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A prospective study of high-frequency auditory function in patients receiving oral neomycin.

Orally administered, neomycin is reported to cause ototoxicity rarely. Most reports on hearing loss due to oral neomycin have been case studies. One prospective study of a pediatric sample demonstrated a significant loss of hearing in the frequency range of 2 to 8 kHz in 9 of 17 children. To our knowledge there are no published prospective studies on this type with adult samples and therefore little is known of the true incidence or nature of ototoxicity from oral neomycin. This prospective study presents the results of long-term use of oral neomycin in 30 adult subjects. Hearing sensitivity was serially monitored in the frequency range 250-20,000 Hz. Two of the 30 subjects subsequently revealed ototoxicity. Thus the results of this investigation suggest that clinical use of oral neomycin implies relatively little risk of ototoxicity.

Administration, Oral↗

Caspase activation in hair cells of the mouse utricle exposed to neomycin.

Aminoglycoside exposure results in the apoptotic destruction of auditory and vestibular hair cells. This ototoxic hair cell death is prevented by broad-spectrum caspase inhibition. We have used in situ substrate detection, immunohistochemistry, and specific caspase inhibitors to determine which caspases are activated in the hair cells of the adult mouse utricle in response to neomycin exposure in vitro. In addition, we have examined the hierarchy of caspase activation. Our data indicate that both upstream caspase-8 and upstream caspase-9, as well as downstream caspase-3 are activated in hair cells exposed to neomycin. The inhibition of caspase-9-like activity provided significant protection of hair cells exposed to neomycin, whereas the inhibition of caspase-8-like activity was not effective in preventing neomycin-induced hair cell death. In addition, caspase-9 inhibition prevented the activation of downstream caspase-3, whereas the inhibition of caspase-8 did not. These data indicate that caspase-9 is the primary upstream caspase mediating neomycin-induced hair cell death in this preparation.

Amino Acid Chloromethyl Ketones↗

Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy.

Hepatic encephalopathy due to cirrhosis is frequently precipitated by exogenous factors, and the effectiveness of a specific treatment with neomycin sulfate has so far not been submitted to clinical trials. Over a period of five years, 102 cirrhotic patients developed hepatic encephalopathy at admission or during hospitalization, and 39 were randomized for treatment with either neomycin sulfate or placebo. Exclusion criteria were: 1. current usage of specific treatment for hepatic encephalopathy, 2. chronic hepatic encephalopathy and 3. multiple organ failure syndrome associated with hepatic encephalopathy. The group of excluded patients (n = 63) was compared with the randomized group (n = 39), and no statistical differences were found regarding sex and age distributions, Child-Pugh classification, etiology of cirrhosis, percipitating factors and grade of hepatic encephalopathy. These same parameters were also comparable among the 20 patients who received active neomycin and the 19 who were treated with placebo. The therapy for hepatic encephalopathy consisted in the control of precipitating factors associated with 6 g of neomycin sulfate "per os" or placebo. Therapeutic failure and death by the fifth day of treatment, occurred in four patients (10.2%), two in each of the randomized groups. The time elapsed between the initiation of the therapeutic procedure and regression to grade zero of hepatic encephalopathy was 39.11 +/- 23.04 hours for the group of active neomycin, and 49.47 +/- 21.92 hours for the placebo group, but this difference did not achieve statistical significance.

Adult↗

[Interaction of neomycin with other antibiotics on selected bacterial strains].

Antimicrobial combinations are used most frequently to provide broad-spectrum empirical coverage in the treatment of bacterial infections. However, combination of two antibiotics may not influence their activity, may lead to synergy or antagonism in the activity. Neomycin may be combined with one of the following antibiotics: ampicillin, procaine penicillin, gramicidin, bacitracin, polymyxin B, lincomycin, oxytetracycline, and erythromycin in some human and veterinary multiantibiotic drugs distributed in Poland. The checkerboard method has been one of the traditional assays for the measurement of antibiotic interactions. The aim of this study was to analyse the activity interaction of neomycin with second antibiotic in multiantibiotic drugs distributed in Poland on standards and clinical bacterial strains. Checkerboard results for all strains demonstrated synergism for 2.5% of combinations, only for standards strains. In one case Salmonella Enteritidis, in combination of neomycin with bacitracin, inhibition effect was observed. Additive effects were predominant--49%. In 18% neutral effects were shown, but in 26% of combinations FIC indexes were not possible to calculate, because of the resistance of clinical strains to the highest concentration of at least one antibiotic. In combination of aminoglycoside (neomycin) with beta-lactams antibiotics (ampicillin, procaine penicillin) in vitro, no synergy was observed for all examined strains. The best results were achieved for combinations of neomycin with peptide antibiotics (polymyxin, gramicidin and bacitracin)--5 for all 6 synergy effect observed.

Anti-Bacterial Agents↗

[Evaluation of tixocortol pivalate-neomycin combination versus ++a placebo excipient in acute rhinopharyngitis in children].

Effectiveness and clinical tolerance of the tixocortol-neomycin combination (Pivalone-Neomycin nasal suspension) used as monotherapy were evaluated in a double-blind placebo-controlled study (placebo: vehicle i.e., N-cetylpyridinium chloride, sodium chloride, sodium hydroxide solution, benzyl alcohol, purified water, monosodium phosphate) in 211 pediatric patients (aged 6 months to 8 years) with uncomplicated acute rhinopharyngitis. After seven days therapy, improvement in symptoms of acute rhinopharyngitis, especially rhinorrhea and nocturnal cough, was greater in the tixocortol-neomycin group. Physical evaluation documented significant improvements in local superinfection with disappearance of mucopurulent nasal secretions and posterior drip. Locoregional outcome, evaluated on severity of infectious complications and antibiotic use, was also more favorable in the tixocortol-neomycin group. These results, together with the good clinical tolerance of the study drug, demonstrate the value of single-drug therapy with this local corticosteroid-neomycin combination in children with uncomplicated acute rhinopharyngitis. They confirm that local administration of corticosteroids to combat inflammatory phenomena is useful not only in the well-recognized lower respiratory tract indications (asthma, respiratory syncitial virus infections) but also in nasal diseases (rhinitis).

Administration, Intranasal↗

The effect of neomycin on contractile activity of the canine cervical lymphatic vessel induced by various agents.

The effects of neomycin on isometric contractions induced by norepinephrine (NE), alpha 1-adrenoceptor agonist phenylephrine (PE), KCl, and an activator of GTP-binding proteins (G-proteins) NaF were studied in the isolated canine cervical lymphatic vessel (CLV). Incubation of the CLV with 0.3 or 1.3 mmol/l neomycin for 30-180 min did not affect significantly either the basal vascular tone or the response to NE, and potentiated the response to KCl by 24 +/- 6% (p less than 0.05). On the other hand, neomycin (1.3 mmol/l) treatment reduced by 22 +/- 6% (p less than 0.05) the contractions induced by PE and completely (by 96 +/- 3%, p less than 0.001) suppressed the effects of NaF. Upon the combined action of NaF and NE, neomycin reduced only NaF-component of the total response. Verapamil (100 mumol/l) had no effect on the magnitude of NaF-induced tension and partially inhibited NE- and PE-induced contractions (by 20 +/- 4% (p less than 0.05) and 53 +/- 5% (p less than 0.01), respectively). Indomethacin (10 mumol/l) did not influence significantly the contractions evoked by NE, KCl, and NaF either under control conditions or in the presence of neomycin. These data suggest that the phosphoinositides may considerably contribute to the CLV contractions evoked by NaF, but do not play a substantial role in the responses of the vessel to alpha-adrenergic stimulation and KCl.

Animals↗

[Lactitol and neomycin: monotherapy or combined therapy in the prevention and treatment of hepatic encephalopathy?].

The beneficial effect of disaccharides, lactulose and lactitol, in prevention and treatment of hepatic encephalopathy is well established but their use in combination with neomycin is still controversial. We studied in vitro the fecal bacterial growth, acid and gas formation in presence of lactitol (beta-galactoside-sorbitol) and neomycin alone or in combination. The results indicate that neomycin only inhibits the growth of susceptible bacteria (E. coli, Staph. aureus) which, conversely, are poor lactitol fermenters. The resistant organisms (Lactobacillus acidophilus, Clostridium perfringens) that are efficient disaccharide fermenters continue to metabolize lactitol still when antibiotic is added. Addition of lactitol 10% increased the inhibitory effect of neomycin on bacterial growth by 25-50% within 60-70 min. These preliminary data suggest that lactitol and neomycin may have additional or synergistic effects in vivo when used together in presence of favourable intestinal microbial environment.

Bacteria↗

Determination of neomycin in animal tissues, using ion-pair liquid chromatography with fluorometric detection.

A liquid chromatographic (LC) method is described for the determination of neomycin in animal tissues. Tissues are homogenized in 0.2M potassium phosphate buffer (pH 8.0); the homogenate is centrifuged, and the supernate is heated to precipitate the protein. The heat-deproteinated extract is acidified to pH 3.5-4 and directly analyzed by LC. The LC method consists of an ion-pairing mobile phase, a reverse phase ODS column, post-column derivatization with o-phthalaldehyde reagent, and fluorometric detection. The LC method uses paromomycin as an internal standard, and separates neomycin from streptomycin or dihydrostreptomycin because they have different retention times. The LC column separates neomycin in 25 min; the detection limit is about 3.5 ng neomycin. The overall recovery of neomycin from kidney tissues spiked at 1-30 ppm was 96% with a 9.0% coefficient of variation. The method was also applied to muscle tissue.

Aminoglycosides↗

Nephrotoxicity and ototoxicity following irrigation of wounds with neomycin.

Renal failure and ototoxicity developed in two patients following wound irrigation with neomycin. In both patients the renal failure was reversible, but the deafness was progressive despite withdrawal of the neomycin. In one patient the serum neomycin concentration was still markedly elevated (42 microgram/ml) 2 days after use of the drug was discontinued. The authors suggest that irrigation of large open wounds with neomycin is dangerous since toxic blood concentrations may ensue. The benefits conferred by neomycin irrigation should be weighed against the possible danger of permanently impaired hearing.

Administration, Topical↗

Contact dermatitis to neomycin sulfate.

The prevalence of contact allergic dermatitis and nonallergic irritant reactions to neomycin sulfate was determined in a large group of young adults who had a noteworthy exposure to topical antibiotics. Only two subjects (0.09%) had contact allergy proved by closed patch testing, while 20 (0.9%) had nonallergic irritant reactions to 20% neomycin sulfate and 17 (0.78%) had nonallergic reactions to one of the hydrophilic ointment bases. In a separate population of 653 children referred for diagnostic patch testing, only one subject had contact allergy to neomycin. All three subjects who had reactions had a history of repeated use of neomycin on chronically damaged skin. These results support the conclusion that intermittent use of neomycin on minor cuts and wounds is not associated with an excessive rate of sensitization.

Adolescent↗

Effect of neomycin on the bioavailability of spironolactone: a single-dose study.

The effect of oral neomycin sulfate on the bioavailability of oral spironolactone in humans was studied. A 100-mg spironolactone tablet was administered alone or with two 500-mg neomycin sulfate tablets to 12 healthy, fasting men in a randomized crossover fashion. Levels of canrenone (an active spironolactone metabolite) in plasma and urine samples collected for 32 and 48 hours after dosing, respectively, were measured fluorimetrically. Neomycin significantly decreased the peak plasma canrenone concentration, significantly increased the time to reach peak concentration of canrenone, and significantly decreased the urinary excretion of canrenone over the first four hours (p less than 0.05). There were no significant differences between treatment groups in elimination half-life, area under the plasma curves or 48-hour urinary excretion of canrenone. Single doses of neomycin appear to delay the rate but not reduce the extent of spironolactone absorption. Thus, neomycin may not interfere with the clinical efficacy of spironolactone.

Adult↗

Neomycin toxicosis in calves.

Calves (n = 4) were given neomycin (2.25 or 4.5 mg/kg) twice daily IM and were compared with 2 calves given penicillin IM. The 2 hallmarks of aminoglycoside toxicosis, nephrotoxicosis and ototoxicosis, were seen with both dosages of parenterally administered neomycin. Nephrotoxicosis was confirmed by abnormal findings in urinalysis (granular casts, proteinuria, low specific gravity), renal biopsy results (tubular degeneration and necrosis), and increased 24-hour amounts of urinary enzymes (alanine aminopeptidase and gamma-glutamyltranspeptidase). Azotemia, decreased creatinine clearance, polyuria, and polydipsia also were documented in calves given neomycin. Clinically, deafness was suspected in 2 calves and was documented by electrical auditory-evoked response tests. Abnormalities in partial thromboplastin times and renal residues of neomycin were seen in all 4 calves that were given neomycin, but not in calves that were given penicillin.

Alanine Transaminase↗

Impairment of membrane phosphoinositide metabolism by aminoglycoside antibiotics: streptomycin, amikacin, kanamycin, dibekacin, gentamicin and neomycin.

Like many amphiphilic cationic drugs, aminoglycosides are able to produce phospholipidosis, mainly by inhibiting enzymes involved in phospholipid metabolism. Phosphoinositides have been suggested to function as receptors for aminoglycosides. Therefore, we investigated the influence of these drugs upon phosphoinositide metabolism by measuring the 32P-incorporation into the polyphosphoinositides, using the rat erythrocyte membrane as a model. Depending upon the experimental conditions, neomycin induced a decrease and/or an increase in the 32P-labeling of triphosphoinositides (TPI) and of diphosphoinositides (DPI), respectively. These variations were rapid and depended upon the drug concentration. At 0.3 mM, neomycin reversed the distribution of radioactivities associated with DPI and TPI without modifying the total radioactivity incorporated. This drug concentration altered neither the Mg++-activated TPI-specific phosphomonoesterase activity nor the Ca++-activated polyphosphoinositide phosphodiesterase activity. It appears likely that the drug inhibits the DPI-kinase activity, by interacting with DPI and thereby lowering the substrate availability. Over the range of concentrations studied (up to 1-2 mM), gentamicin, kanamycin and dibekacin behave as neomycin. However, their effects could be observed only at drug concentrations higher than those of neomycin. By contrast, streptomycin and amikacin did not alter the 32P-labeling of TPI and of DPI. The order of potency of aminoglycosides for the impairment of the phosphoinositide interconversion was neomycin, gentamicin, dibekacin, kanamycin. A possible relationship between the toxicity of aminoglycosides and their capacity to impair the phosphoinositide metabolism is discussed.

Amikacin↗

Effects of neomycin alone and in combination with cholestyramine on serum methyl sterols and conversion of acetate and mevalonate to cholesterol.

Serum free methyl sterols (cholesterol precursors) and the acetate-mevalonate test (the 14C/3H ratio in serum cholesterol after an intravenous injection of a 14C-acetate-3H-mevalonate mixture) were studied in hypercholesterolaemic patients treated with neomycin, cholestyramine or their combination so as to show whether the two tests could detect changes in cholesterol synthesis (measured with faecal steroids). During a 2-week neomycin treatment the ratio increased (+55%) proportionately with the increase in faecal steroids (+29%), the decrease in serum cholesterol (-20%) being negatively correlated with the change in serum methyl sterols. After 1 to 2 years on neomycin, faecal steroids were still high and serum cholesterol low. The ratio had fallen, however, below the initial level, the respective proportionate decrease in methyl sterols being insignificant. In cholestyramine-treated patients a marked increase in cholesterol synthesis (171% increase in faecal steroids) was reflected in a proportionate increase in the ratio (+196%) and serum methyl sterols (+134%). Inclusion of neomycin in the cholestyramine treatment increased faecal steroids (overall increase 206%) and further decreased serum cholesterol (from -25% to -38%) but tended to reduce the ratio and serum methyl sterols. The findings suggest that neomycin activates the pre- and post-mevalonate steps of cholesterol synthesis.

Acetates↗

Inhibition of the hammerhead ribozyme by neomycin.

A series of antibiotics was tested for stimulation or inhibition of the hammerhead ribozyme cleavage reaction. Neomycin was found to be a potent inhibitor of the reaction with a Kl of 13.5 microM. Two hammerheads with well-characterized kinetics were used to determine which steps in the reaction mechanism were inhibited by neomycin. The data suggest that neomycin interacts preferentially with the enzyme-substrate complex and that this interaction leads to a reduction in the cleavage rate by stabilizing the ground state of the complex and destabilizing the transition state of the cleavage step. A comparison of neomycin with other aminoglycosides and inhibitors of hammerhead cleavage implies that the ammonium ions of neomycin are important for the antibiotic-hammerhead interaction.

Base Sequence↗

Toxicity of neomycin on enzyme activities of kidney and duodenal mucosa in vivo: organ specificity and species difference between rats and mice.

Inhibitory effects of neomycin administration (10-80 mg/kg body weight/day, s.c. for 7 days) on several enzyme activities of kidney and duodenal mucosa were compared between male rats and mice. In Wistar rat kidney, tubular brush border Mg(2+)-dependent, HCO3(-)-stimulated ATPase activity was inhibited by neomycin in a dose-dependent manner, while microsomal Mg(2+)-Na(+)-K(+)-ATPase activity and cytosol carbonic anhydrase (CA) activity were inhibited only by larger doses. In rat duodenal mucosa, Mg(2+)-HCO3(-)-ATPase and CA activities were also inhibited only by larger doses. Serum urea nitrogen (UN) concentration and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity were increased in a dose-dependent manner. In ddY and C57black mice, however, all enzyme activities in kidney and duodenal mucosa were almost unaffected by any dose of neomycin and showed no changes in serum UN concentration and urinary NAG activity except for ddY mice in which NAG activity was only increased by the largest dose of neomycin. In light microscopic analysis, 80 mg neomycin/kg produced necrosis in the greater part of rat proximal tubuli with no changes in duodenal brush border. On the other hand, no histological changes were produced in the renal cortex or duodenal mucosa of mice by any dosage. In conclusion, there are organ-specific and species differences in the effects of neomycin between rats and mice.

Acetylglucosaminidase↗

Cardiovascular depressant effects of the neomycin-streptomycin group of antibiotics.

Cardiovascular depressant effects of the neomycin-streptomycin group of antibiotics (aminoglycoside antibiotics) were examined during pentobarbital anesthesia in cats, dogs, and 4 species of nonhuman primates: owl (Aotus trivirgatus), squirrel (Saimiri sciureus), and rhesus (Macaca mulatta) monkeys, and dog-faced baboons (Papio cynocephalus). Intravenous administration of kanamycin, streptomycin, gentamicin, or neomycin produced various degrees of hypotension and relative bradycardia in all species examined. In surgically prepared (open-chest) baboons, neomycin consistently induced a dose-related depression of myocardial contractile force, maximum dF/dt of myocardial contraction, cardiac output, heart rate, and systolic and diastolic blood pressures. Maximum depression of hemodynamic values usually occurred within 2 to 5 minutes after administration of neomycin; cardiovascular function then gradually returned to control or near control levels within 30 to 60 minutes. Intravenous administration of calcium chloride rapidly reversed the neomycin-mediated alterations of cardiovascular function. Present findings indicated that aminoglycoside antibiotics altered cardiovascular dynamics in anesthetized animals, and indicated that this deleterious action(s) may be related to modification of calcium ion function.

Animals↗

Effect of neomycin on glycosyl-phosphatidylinositol and phosphatidylinositol system of Tetrahymena.

Neomycin does not inhibit but increases the incorporation of 32P into phosphatidylinositols of Tetrahymena. This elevation is due to neomycin inhibition on the turnover of the phosphatidylinositol (PI) system. Neomycin also prevents the synthesis of glycosyl-phosphatidylinositol (GPI). These experiments draw attention to the inhibitory effect of neomycin both on GPI synthesis and PI turnover, and the connection between these systems. An explanation for the inhibitory effect of neomycin on hormonal imprinting is discussed.

Animals↗