gentamicin were almost equal. The above correlation was used for calculation of the maximum value of the sisomycin safe concentration in blood serum. The safe concentration of gentamicin in blood serum is 8 micrograms/ml, while that of sisomycin in 6 micrograms/ml. This approach may be used in estimation of safe concentrations for new aminoglycosides.

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The kinetics of urine nitrogen in the blood serum and morphological changes in the kidneys after a single and repeated intramuscular administrations of the antibiotic in doses of 12.5 and 25 mg/kg a day were studied in Wistar rats. When sisomycin was administered in a dose of 12.5 mg/kg, the increase in the urine nitrogen level after 1--30 injections was reversible, whereas at a dose of 25 mg/kg it became irreversible already after the 5th injection. Maximum deviations in the urine nitrogen level observed within 3--6 hours after each injection of sisomicin were recorded after the 5th injection of the drug in a dose of 12.5 mg/kg and even after the 1st injection of the drug in a dose of 25 mg/kg. The deviations increased up to the 5th and 16th injection of sisomycin in doses of 12.5 and 25 mg/kg respectively. Later the deviations were less pronounced. Regardless of the dose, adipose degeneration in renal tubules was registered after 8--16 injections of the drug. By the 30th and 16th days of the drug administration in doses of 12.5 and 25 mg/kg respectively, the above changes also decreased. On the whole, pronounced functional and morphological changes in the kidneys correlated with the antibiotic dose. Relationship between the time from the beginning of sisomycin administration and the moment when the average integral concentration of the urine nitrogen increased to the upper limit of normal and the logarithm of the average integral concentration of the antibiotic in the serum was found. The safety of the clinical schemes for the use of sisomicin was estimated with the help of this relationship with respect to its nephrotoxic effect.

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The pharmacokinetics of sisomicin was studied on Wistar rats. The antibiotic was used in single or repeated doses of 12.5 and 25 mg/kg. The kinetic data of the antibiotic titration in blood serum within 1 and 24 hours of intramuscular administration of the drug were formalized with the use of a linear two-compartment model. The average values of the elimination constant and the constants of sisomycin transfer from the central compartment into the peripheral one were 0.64, 0.34 and 0.13 hours-1 respectively. The value of the apparent distribution volume in the central compartment was 0.38 ml/kg and that of the stationary and kinetic distribution volumes was 1.37 and 3.06 1/kg respectively. The value of the general clearance was 0.24 1/(kg.hour) and that of the sisomicin half-life was 8.7 hours. Comparison of the antibiotic levels estimated with a model and actually measured in the blood after repeated administrations revealed the drug cumulation. When the antibiotic was used in a dose of 25 mg/kg daily, its cumulation was observed earlier (by the 5th--8th day) than on its use in a dose of 12.5 mg/kg (by the 30th day). Irrespective of the dose, sisomicin cumulation was accompanied by prolongation of the antibiotic half-life in the rats.

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Sisomicin is a new broad-spectrum aminoglycoside most closely related structurally to gentamicin C1a. In vitro and in experimental infections, sisomicin has been found to be more potent than or nearly as potent as the most active of the other available aminoglycosides. Although susceptible to many (but not all) aminoglycoside-inactivating enzymes, sisomicin is active against many microorganisms that are resistant to other aminoglycosides by nonenzymatic mechanisms. Sisomicin has been shown to interact synergistically with various beta-lactam antibiotics against enterococci, staphylocicci, Enterobacteriaceae, and nonfermentative gram-negative bacilli. The pharmacokinetics and toxicity of sisomicin in humans appear to be similar to those of gentamicin, despite earlier reports of greater acute toxicity in animals. Sisomicin has been shown to be effective for treatment of severe infections in humans, including some infections caused by gentamicin-resistant bacteria.

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The audiotoxic effect of sisomicin was investigated in guinea pig injected intramuscularly with 6.25, 12.5, 25 and 50 mg/kg of sisomicin sulfate (potential) during weeks 1--5 or 5--9 of pregnancy, and the transplacental effect on their offspring was studied. While, in some dams the higher doses of sisomicin produced a limited effect on the pinna reflex and the outer hair cells of the organ of Corti, no such effects were noted in any of the offspring during the 3-week postnatal observation period.

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Twenty-one days s.c. treatment with netilmicin, gentamicin, sisomicin, and kanamicin at different doses were performed in albino guinea pigs of both sexes. Block surface preparation of Corti's organ was carried out and missing OHCs and IHCs counted in selected areas of each turn. The animals treated with gentamicin and sisomicin showed a dose-depending missing of hair cells, preferably relative to the outer ones and quantitatively the same for both the antibiotics. Furthermore, a characteristic distribution of the damage progressively increasing from the apex to the basal turn of the cochlea was detected. Kanamicin at 267 and 400 mg/kg gave the complete destruction of OHCs and IHCs along the whole cochlea while at 178 mg/kg did not show any significant damage in comparison to the control group. Finally, netilmicin neither damaged Corti's organ nor statistically determined missing OHCs and IHCs at all the doses used. These histological results and the previous electrophysiological and reflexological observations obtained in the guinea pig show a higher safety of netilmicin in comparison to the other aminoglycosides used for the problem relative to ototoxicity.

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In guinea pigs that had been treated with very large doses of the aminoglycoside amikacin (14 x 450 mg/kg/day, i.m.) clear, short-latency responses to various click stimuli could be recorded at the round window. When the same cochleas were examined histologically, no outer or inner hair cells could be found along the entire length of the basilar membrane, save for a very few outer hair cells remaining at the apex. The response patterns resembled that of the compound action potential, and various characteristics suggest that they were of neural origin. Vestibular function, investigated by electronystagmography during rotation, appeared normal, as did most of the saccular and utricular hair cells. Transmission electron microscopy revealed a significant number of cochlear nerve fibres still innervating the remnants of Corti's organ. In other cochleas with similarly extensive destruction induced by another aminoglycoside (sisomycin, 14 x 125 mg/kg/day, 15 days as well as 3 months post-Rx), no responses could be recorded from the round window. Cochleas that were less affected, with the upper turns preserved, gave only small, long-latency responses. These preliminary observations are confirmed by further experiments now in progress. They suggest that unless a considerable number of inner hair cells remained undetected in the lower basal turn, a possibility that appears highly unlikely, there was either a direct mechanical excitation of cochlear nerve fibres, or an acoustical stimulation of vestibular sense organs.

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Tobramycin, gentamicin, sisomicin and amikacin are aminoglycoside antibiotics that are used clinically. A significant side effect of aminoglycoside antibiotics is the production of hearing loss. Our study was done to determine the relative ototoxic liability of these 4 drugs. All drugs were given in daily doses of 0, 50,100 or 150 mg/kg to guinea pigs subcutaneously for 4 weeks. In addition, 200 mg/kg was was given to the animals receiving amikacin and sisomicin. There were 10 animals in each dosage group. Seven animals were used for auditory study and 3 were used for pharmacokinetic study. Auditory damage was assessed by determining the Preyer pinna reflex, the ability of the cochlea to generate the AC cochlear potential, and the number of sensory hair cells missing from the organ of Corti. The concentration of aminoglycoside antibiotics is determined in the cochlear perilymph and plasma by a radioenzymatic assay. On a equal dose basis the ototoxic liability of gentamicin and sisomicin were very similar and tobramycin and amikacin being less ototoxic than the gentamicin and sisomicin. The pharmacokinetics of single 150 mg/gk doses of the drugs were similar. The exception was that tobramycin reached lower peak levels in plasma and perilymph and its time to peak level in perilymph was delayed relative to the other drugs. Analysis of plasma and perilymph following chronic administration revealed higher concentration of gentamicin and sisomicin than of tobramycin and amikacin.

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