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At least 19 recordsLinked to original sources
PubMed1989

Reduction of dibekacin-induced nephrotoxicity in the rat by the formation of N-alkylsulfonate derivatives.

Seven N-alkylsulfonate derivatives of an aminoglycoside antibiotic, dibekacin, were prepared and their nephrotoxicity was examined. Using water-supplied and water-depleted rats and the BUN value as a nephrotoxic measure, dibekacin-di-N-methanesulfonate, pentasodium dibekacin-penta-N-methanesulfonate, -penta-N-ethanesulfonate, disodium dibekacin-di-N-methanesulfonate sesquisulfate, disodium and dipotassium dibekacin-di-N-ethanesulfonate sesquisulfates and sodium dibekacin-mono-N-ethane-sulfonate disulfate showed low nephrotoxicity as compared to that of the original dibekacin sulfate. Notably, dibekacin-di-N-methanesulfonate caused little change in the BUN value and was bioactive in vitro but not active in vivo against a Pseudomonas aeruginosa infection model in mice. Among the bioactive N-alkylsulfonates in vivo, disodium and dipotassium dibekacin-di-N-ethanesulfonate sesquisulfates showed a lower degree of elevation of BUN, urine volume and urine protein, lower mortality and better body weight gain than those of dibekacin sulfate during consecutive treatment for 12 and 28 days.

Animals↗
PubMed1987

Electron microscopy of Pseudomonas aeruginosa treated with sulbenicillin and dibekacin.

A possible mechanism responsible for the combined effects of sulbenicillin and dibekacin on Pseudomonas aeruginosa IAM 1007 was investigated. The bactericidal activity of the above two drugs in combination was very strong. The regrowth of test strains after removal of the drugs was suppressed markedly, even when they were exposed to sulbenicillin plus dibekacin at a subinhibitory concentration of individual drugs. Sulbenicillin caused elongation of the bacterial cells. At the early stage of elongation, no demonstrable changes of ultrastructure of the cell wall were observed. At the late stage, lysis of the peptidoglycan layer occurred and spheroplast was formed. However, most of the outer membrane of the cell wall remained intact. Sulbenicillin acts upon the peptidoglycan layer, but not on the outer membrane. Thus it is difficult for sulbenicillin alone to cause cell lysis. On the other hand, dibekacin caused destruction of ribosomes and lysis of the outer membrane of the cell wall. Both sulbenicillin and dibekacin act on the cell wall, the former on the peptidoglycan layer (the inner membrane) and the latter on the outer membrane. The combined use of sulbenicillin and dibekacin caused elongation of bacilli and severe destruction of the inner and outer membranes of the cell wall. These morphological changes occurred even when the concentration of the individual drug was lower than its minimum inhibitory concentration (MIC). Furthermore, the cells elongated by sulbenicillin were ruptured easily when treated with dibekacin subsequently. The bacilli treated with dibekacin at a concentration lower than MIC and then treated with sulbenicillin at a concentration lower than MIC showed a marked elongation of the cells, which indicated that the effects of sulbenicillin was enhanced by dibekacin. These findings suggested strongly that sulbenicillin and dibekacin act on cell wall constituents and that their effects were complementary and synergistic.

Cell Wall↗
PubMed1982

[Pharmacokinetic studies on intravenous drip infusion of dibekacin in elderly subjects without apparent renal failure (author's transl)].

The pharmacokinetic behavior of dibekacin was studied in 8 elderly subjects. These subjects had not apparent renal failure, although they were diagnosed as having various diseases such as arteriosclerosis, essential hypertension, etc. Dibekacin, 50 mg/subject, was infused intravenously for 1 hour. Serum and urine concentrations of dibekacin were measured by the bioassay and radioimmunoassay methods. The peak serum concentration of dibekacin ranged from 3.55 to 5.35 micrograms/ml when measured by bioassay, and from 3.19 to 8.9 micrograms/ml by radioimmunoassay. The biological half-life of dibekacin ranged from 2.13 to 3.45 hours, and from 1.57 to 3.55 hours, with these 2 methods. The area under the curve (AUC) ranged from 14.8 to 25.6 micrograms/ml-hr and from 11.3 to 18.0 microgram/ml . hr, respectively. Creatinine clearance showed a positive correlation with the elimination rate constant and a negative correlation with the distribution volume of dibekacin. These relationships were more pronounced when determined by radioimmunoassay. These data suggest that the peak serum concentration of dibekacin decreases with creatinine clearance. The serum and urine concentrations of dibekacin measured by the radioimmunoassay method correlated well with those measured by the bioassay method. Therefore, it was concluded that the radioimmunoassay method is a useful technique for monitoring the serum concentration of dibekacin.

Aged↗
PubMedDate not supplied

Dibekacin intrarenal distribution characteristics and renal cortical elution kinetics. Comparison with gentamicin and tobramycin.

Dibekacin (3',4-dideoxykanamycin B) is a new semisynthetic aminoglycoside developed in Japan and one which has found wide clinical acceptance in that country. The antibacterial activity of this compound indicates that it is relatively similar to gentamicin. Since it appears that the intrarenal distributional characteristics and renal cortical kinetics of aminoglycosides provide some predictive information concerning the clinical incidence of nephrotoxicity, we designed a series of pharmacokinetic studies in healthy mongrel dogs which would define such kinetic information for dibekacin and would contrast the results with similar studies for gentamicin and tobramycin. The renal cortical kinetics of dibekacin, as developed in these studies, show that in a canine model the behavior of dibekacin is similar to that of gentamicin and significantly different from tobramycin. Dibekacin and gentamicin show reproducibly higher renal cortical tissue concentrations than tobramycin in both the acute infusion studies and multiple dosing studies. The results suggest that dibekacin may possess the same inherent nephrotoxic potential as that of gentamicin. In order to show any difference in clinical toxicity between gentamicin and dibekacin, a very extensive randomized, double-blind, prospective clinical trial of efficacy and toxicity will be needed.

Animals↗
PubMed1981

[Animal experiments on the nephrotoxicity, pharmacokinetics and therapeutic efficacy of dibekacin].

Nephrotoxicity, pharmacokinetics, and therapeutic efficacy of 3',4'-dideoxykanamycin (dibekacin), a semisynthetic aminoglycoside, were evaluated in rats. As with other aminoglycosides, therapy with dibekacin led to an increased urinary cell and malic-dehydrogenase excretion. The lowest dose resulting in an increased urinary cell excretion was 2.5 mg/kg/d. Serum levels of dibekacin after i.m. injection of 5 mg/kg were similar to those of other aminoglycosides. The kidneys accumulated high amounts of dibekacin, and eliminated it with a half-life of about 7 days. After repetitive dosing a distinct tendency to accumulation (highest renal concentration: 330 microgram/g) could be detected. Experimental chemotherapy of the chronic estrogen induced pyelonephritis revealed that dibekacin and sisomicin fed to significant reductions of renal bacterial counts at a dosage of 2 x 5 mg/kg/d for 7 days. A dosage of 2 x 2.5 mg/kg/d diminished the effectiveness of dibekacin distinctly, that of sisomicin only slightly.

Animals↗
PubMed1986

Comparative oto-vestibular effects in the pigmented guinea pig after dibekacin and netilmicin treatment.

We treated groups of pigmented guinea pigs with either intramuscular netilmicin or dibekacin at 100 and 150 mg/kg per day for 3 weeks. Saline was used as the control solution. All animals were tested weekly for both vestibular and auditory functions. The vestibular function was evaluated by the duration of post-rotatory nystagmus (PRN) elicited by interrupting the rotation of the animal around the vertical axis; auditory function was evaluated by the threshold response for the Preyer's pinna reflex (PPR). All animals were then sacrificed and either their labyrinths or Corti organs were processed for further investigations using the scanning electron microscope (SEM). The duration of PRN decreased over the treatment period in all of the groups as a result of adaptation. However, 150 mg/kg dibekacin produced a significant decrease of the PRN responses as compared to the control and other groups. This effect also continued during the recovery period. Likewise, the PPR threshold of the animals receiving 150 mg/kg dibekacin showed a significant increase at the end of the treatments and during the recovery period, while the other dibekacin group had no significant auditory impairment. Netilmicin at both doses did not significantly affect responses following either vestibular or auditory stimulations. SEM observations demonstrated that the sensory epithelia of the labyrinths and Corti organs affected by 150 mg/kg dibekacin had great losses of stereocilia, while comparable doses of netilmicin (150 mg/kg) had only very moderate losses of stereocilia in the labyrinths but not in the Corti organs.

Animals↗
PubMed1984

Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits.

The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin. Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low- or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group. Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption. Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regiment. No nephrotoxicity was noted with netilmicin or amikacin compared with the control group. Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity. Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside. It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity.

Amikacin↗
PubMed1981

Acute toxicity and pharmacokinetics of dibekacin mice.

The LD50 values of dibekacin to mice were determined following three different methods of administration, namely, intravenous constant infusion, intravenous bolus injection, and intramuscular injection. The serum levels of dibekacin were pharmacokinetically analyzed. The differences in LD50 values between the methods of administration were discussed from the viewpoints of pharmacokinetics. 1) The LD50 value following the intravenous constant infusion was higher than that following the intravenous bolus injection and approached the level of that following the intramuscular injection, when the infusion rate of the drug was decreased by increasing the infusion period. 2) The biological half-life of dibekacin in mice was 24--45 min. 3) The volume of distribution increased as its dose increased, and a linear correlation was noted between log Vd and log (dose). 4) The difference among the maximum serum concentrations calculated with dibekacin following the administration of LD50 was small, which coincided with the results of the experiment that the serum concentrations of dibekacin at the death following the administration of LD100 were almost the same regardless of the method of administration.

Animals↗
PubMed1986

Electron microscopic study of the cell surface of dibekacin-treated Pseudomonas aeruginosa.

Electron microscopy of thin sections of Pseudomonas aeruginosa IAM 1007 treated with dibekacin revealed blebs, disintegration of the outer membrane of the cell wall and degenerative features of the cytoplasm. In the next experiment, the cell wall fraction was isolated from the mechanically disrupted cells, incubated with dibekacin and was subjected to electron microscopy, in order to find a clue to the action mechanism of dibekacin on the cell wall of Pseudomonas aeruginosa IAM 1007. As a result, it was found that unidentified substances were released from the surface of the cell wall and that the outer membrane of the cell wall disappeared. The degree of changes of the cell wall ultrastructure was almost proportional to the length of incubation with dibekacin. These findings strongly suggest that dibekacin directly disintegrates the outer membrane of the cell wall of Pseudomonas aeruginosa IAM 1007.

Cell Membrane↗
PubMed1983

[Comparative study of circadian changes of the mortality of mice with respect to 2 aminoglycosides, gentamycin and dibekacin].

We compare the acute toxicity of a dose of gentamicin or dibekacin in Mice at different times of the day. The female Mice are housed with food and water ad libitum for one and half week, ten or fifteen per cage in a light controlled room (lights on from 8 to 20 hrs). Each animal was given gentamycin (250, 275, 300 or 325 mg/kg) intramuscular and dibekacin (320, 355, 390, 425 or 460 mg/kg) at one of four times: 8, 14, 20 and 2 hrs). After injection, the animals are kept in their cages and observed for 10 days. We show that the circadian biosusceptibility rhythm in dibekacin toxicity is similar to that of gentamycin with significant differences in the mortality at the four hours. There is an evident parallelism between the curves for gentamycin and dibekacin but the differences in the percentage of mortality rate are more important for gentamycin than for dibekacin.

Animals↗
PubMed1984

[Dibekacin in the treatment of urinary infections in the elderly].

Urinary tract infections in the elderly are severe and intractable, often justifying the use of aminoglycosides. We studied the effects of dibekacin in 28 patients, with no vesical catheter, whose average age was 78 +/- 6.1 years. The drug was given for ten days, in an average dose of 2.1 mg/kg/day divided into two injections. Serum concentration was measured after one hour on day 1 and after eight hours on days 1 and 10. Causative pathogens, all susceptible to dibekacin, were: 18 E. coli, 3 Proteus mirabilis, 3 Klebsiella, 1 Enterobacter cloacae, 1 Citrobacter and 2 Staphylococci. MIC and MBC of dibekacin were determined for each microorganism. Dibekacin was discontinued in four cases on day three because of persistent bacteriuria. Ten days after treatment end, 19 patients were cured, 4 had a relapse and 1 was reinfected. Average serum concentration of dibekacin, measured after eight hours, increased from 0.77 +/- 0.48 micrograms/ml on day 1 to 1.78 +/- 1.22 microgram/ml on day 10 (t = 4.42; p less than 0.0005), while, over the same period, there was no significant change in serum creatinine.

Aged↗
PubMed1981

Comparative nephrotoxicity of dibekacin and gentamicin in rats.

To evaluate the nephrotoxicity of the new aminoglycoside, dibekacin, relative to gentamicin, we administered both drugs in doses of 40 and 120 mg/kg per day to male and female Fischer 344 rats. At sacrifice, we determined serum creatinine, in vitro renal cortical uptake of 14C N-methyl nicotinamide and para-aminohippurate, renal cortical antibiotic concentrations, and real histology. Dibekacin and gentamicin were similar in overall toxicity. Dibekacin differed from gentamicin and other aminoglycosides (1) in failing to cause early transient stimulation of para-aminohippurate uptake in male rats and (2) in the location of histologic damage at the 120 mg/kg dose. We conclude that: 1) in this model, dibekacin is comparable to gentamicin in nephrotoxic potential, and 2) the lack of early stimulation of para-aminohippurate uptake in male rates after dibekacin treatment may be related to greater initial injury to the late proximal tubule than is caused by gentamicin.

Animals↗
PubMed1989

The neuromuscular blocking effect of dibekacin and its reversal by Ca2+ and drugs in the isolated rat phrenic-hemidiaphragm preparation.

1. Dibekacin (0.3-3 mM) reduced indirectly elicited twitches in rat phrenic-hemidiaphragm. This effect was potentiated in low extracellular calcium media. 2. The blockade induced by dibekacin (3 mM) could be reversed by calcium (2.5 mM), 3,4-diamino-pyridine (3,4-DAP, 10 microM) or guanidine (3 mM), whereas neostigmine (3 microM), eserine (25 microM) or tetraethylammonium (100 microM) were less potent. 3. Dibekacin (3 mM) blocked directly-elicited twitches. Low concentrations were unable to obtain any effect. 4. It is concluded that dibekacin exerts its blocking action by limiting the calcium entry at motor nerve terminals, but a postsynaptic effect is also present. 3,4-DAP, guanidine and calcium were the most potent drugs in reversing the blockade.

Animals↗
PubMedDate not supplied

Quantitative determination of dibekacin using radioimmunoassay, substrate-labelled fluorescent immunoassay and rate nephelometric inhibition immunoassay for tobramycin.

Radioimmunoassay, rate nephelometric inhibition immunoassay and substrate-labelled fluorescent immunoassay were employed for the quantitative determination of dibekacin in serum. The cross-reactivity of the antibody provided with each assay allowed the use of tobramycin assay procedures for measuring dibekacin concentrations. With radioimmunoassay and nephelometric immunoassay, a dibekacin calibration curve was required, whereas fluorescent immunoassay was directly suitable for dibekacin assay, with cross-reactivity of nearly 100%. This allows the purchase of one assay kit for testing two antibiotics and thus reduces the cost to medical laboratories.

Cross Reactions↗
PubMed1978

Comparative in vitro activities of SCE-129, sulbenicillin, gentamicin, and dibekacin against Pseudomonas.

Against sulbenicillin- and gentamicin-susceptible strains of Pseudomonas aeruginosa, SCE-129 was about 10 times more active than sulbenicillin and had a similar activity to gentamicin and dibekacin. Sulbenicillin-resistant strains of P. aeruginosa were moderately resistant to SCE-129, whether these strains were gentamicin-resistant or not. Gentamicin-resistant strains of P. aeruginosa were resistant to dibekacin but not to SCE-129. Against P. maltophilia, the minimum inhibitory concentration of SCE-129 resembled those of sulbenicillin, gentamicin, and dibekacin. Most strains of P. cepacia were moderately resistant to SCE-129 and sulbenicillin and highly resistant to gentamicin and dibekacin.

Cefsulodin↗
PubMed1983

Substrate-labeled fluorescent immunoassay for measuring dibekacin concentrations in serum and plasma.

We have developed a homogeneous substrate-labeled fluorescent immunoassay for the measurement of dibekacin concentrations in serum and plasma. The fluorogenic enzyme substrate beta-galactosyl-umbelliferone was covalently attached to tobramycin, an aminoglycoside structurally similar to dibekacin, to prepare a fluorogenic drug reagent (FDR). The FDR is nonfluorescent under assay conditions, but fluoresces upon hydrolysis by beta-galactosidase. However, binding of the FDR by antiserum to the cross-reactive drug kanamycin prevents enzyme hydrolysis. The fixed level of FDR competes with dibekacin within the sample for the limiting number of antibody-binding sites in the reaction mixture. Unbound FDR is hydrolyzed by beta-galactosidase to release a fluorescent product that is proportional to the dibekacin concentration in the sample. The assay exhibits good precision, standard curve reproducibility, recovery, sensitivity, and correlation with a comparative method. Additionally, the substrate-labeled fluorescent immunoassay is rapid and easy to perform.

Binding Sites, Antibody↗
PubMed1981

Pharmacokinetics of dibekacin in rabbits and dogs.

The behaviors of dibekacin after three administration methods to rabbits and dogs were pharmacokinetically analysed. 1) In both rabbits and dogs, the pharmacokinetic constants for the intravenous constant infusion and intramuscular injection were similar to each other, and the serum levels after the intravenous constant infusion for 1 hr were similar to those after the intramuscular injection except the peak time. 2) In both rabbits and dogs, Vd increased with the dose and a linear correlation was noted between log Vd and log (dose). 3) The tissue concentrations of dibekacin decreased with the decrease in the serum concentration. 4) A correlation equation, log T 1/2 = 0.194 . log B + 1.128, was obtained, where T 1/2 and B represent the biological half-life of dibekacin and the body weight of animals, respectively. It was suggested that the pharmacokinetic behaviors of dibekacin in human beings can be predicted from the results of the animal experiments.

Animals↗
PubMed1982

Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin.

Protection by fosfomycin of the nephrotoxicity of dibekacin was studied using Fischer 344 rats and urinary parameters such as volume, osmolality, protein, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, lactate dehydrogenase and nucleated cells were determined as markers of nephrotoxicity. The duration of treatment was 11 d. Fosfomycin reduced polyuria, proteinuria, enzymuria and cyturia induced by dibekacin best by the concomitant administration, followed by pre-treatment, but not by post-treatment. Protection was effective in the dose ratio of dibekacin: fosfomycin = 1:2 - 1:32, regardless of administration routes. As judged from urinalysis, protection by fosfomycin (320 mg/kg) was almost complete for the experimental nephrotoxicity induced by 10 mg/kg of dibekacin, and still significant for that by 40 mg/kg. This was supported by the histo-pathological and ultrastructural improvement of proximal tubules and by suppressed blood urea nitrogen and creatinine values. Protective activity of fosfomycin was more potent than that of cephalothin, when compared on the weight basis.

Animals↗