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PubMed1996

Reduced enzymatic antioxidant defense mechanism in kidney tissues from gentamicin-treated guinea pigs: effects of vitamins E and C.

In this study, the activities of major enzymes participating in free radical metabolism (xanthine oxidase, XO; Cu,Zn and Mn superoxide dismutases, SOD; glutathione peroxidase, GSH-Px; catalase, CAT) were measured in kidney tissues from guinea pigs treated with gentamicin alone (200 mg/kg/day), gentamicin plus vitamin C (600 mg/kg/day), gentamicin plus vitamin E (400 mg/kg/day), and gentamicin plus vitamins C and E together for 10 days, and from animals treated with physiological saline solution alone during this period. We found no significant differences between control and gentamicin groups with respect to XO and Cu,Zn-SOD activities. However, the activities of Mn-SOD, GSH-Px, and CAT were found to be significantly depressed in the gentamicin-treated group relative to controls. In the gentamicin plus vitamin C group, the renal tissue Mn-SOD activity was found to be higher as compared with control and gentamicin groups. In this group, XO, GSH-Px and CAT activities were also higher than in the gentamicin-treated group, but no statistically significant differences existed between the values of this group and controls. Similar results were also observed in the gentamicin plus vitamin E group for Mn-SOD, GSH-Px, CAT, and XO. In this group, the Cu,Zn-SOD activity was found to be decreased as compared with control and gentamicin groups. In the gentamicin plus vitamins C and E group, the Cu,Zn-SOD activity was found to be decreased, the XO activity to be unchanged, and Mn-SOD, GSH-Px, and CAT activities to be increased as compared with the gentamicin and control groups. The results suggest that the enzymatic antioxidant defense system was significantly disturbed because of the suppressed activities of Mn-SOD, GSH-Px, and CAT in the kidney tissues from animals treated with gentamicin. However, vitamins C and E given concurrently with gentamicin completely abrogated this enzymatic suppression.

Animals↗
PubMed1994

Effects of gentamicin on glomerular renin release.

Gentamicin nephrotoxicity is associated with impaired glomerular function. To examine whether the effects of gentamicin on glomerular function are mediated through alterations in the renal-angiotensin system, basal and stimulated glomerular renin release was assessed in isolated glomeruli from control and gentamicin-treated rats. Male Sprague-Dawley rats (220 +/- 20 g) were studied immediately after treatment with gentamicin sulfate (4 mg/kg BW/day, n = 6) for 1 or 2 consecutive weeks and after 1 week of recovery from 2 weeks of treatment. Control rats received an equivalent volume of saline (n = 9). After the respective treatment, renal renin content was measured. In addition, glomeruli from control and gentamicin-treated rats were isolated and glomerular renin release was measured under basal conditions and after stimulation with the calmodulin inhibitor trifluoperazine (1 x 10(-4) M). Renin concentration was determined in aliquots of the supernatant by measuring the generation of angiotensin I using radioimmunoassay techniques at 15-min intervals. Renal renin content was significantly increased after 2 weeks of gentamicin treatment (+47%) and remained elevated (+62%) 1 week after discontinuing a 2-week gentamicin treatment. Both basal and stimulated glomerular renin release were lower in glomeruli isolated from gentamicin-treated rats. The effect of gentamicin added in vitro to glomeruli isolated from untreated rats was also evaluated. Exposure of normal glomeruli to in vitro gentamicin (1 mM) resulted in a significant inhibition of both basal (-47%, p < .05) and stimulated (-84%, p < .05) glomerular renin release. To determine whether the inhibitory action of gentamicin on glomerular renin release was dependent on extracellular calcium concentration, the effects of gentamicin on glomerular renin release were also assessed in the absence of extracellular calcium. Our data revealed that in the absence of extracellular calcium, the inhibitory effect of gentamicin on both basal and stimulated glomerular renin release was abolished. Taken together, these findings strongly suggest an inhibitory effect of gentamicin on glomerular renin release. Furthermore, the inhibition of glomerular renin release induced by gentamicin appears to be dependent on extracellular calcium.

Acute Kidney Injury↗
PubMed2005

Gentamicin-loaded calcium carbonate materials: comparison of two drug-loading modes.

Synthetic aragonite-based porous materials were drug loaded with gentamicin sulphate, an antibiotic active on Staphylococcus aureus responsible for osteomyelitis. Drug loading was accomplished by two different ways: by integration of gentamicin in material during processing or by soaking material into gentamicin solutions. We first investigated the influence of drug loading on compressive strength of materials. Results indicate that soaked materials presented the same compressive strength than unloaded materials with the same porosity. By contrast, the integration of gentamicin during processing increased significantly the compressive strength of materials. The materials drug content before elution was a least 10 times higher when gentamicin was integrated during processing comparatively to soaked materials. The study of in vitro gentamicin release showed that for materials with gentamicin integrated during material processing, high concentrations of gentamicin were released up to 8 or 12 days, against 4 days for soaked materials. The transport coefficients calculation, for the first step of release, indicated that the rate of release was higher for materials with integrated gentamicin because of the higher gentamicin content. The porosity rate influenced the rate of release for materials positively with gentamicin integrated during processing contrary to soaked materials for which a higher porosity rate allowed a deeper penetration of gentamicin during drug loading and then a slightly slower release. Results indicate that aragonite-based material with gentamicin integrated during material processing may be used either as resorbable device for release of high concentrations of gentamicin or as biomaterial for combined therapy: bone substitution and prevention or treatment of osteomyelitis.

Anti-Bacterial Agents↗
PubMed1987

Failure of inhibition of lipid peroxidation by vitamin E to protect against gentamicin nephrotoxicity in the rat.

We tested the hypothesis that accelerated lipid peroxidation, possibly at the level of the lysosome, is linked causally to the pathogenesis of aminoglycoside nephrotoxicity by investigating whether administration of vitamin E would inhibit lipid peroxidation and prevent or ameliorate gentamicin-induced proximal tubular cell injury. Five groups of rats were injected with either saline, vitamin E (600 mg/kg per day) for 6 days, gentamicin (100 mg/kg per day) for 6 days, vitamin E for 6 days plus gentamicin for 6 days or vitamin E for 12 days and gentamicin for the last 6 days. Gentamicin alone induced a 16% increase in renal cortical phospholipids; vitamin E had no significant effect on this change. Gentamicin alone caused accelerated lipid peroxidation evident by a doubling of renal cortical malondialdehyde to 1.23 nmol/mg protein, and a sharp decline of esterified polyunsaturated fatty acids, especially arachidonic acid which fell 43%. These changes were accompanied by depressions of superoxide dismutase, catalase, and total glutathione and a shift from reduced to oxidized glutathione. Concurrent treatment of rats with vitamin E plus gentamicin for 6 days had no significant effect on the gentamicin-induced alterations of malondialdehyde, superoxide dismutase, catalase or the glutathione cascade; however, the shift from polyunsaturated to saturated fatty acids was largely reversed. In rats pretreated with vitamin E for 6 days, gentamicin failed to raise renal cortical malondialdehyde above that of saline-treated rats. The changes in esterified fatty acids were prevented almost entirely, and there were no significant alterations from control of the glutathione cascade. The depressions of superoxide dismutase and of catalase, however, were not reversed. Vitamin E did not affect the amount of gentamicin accumulated in renal cortex nor did it prevent the gentamicin-induced rise of serum creatinine. Examination of renal cortex by light and electron microscopy revealed that vitamin E did not prevent or even reduce the severity of gentamicin-induced proximal tubular cell lesions and necrosis. These results confirm those we obtained in a previous study with the antioxidant diphenyl-phenylenediamine. The observation that inhibition of lipid peroxidation by two distinct antioxidants failed to prevent proximal tubular cell injury and renal dysfunction associated with gentamicin administration leads us to conclude that lipid peroxidation is a consequence and not a cause of gentamicin-induced nephrotoxicity.

Animals↗
PubMed1995

Protection against gentamicin nephrotoxicity by daptomycin in nephrectomized rats.

Daptomycin was previously shown to reduce gentamicin renal toxicity and this toxicity was not delayed by the concomitant injection of daptomycin (Thibault N., L. Grenier, M. Simard, M. G. Bergeron, and D. Beauchamp, Antimicrob. Agents Chemother., 38 1027-1035 (1994)). The protective effect of daptomycin against gentamicin toxicity was evaluated in 96 female Sprague-Dawley rats. Normal and nephrectomized rats were treated with saline (NaCl, 0.9%), gentamicin (30 mg/kg/12 hrs, i.p.), daptomycin (10 mg/kg/12 hrs, s.c.) or with a combination of daptomycin plus gentamicin during 4 and 10 days. On day 4, gentamicin and daptomycin cortical levels were higher in nephrectomized gentamicin-daptomycin-treated rats (p < 0.05) as compared to all other groups. The accumulation of gentamicin or daptomycin in nephrectomized gentamicin-daptomycin-treated or gentamicin-saline-treated rats was higher on day 4 (p < 0.01) than on day 10. Other parameters such as the sphingomyelinase activity in the renal cortex, the serum creatinine, and the histopathology showed significantly fewer changes in daptomycin-gentamicin-treated rats as compared to animals given gentamicin alone. On the other hand, the protection of daptomycin was less extensive in nephrectomized rats as compared to normal rats. Daptomycin and gentamicin were localized in the lysosomes of proximal tubular cells of animals treated with daptomycin and gentamicin given alone or in combination. These results suggest that daptomycin protects against gentamicin toxicity in nephrectomized rats but to a lesser extent than in normal rats.

Animals↗
PubMed1983

Effects of acute exposures to gentamicin on renal handling of proteins.

The polycationic aminoglycoside gentamicin has been reported to compete with other aminoglycosides and cationic compounds for uptake into renal tubular cells at brush border membranes and during subsequent endocytosis. Gentamicin has also been reported to decrease the activity of lysosomal proteolytic enzymes in the rat kidney. In vivo and in vitro experiments were carried out to determine the effect of acute exposure to gentamicin on renal handling of the cationic low molecular weight protein, lysozyme. Thirty or 60 mg/kg of gentamicin was given to male Wistar rats (250-300 g) intravenously or isolated rat kidneys were perfused with gentamicin concentrations of 0.25, 0.50, 1.0 and 2.5 mg/ml. Subsequently, clearances of lysozyme (CLY) and inulin (GFR, glomerular filtration rate) were measured in the intact rat and in the isolated perfused rat kidney. The glomerular sieving coefficient of lysozyme was determined in control and gentamicin perfused kidneys after complete inhibition of tubular lysozyme reabsorption by sodium iodoacetate. Renal degradation of 125I-labelled lysozyme was quantified in control and gentamicin perfused kidneys by measuring the release of [125I] monoiodotyrosine to the perfusate. The glomerular sieving coefficient of lysozyme increased in kidneys perfused with gentamicin from a control value of 0.8-1.0. A dose-dependent increase of the ratio CLY/GFR in intact rats treated with gentamicin and dose-dependent decrease of percentage reabsorption of lysozyme in the isolated perfused kidneys demonstrate inhibition of renal reabsorption of lysozyme by gentamicin. Perfusion of kidneys with 0.25 mg/ml gentamicin reduced renal degradation of lysozyme to about 50% after 2 h perfusion; at gentamicin concentrations of 0.5 mg/ml and higher almost all degradation of lysozyme was inhibited. Thus, acute exposure to gentamicin causes impairment of filtration, tubular reabsorption and catabolism of the protein lysozyme, effects which are due to pharmacological interactions between the molecules of the 2 cations gentamicin and lysozyme.

Absorption↗
PubMed2002

Melanin potentiates gentamicin-induced inhibition of collagen biosynthesis in human skin fibroblasts.

One of the recognized side effects of gentamicin is ototoxicity. The mechanism underlying the organ specificity of this side effect of gentamicin has not been fully established. In view of the fact that a number of pharmacologic agents are known to form complexes with melanin and melanin is an abundant constituent of the inner ear tissues, we determined whether gentamicin interacts with melanin and how this process affects the biosynthesis of collagen in cultured human skin fibroblasts. Our results indicate that gentamicin forms complexes with melanin. The amount of gentamicin bound to melanin increases with increasing of initial drug concentration. The Scatchard plot analysis of drug binding to melanin showed that at least two classes of independent binding sites are implicated in gentamicin-melanin complex formation: one class with an association constant K(1) approximately 4 x 10(3) M(-1), and the second class with an association constant K(2) approximately 3 x 10(2) M(-1). The number of total binding sites (n(1)+n(2)) was calculated as about 1.36 micromol gentamicin per 1 mg melanin. We have suggested that prolidase, an enzyme involved in collagen metabolism, may be one of the targets for gentamicin-induced inhibition of collagen biosynthesis. We found that gentamicin-induced inhibition of prolidase activity (IC(50) approximately 100 microM) and collagen biosynthesis (IC(50) approximately 100 microM). At this concentration of gentamicin, DNA biosynthesis in human skin fibroblasts was inhibited only by about 30%. Melanin at 100 microg/ml produced about 25% inhibition of DNA synthesis and about 30% inhibition of prolidase activity, but it had no effect on collagen biosynthesis in cultured fibroblasts. However, the addition of melanin (100 microg/ml) to gentamicin-treated cells (100 microM) augmented the inhibitory action of gentamicin on collagen and DNA biosynthesis and partially reversed its inhibitory effect on prolidase activity. A melanin-induced augmentation of the inhibitory effects of gentamicin on collagen and DNA biosynthesis may explain the mechanism for the organ specificity of gentamicin-induced hearing loss in patients administered this drug.

Anti-Bacterial Agents↗
PubMed1982

Penetration of gentamicin into burn wounds.

This study was originated in recognition that little data have been accumulated in the literature regarding concentrations of gentamicin in various infected tissues. The study was undertaken to determine if systemically administered gentamicin penetrates burn wound eschar and to determine if there is a relationship between gentamicin serum levels attained and concentration of gentamicin reaching the eschar. Five hospitalized adult patients requiring parenteral gentamicin for sepsis secondary to third-degree burns were studied prospectively. For the purpose of determining the amount of gentamicin reaching the eschar, biopsy of the burn wound eschar was performed on each patient. Venous blood samples were also obtained to examine the relationship of serial serum samples to eschar levels. Calculated pharmacokinetic parameters include elimination rate constants, apparent volume of distribution, beta, and gentamicin half-life. The data indicate that systemically administered gentamicin does penetrate burn eschar in measurable quantities. Deeper layers of eschar tissue contained significantly greater quantities of gentamicin. Analysis of variance resulted in statistically significant (p less than 0.05) rise is eschar concentration with time. A positive correlation between the peak serum gentamicin concentration and the concentration of gentamicin reaching the burn tissue was found. The quantity of gentamicin attained was sufficient to prevent proliferation of organisms cultured from the eschar of patients. Accumulation of gentamicin in the eschar occurred in every patient studied. This study suggests the eradication of organisms in eschar samples is due to the achievable concentration of gentamicin at this site.

Adult↗
PubMed2006

Use of tissue-fluid correlations to estimate gentamicin residues in kidney tissue of Holstein steers.

Gentamicin continues to be one of the most effective antibiotics for the treatment of gram-negative infections. Greater than 90% of the drug is rapidly eliminated from the body in <2 days, however, a small residue remains bound to the kidney cortex tissue for many months. In beef steers, the gentamicin residue is unacceptable and its presence is monitored by the FAST (Fast Antimicrobial Screen Test) applied to the kidney at the time of slaughter. The sensitivity of the FAST to gentamicin in the kidney cortex is reported to be 100 ng/g, therefore, this level of gentamicin defines the acceptable limit of gentamicin drug residue in the bovine kidney. In the present study, three doses of 4 mg/kg gentamicin was administered intramuscularly to eight steers. Gentamicin was allowed to deplete from the kidneys for a range of times from 7 to 10 months. At slaughter the level of gentamicin in the kidney cortex varied from 91 to 193 ng/g, but a total of 160 FAST tests performed on the kidneys were negative. Blood and urine samples were collected at varying times following the last dose of gentamicin. Kidney tissue samples were collected by laparoscopic surgery in the live steers as well as the final sample obtained at slaughter. Plasma levels of gentamicin declined rapidly to nondetectable within 3 days, while measurable urine persisted for 75 days before the concentration of gentamicin declined to levels too low to quantitate by the available liquid chromatography tandem mass spectrometry (LC/MS/MS) technique. An estimated correlation between an extrapolation of urine gentamicin concentration to the corresponding kidney tissue sample suggests a urine to kidney tissue relationship of 1:100. A test system sufficiently sensitive to a urine gentamicin concentration of 1 ng/mL will correlate with the estimated 100 ng/g gentamicin limit of the FAST applied to the fresh kidney of the recently slaughtered bovine.

Animals↗
PubMed2000

Melatonin, a pineal hormone with antioxidant property, protects against gentamicin-induced nephrotoxicity in rats.

The present study investigated the effects of melatonin, an antioxidant, on gentamicin-induced nephrotoxicity in rats. Melatonin (5 mg/kg p.o.) was used 3 days before and 8 days simultaneously with gentamicin (80 mg/kg i.p.) Saline-treated animals served as controls. Determinations of urinary creatinine, N-acetyl-beta-D-glucosaminidase, glucose, protein, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA), and antioxidant enzyme levels in kidney tissue were done after 8 days of gentamicin treatment. The kidneys were also examined for morphological changes using histological techniques. Gentamicin caused nephrotoxicity as evidenced by marked elevation in blood urea and serum creatinine. Mean blood urea and serum creatinine levels were 289+/-50, and 2.5+/-0.5 mg/dl, respectively, in rats treated with gentamicin. Melatonin significantly protected the rats from gentamicin-induced nephrotoxicity; blood urea and serum creatinine levels were 23+/-2.7 and 0.88+/-0.19 mg/dl, respectively. The creatinine clearance was decreased with gentamicin treatment (0.048+/- 0.007 ml/min) as compared with controls (0.41+/-0.08 ml/h/kg). In rats treated with melatonin plus gentamicin, the creatinine clearance was similar to controls (0.41+/-0.08 ml/h/kg). The product of lipid peroxidation (MDA) was markedly increased in plasma (2.10+/-0.15 nmol) and kidney tissue (8.87+/-3.2 nmol/mg protein) with gentamicin treatment. Melatonin prevented the gentamicin-induced rise in plasma MDA (1.03+/-0.27 nmol) and kidney tissue MDA (2.57+/-0.87 nmol/mg protein). An increased excretion of urinary N-acetyl-beta-D-glucosaminidase, glucose, and protein by gentamicin was also prevented by melatonin. Kidneys from gentamicin-treated rats showed tubular epithelial loss with intense granular degeneration involving more than 50% of renal cortex, while there were findings comparable to controls in melatonin plus gentamicin treated rats. The present study indicates that melatonin significantly protects against gentamicin-induced renal toxicity in Wistar rats.

Animals↗
PubMed1977

Effect of gentamicin on p - aminohippurate metabolism and transport in rat kidney slices.

The mechanism by which gentamicin augments the uptake of p-aminohippurate (PAH) by rat renal cortical slices was investigated. In all experiments, gentamicin was administered as gentamicin sulfate at 100 mg/kg b.wt. per day for 2 days; control rats were injected with saline. The effect of gentamicin on the metabolism of PAH to p-aminobenzoic acid (PABA), acetyl-PABA and acetyl-PAH was studied by high performance liquid chromatography. No metabolites of PAH were detected in renal slices of gentamicin-injected or control rats incubated in medium containing PAH. Efflux of 14C-PAH was measured after incubating renal cortical slices for 2 hours in medium containing 8 X 10(-5) M 14C-PAH. The efflux rate constant was 0.080 +/- 0.003/min in control slices and 0.059 +/- 0.003/min in gentamicin slices, P less than .001. No significant difference in the diffusible pool of PAH was found between the two groups which supports an argument against increased tissue-binding of PAH as the explanation for the augmented uptake of PAH by slices of gentamicin-injected rats. Active PAH transport was assessed in terms of Michaelis-Menten kinetics. Vmax was 0.93 +/- 0.08 micronmol/g/15 min in control slices and 1.37 +/- 0.10 micronmol/g/15 min in gentamicin slices (P less than .005). The apparent reaction rate constant (Km) was not different; Km was 0.25 +/- 0.03 and 0.29 +/- 0.04 mM in control and gentamicin slices, respectively (P less than .4). In contrast to PAH, gentamicin did not alter uptake of N'-methynicotinamide, an organic base; nor did it alter the efflux rate constant or diffusible pool of N'-methylnicotinamide. Increased PAH uptake was still evident when slices of gentamicin-injected rats were incubated in medium without acetate. These studies indicate that gentamicin stimulates active PAH transport and decreases PAH efflux in rat renal cortical slices. Both changes implicate an effect of gentamicin at the antiluminal membrane of proximal tubular cells. The finding of an increase in Vmax without a change in Km raises the possibility that gentamicin increases the amount or availability of carrier protein-mediating PAH transport.

Acetates↗
PubMed1990

Depression of vitamin B6 levels due to gentamicin.

The renal toxicity of gentamicin is altered by dietary protein modifications, bicarbonate and acetazolamide administration, magnesium supplementation, polyaspartic acid, piperacillin, hypercalcemia and calcium channel blockers. Renal tissue gentamicin levels have an undetermined role. Reduction of renal pyridoxal 5'-phosphate (PLP- by gentamicin has been shown, as has protection from nephrotoxicity by administration of vitamin B6. To explore an interaction between gentamicin and vitamin B6, gentamicin (5 mg/kg) was given to rabbits by ip injection, with either pyridoxine (10 mg) or isovolemic saline for 3 weeks. There was not a difference between gentamicin levels for animals given gentamicin and pyridoxine versus those given gentamicin and saline. Gentamicin administration led to a 47% fall (p = .0001) in plasma PLP levels. Three days after the last gentamicin administration, the animals maintained a 32% decrease from the pre-gentamicin baseline values (p = 0.02). When pyridoxine was administered concurrently with gentamicin, the PLP rise of 49% was significant (p = 0.001). The mean level after the study (6%) was not significantly lower than baseline (p = .6). We believe that gentamicin interfers with vitamin B6 metabolism, but that vitamin B6 status does not affect levels of gentamicin. A number of drugs affect B6 levels, creating the potential for hypovitaminosis B6 to be an important mechanism of drug-drug interaction in seriously ill patients, particularly in sick newborns or the elderly with lower average PLP levels.

Animals↗
PubMedDate not supplied

Effect of methimazole and fish oil treatment on gentamicin nephrotoxicity in rats.

Gentamicin, a nephrotoxic aminoglycoside antibiotic, was injected into adult male albino rats, alone or together with methimazole and fish oil. The effects on renal and liver functions and renal thiol status were studied. Gentamicin was administered as two i.p. injections (40 mg/kg body weight) for 3, 7 and 10 consecutive days. The animals were sacrificed 12 hours after the last injection. In gentamicin-treated rats, for 7 and 10 days, blood urea nitrogen (BUN) and serum creatinine concentrations and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity were significantly increased compared with saline-treated controls. Administration of methimazole (20 mg/kg) and fish oil (5 ml/kg) together with gentamicin partially protected against the nephrotoxicity induced by gentamicin by returning the urea and creatinine concentrations and urinary NAG activity to normal levels, despite having higher kidney gentamicin concentrations, especially with methimazole. Rats given gentamicin alone for 3 days exhibited no elevation of BNU, serum creatinine and urinary NAG values. However, these rats exhibited an increase in nonprotein disulfide concentrations and a decrease in renal protein thiol and protein disulfide concentrations, as opposed to rats given gentamicin and methimazole and rats given gentamicin and fish oil. These results show that methimazole and fish oil were effective antagonists of gentamicin-induced nephrotoxicity. Methimazole did not inhibit gentamicin renal uptake but may protect against gentamicin-induced nephrotoxicity by acting as an antioxidant within the kidneys. On the other hand, fish oil may protect against gentamicin-induced nephrotoxicity by counteracting the biochemical alterations induced by the drug in the renal cortex. We conclude that methimazole and fish oil may be compounds for reducing gentamicin-toxic side effects, including nephrotoxicity, without compromising its antibiotic activity.

Animals↗
PubMed2004

Gentamicin release from two-solution and powder-liquid poly(methyl methacrylate)-based bone cements by using novel pH method.

The release of gentamicin as a function of time was measured for Palacos and two-solution bone cements by using a novel pH technique. The pH of an aqueous solution of gentamicin is a function of the gentamicin concentration and it decreases linearly over concentrations of 0.0-0.1 wt %. Therefore, a new, direct, and inexpensive in vitro technique was developed based on continuous readings of the pH in phosphate-buffered saline (PBS) at 37 degrees C to determine the release kinetics of gentamicin from poly(methyl methacrylate) (PMMA)-based bone cement. In addition, this method was used to compare the release profiles of Palacos R-40 bone cement with a two-solution bone cement developed in our laboratory and loaded with two different concentrations of gentamicin sulfate. Finally, the pH-based method was used to track the elution of gentamicin in both mixed and static conditions to determine the effect of mixing on the diffusion of gentamicin out of the cement. It was found that Palacos R-40 released 4.95 +/- 0.22 wt % of its gentamicin after 24 h in PBS solution. This data compares favorably with previously reported values of gentamicin elution from Palacos R-40, which ranged from 3 to 8 wt % of the total amount of incorporated gentamicin, depending on the size and the surface area of the samples. The results show that Palacos samples released 4.84 +/- 0.27 mg after 24 h, a two-solution cement loaded with an equivalent concentration of gentamicin sulfate released 3.81 +/- 0.52 mg, and two-solution cement loaded with twice the concentration of Palacos released 5.53 +/- 0.26 mg of gentamicin. A higher percentage of release was recorded from Palacos than from the two-solution bone cement, and the effect of PBS mixing conditions on the release kinetics was only significant in the early stages of release and not at 24 h. It was concluded that monitoring the pH is an effective technique to measure gentamicin release from PMMA-based bone cements in PBS solution.

Anti-Bacterial Agents↗
PubMedDate not supplied

Gentamicin-induced alterations in phospholipid metabolism in cultured human proximal tubular cells.

The effects of gentamicin on phospholipid levels and metabolism and the uptake of phosphatidylcholine (PC) adsorbed to low-density lipoprotein (LDL) were investigated in cultured human proximal tubular (PT) cells. Cells incubated with gentamicin (0.3 mM) for one to 21 days had a similar increase in the cell number and protein as compared to control cells. However, the cellular levels of phosphatidylcholine (PC) and sphingomyelin (SM), but not other phospholipids, increased in a time-dependent manner. Incubation of gentamicin (0.3 to 3.0 mM) resulted in a concentration-dependent increase in the cellular levels of PC (50% to 320%) and SM (20% to 40%). Gentamicin stimulated the incorporation of [14C]-acetate into diacylglycerol, PC, and SM in the order of 300%, 66%, and 20%, respectively, but not into lysophosphatidylcholine (LPC). Similarly, gentamicin stimulated the incorporation of [14C]-choline into PC and SM in the order of 300% and 172%, respectively, but not into LPC as compared to control cells. In addition, gentamicin also stimulated the incorporation of [14C]-choline into cytidine diphosphocholine (CDP-choline). However, the endocytosis of [14C]-PC-LDL was lower in cells incubated with gentamicin than in control cells. Thus, exogenously derived PC on LDL does not contribute to the increased cellular levels of PC in PT cells incubated with gentamicin. The activity of cytidine triphosphate (CTP):phosphocholine cytidyltransferase was moderately lower in cells incubated with gentamicin as compared to control. By contrast, the activity of phospholipase A1 and phospholipase C was twofold lower in cells incubated with gentamicin for 21 days as compared to control. Thus, increased incorporation of [14C]-acetate and [14C]-choline into PC in cells incubated with gentamicin may not only be due to increased endogenous synthesis but to decreased catabolism of newly synthesized PC. We conclude that gentamicin impairs the lysosomal catabolism of PC, leading to its accumulation in PT cells. This phenomenon may be an indication of gentamicin-induced nephrotoxicity in man.

Cells, Cultured↗
PubMed2004

Iontophoresis-gentamicin delivery into the rabbit cornea, using a hydrogel delivery probe.

PURPOSE: To evaluate the efficacy of penetration of gentamicin into the cornea of rabbits using iontophoresis with a hydrogel-gentamicin containing probe. METHODS: Eight of 10 groups (groups 3-10) of 6 rabbits (one eye per rabbit), underwent corneal iontophoresis using soft stable hydroxyethyl methacrylate hydrogel discs (80% water content) loaded with gentamicin sulphate which were mounted on an iontophoresis probe. The studied current intensities were 0, 0.1, 0.3 and 0.6 mAmp, and the durations of iontophoresis were 10 and 60 sec. Two control groups received 1.4% topical drops of gentamicin every 5 min for 1 hr (group 1) or sub-conjunctival injection of 10 mg gentamicin (group 2). Following sacrifice, aqueous humour was taken, corneas were excised, and gentamicin concentration was determined in aqueous humour and cornea samples. RESULTS: Post-iontophoresis, the concentration of gentamicin in the corneas ranged from high (88.60 +/- 38.64 microg ml(-1)) to very low (0.10 +/- 0.89 microg ml(-1)). Both the control groups and those rabbits treated with current intensity of 0.1 mAmp or greater obtained therapeutic gentamicin levels in the corneas. Use of iontophoresis for 60 sec or current intensity greater than 0.1 mAmp obtained corneal gentamicin levels not different from sub-conjunctival injection. Application of current intensity of 0.1 mAmp or greater gave corneal gentamicin concentrations comparable to topical application of the drug, except when 0.6 mAmp were used for 60 sec (p = 0.05). Increasing current intensity or duration of iontophoresis significantly increased (p = 0.001 for both) gentamicin penetration into the cornea. Current intensity had more influence (Beta2 = 0.40) than duration (Beta2 = 0.13) on drug penetration. A significant interaction was found between the duration of iontophoresis and the current intensity. Very small or no concentrations of the drug were discovered in the anterior chambers of rabbits. CONCLUSIONS: Iontophoresis using hydrogel-gentamicin probe may deliver therapeutic concentrations of gentamicin into the cornea.

Animals↗
PubMed2000

Carvedilol: a beta blocker with antioxidant property protects against gentamicin-induced nephrotoxicity in rats.

Gentamicin is an antibiotic effective against gram negative infections, whose clinical use is limited by its nephrotoxicity. Since the pathogenesis of gentamicin-induced nephrotoxicity involves oxygen free radicals, the antioxidant carvedilol may protect against gentamicin-induced renal toxicity. We therefore tested this hypothesis using a rat model of gentamicin nephrotoxicity. Carvedilol (2 mg/kg) was administered intraperitoneally 3 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA) were carried out, after the last dose of gentamicin. Kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity as evidenced by increase in blood urea, serum creatinine and decreased in creatinine clearance. Blood urea and serum creatinine was increased by 883% and 480% respectively with gentamicin compared to control. Carvedilol protected the rats from gentamicin induced nephrotoxicity. Rise in blood urea, serum creatinine and decrease in creatinine clearance was significantly prevented by carvedilol. There was 190% and 377% rise in plasma and kidney tissue MDA with gentamicin. Carvedilol prevented the gentamicin induced rise in both plasma and kidney tissue MDA. Kidney from gentamicin treated rats, histologically showed necrosis and desquamation of tubular epithelial cells in renal cortex, whereas it was very much comparable to control with carvedilol. In conclusion, carvedilol with its antioxidant property protected the rats from gentamicin-induced nephrotoxicity.

Adrenergic beta-Antagonists↗
PubMed1990

Mild ischemia predisposes the S3 segment to gentamicin toxicity.

The purpose of these studies was to determine if a functionally insignificant ischemic insult, occurring prior to gentamicin administration, enhanced gentamicin nephrotoxicity. Bilateral renal pedicle clamp studies demonstrated that 15 minutes of ischemia did not increase the plasma creatinine yet markedly enhanced gentamicin nephrotoxicity. Further studies, in uninephrectomized rats, demonstrated that following fifteen minutes of renal ischemia and four hours of reperfusion inulin clearance, FENa+ and cellular morphology were normal. This model, therefore, was used in all subsequent studies. While the plasma creatinine concentrations were normal 24 hours following 15 minutes of ischemia and only slightly increased following gentamicin administration (100 mg/kg, i.p.) gentamicin administered four hours following 15 minutes of renal ischemia resulted in significantly increased 24-hour plasma creatinine values. Light microscopic quantitation of tissue injury, performed 24 hours following experimental manipulation, was notable for S3 segment damage in the ischemia plus gentamicin group. This was not observed in either the ischemia group or the sham operated gentamicin group. Cortical gentamicin levels were elevated in the ischemia plus gentamicin group, despite similar plasma gentamicin half-lives. However, the elevation in cortical gentamicin levels was dissociated from the enhanced nephrotoxicity seen following mild ischemic injury. Taken together these data indicate that mild renal ischemia, occurring prior to gentamicin administration, greatly enhanced gentamicin nephrotoxicity with the greatest damage occurring to S3 cells.

Acute Kidney Injury↗