The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats

Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.     

10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats

Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis–induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues. Conclusion: 10-DHGD exhibited a marked anti-inflammatory potential, alleviated to a great extent of nephrotoxicity and renal fibrosis induced by cisplatin.     

Stereoselective inhibition of amantadine accumulation by quinine and quinidine in rat renal proximal tubules and cortical slices

The renal organic cation transport system was examined. The accumulation of a nonchiral cation, amantadine, by rat renal proximal tubules and cortical slices was investigated, together with the effects of two diastereoisomers, quinine and quinidine. The proximal tubules actively concentrated amantadine with a tissue/medium ratio of 96.3 +/- 1.7 (mean +/- S.E.M., n = 18). Apparent Km was 85 +/- 2 microM and Vmax was 8.0 +/- 0.2 nmol/mg of tubular protein per min. Amantadine accumulation was inhibited competitively by quinine and quinidine with Ki values of 32 +/- 3 and 84 +/- 11 microM, respectively (n = 4). Amantadine was also concentrated by renal cortical slices with tissue/medium ratio of 3.3 +/- 0.3 (n = 4). Apparent Km and Vmax were 94.0 +/- 5.2 microM and 1.27 +/- 0.08 nmol/mg of tubular protein per min, respectively (n = 10). Quinine and quinidine again inhibited amantadine accumulation competitively by the slices, with Ki values of 368 +/- 28 and 780 +/- 84 microM, respectively (n = 4). A similar affinity (Km) for amantadine was observed in both preparations. However, the lower Vmax value in the slice system may be due to additional amantadine transport sites with lower capacity, lesser luminal accumulation and/or limited substrate(s) penetration in the cortical slices. In either preparation, quinine and quinidine functioned as competitive inhibitors and stereoselectivity was observed for the (-)-isomer, quinine, over the (+)-isomer, quinidine. Additional transport sites, reduced luminal substrate accumulation and/or diffusional restraints in the slices are also feasible mechanisms in explaining the differences in Ki values between the two preparations, and their relative contributions await further investigation.     

Investigations on metabolic modulation of p-aminohippurate accumulation by rabbit renal cortical slices.

Preparation and incubation of renal cortical slices from adult, female, New Zealand white rabbit depleted tissue citrate concentration. Acetate (10.0 mM) in the incubation significantly increased slice citrate concentration and p-aminohippurate (PAH) accumulation. Physiological concentrations of citrate increased PAH accumulation and final medium pH. increasing concentrations of citrate produced a biphasic effect on PAH accumulation. These data suggested that citrate may act as an intracellular modulator of organic anion transport. This hypothesis was tested with other stimulators of PAH accumulation. Physiological concentrations of alpha-ketoglutarate or succinate increased slice accumulation of PAH. Higher concentrations of either substrate significantly inhibited PAH accumulation. Final medium pH increased with increased medium concentration of both substrates. alpha-Ketoglutarate (0.5 mM) increased PAH accumulation but had no effect on slice citrate concentration. Glucose did not alter either PAH accumulation or slice citrate concentration. Slices incubated without substrate were depleted of citrate but not of alpha-ketoglutarate. Acetate (1.0 mM) significantly increased slice concentration of both alpha-ketoglutarate and citrate. These data suggested that organic anion transport could be modulated by several metabolic intermediates acting through similar but separate mechanisms.     

Protection effects of Taurine supplementation against cisplatin-induced nephrotoxicity in rats

BACKGROUND: Taurine, which is the major intracellular free beta-amino acid, is known to be an antioxidant and a membrane-stabilizing agent. This study was designed to investigate the protective role of taurine supplementation against cisplatin-induced nephrotoxicity. METHODS: Male Wistar rats were divided into six groups and treated as follows: (1) saline-treated control drinking tap water, (2) saline-treated plus taurine-supplemented (1.5% taurine in the drinking water), (3) saline-treated plus taurine-depleted (3% beta-alanine in the drinking water), (4) cisplatin-treated, CDDP 6 mg/kg intraperitoneally, (5) taurine-supplemented plus CDDP-treated and (6) taurine-depleted plus CDDP-treated. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analyzed. RESULTS: CDDP-treated rats showed increased kidney weight as a percentage of total body weight, serum creatinine and BUN levels and decreased serum albumin and calcium levels. Also, CDDP treatment resulted in a depletion of kidney GSH content, a reduction in the kidney glutathione peroxidase (GSH-Px) activity and increased kidney MDA production level. Taurine supplementation attenuated CDDP-induced nephrotoxicity which was manifested by jeopardizing the elevation in serum creatinine and BUN levels and the reduction in serum albumin and calcium levels. Moreover, taurine supplementation restored kidney GSH content and GSH-Px activity and reduced platinum accumulation and MDA production levels in the kidney tissue following CDDP treatment. Histopathological examination of the kidney of CDDP-treated rats revealed tubular atrophy, tubular necrosis and desquamation of renal tubular cells. However, taurine supplementation protected against CDDP-induced histopathological changes. CONCLUSIONS: The data suggest that taurine supplementation effectively attenuates the accumulation of platinum within kidney tissue and counteracts the deleterious effect of CDDP on the renal tubular function.     

Inhibition of nitric oxide synthase aggravates cisplatin-induced nephrotoxicity: effect of 2-amino-4-methylpyridine

BACKGROUND: Nitric oxide (NO) has been shown to play a role in maintaining normal renal function. However, the role of NO in cisplatin (CDDP)-induced nephrotoxicity is still unclear. The aim of the present work was to examine the effect of the NO synthase (NOS) inhibitor, 2-amino-4-methylpyridine, on the severity of CDDP-induced nephrotoxicity. METHODS: Male Wistar rats were divided into six groups. Three control groups received plain drinking water or water containing 1.5% L-arginine. One of the two groups receiving plain water was treated with an intraperitoneal injection of 2-amino-4-methylpyridine (1 mg/kg in normal saline), and the other two control groups were injected intraperitoneally with normal saline. Another three groups were treated in the same manner and injected with CDDP (6 mg/kg, i.p.). CDDP was injected 1 h after 2-amino-4-methylpyridine treatment. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analysed. RESULTS: CDDP-treated rats showed increases in the kidney weight as a percentage of the total body weight and serum creatinine and urea levels and decreases in serum albumin and calcium levels. Also, CDDP treatment induced reductions in the kidney total nitrate/nitrite (NO(x)), reduced glutathione (GSH) and glutathione peroxidase activity (GSH-Px) levels and an increase in the kidney malondialdehyde (MDA) production level. In contrast, 2-amino-4-methylpyridine treatment 1 h prior to CDDP injection induced marked exacerbation of CDDP-induced nephrotoxicity, as manifested by severe aggravation of the indices of nephrotoxicity. Also, 2-amino-4-methylpyridine plus CDDP-treated rats showed exaggeration of the reduction in the kidney total NO(x) content and GSH-Px activity and elevation of the kidney platinum accumulation level with normalization of the kidney MDA production level and rebound in the kidney GSH content. Histopathologically, CDDP-treated rats showed marked interstitial nephritis, tubular atrophy and tubular necrosis. However, treatment with 2-amino-4-methylpyridine 1 h prior to CDDP injection revealed marked exacerbation of CDDP-induced histopathological changes. CONCLUSIONS: The present findings suggest that NO plays a role in CDDP-induced nephrotoxicity. Administration of 2-amino-4-methylpyridine, an NOS inhibitor, exacerbates CDDP-induced nephrotoxicity.     

Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity

One of the dose-limiting toxicities of cisplatin is nephrotoxicity. Renal toxicity is localized to quiescent proximal tubule cells, where the formation of DNA-adducts cannot account for the dose-limiting toxicity. Our earlier results have shown that a glutathione conjugate of cisplatin is metabolized to a nephrotoxicant via gamma-glutamyl transpeptidase (GGT) and a cysteine S-conjugate beta-lyase. The present study was designed to evaluate the potential role of glutathione S-transferase Pi (GSTP) in the initial steps of the bioactivation of cisplatin. Wild-type mice and mice deficient in both murine GSTP genes (GstP1/P2) were treated with cisplatin. Toxicity in both male and female mice was evaluated 5 days after treatment and renal damage was most severe in wild-type male mice. Wild-type males have ∼10-fold higher levels of GSTP expression in the liver than females, suggesting that hepatic GSTP in the wild-type males contributed to the formation of the nephrotoxic platinum–glutathione conjugate. In GstP1/P2 null mice the gender difference in toxicity was eliminated. Our data show that GSTP expression is a determinant in cisplatin-induced nephrotoxicity and its levels contribute to sex-dependent differences.     

Stimulatory action of verapamil on transport of organic acids in rat kidney cortical slices

Effect of verapamil on the organic acid transport was examined with rat kidney cortical slices. Verapamil increased the initial rate of p-aminohippurate (PAH) uptake, markedly enhanced its maximal accumulation under steady-state conditions and depressed the efflux of PAH. The accumulation of urate was also stimulated by verapamil. D600, a derivative of verapamil, showed the same effect as verapamil with regard to the stimulation of PAH accumulation. Kinetic studies revealed that verapamil resulted in an increase in the Vmax of the transport of PAH. The apparent Km remained essentially constant. The PAH accumulation was enhanced by aerobic preincubation of the slices with verapamil at 37 degrees C. On the other hand, the preincubation of the slices with verapamil at 0 degrees C did not alter the PAH accumulation. Oxygen consumption and ATP content in the slices and microsomal (Na+ + K+)adenosine triphosphatase activity were not affected by verapamil. Verapamil enhanced a Na+ gradient to some degree. however, the PAH accumulation in the presence of verapamil and ouabain was increased approximately the same amount as in the absence of these drugs regardless of the dissipation of the Na+ gradient by ouabain. These results suggest that verapamil accumulated by the slices stimulates the PAH uptake and its stimulatory action cannot be explained by the increase in the Na+ gradient and stimulation of (Na+ + K+)adenosine triphosphatase activity.     

The effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats

The effect of coadministration of fosfomycin (FOM) on nedaplatin-induced nephrotoxicity in rats was investigated for 6 days. FOM decreased nedaplatin-induced nephrotoxicity, as shown by reduced blood urea nitrogen (BUN), serum creatinine levels, and urinary excretion of N-acetyl--d-glucosaminidase (NAG). Further, there were fewer histopathological signs of nephrotoxicity in the groups treated with the combination of nedaplatin and FOM as compared with the nedaplatin-alone group. The concentration of nedaplatin was significantly lower in the renal cortex of rats treated with the combination of nedaplatin and FOM as compared with those treated with nedaplatin alone (p < 0.05). In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin.     

Oxytocin inhibits NADPH oxidase and P38 MAPK in cisplatin-induced nephrotoxicity

Oxidative stress significantly contributes to cisplatin (CP)-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of CP. The major biochemical pathway for reactive oxygen species (ROS) formation proceeds through O₂⁻ production, which is generated by NADPH oxidase, such oxidative stress can activate p38 MAPK to intensify the cytotoxic effect of CP. We mainly aimed to study the protective effect of oxytocin (OT) on CP-induced nephrotoxicity whereas; it was previously shown to have anti-inflammatory effects in different inflammation models. Administration of OT significantly decreased the gene expression of both NADPH oxidase and P38 MAPK, nitric oxide (NO), myloperoxidase (MPO), and TBARS, furthermore it increased the renal tissue levels of antioxidants; reduced glutathione (GSH), and superoxide dismutase (SOD). Histologically, OT reduced the monocellular infiltration as well as the tubular damage in CP-induced nephrotoxicity. In conclusion OT has a powerful antioxidant effect that can alleviate the CP-induced nephrotoxicity through inhibition of NADPH oxidase and P38 MAPK resulting in improvement of kidney functions.     

Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity

Adult male Sprague-Dawley rats maintained on a low sodium diet were administered 100 mg of cyclosporine per kg b.wt. per day s.c. for 4 to 10 days. Serum urea nitrogen was significantly elevated by day 4 and continued to rise, whereas serum creatinine was not elevated above control until day 10. Morphologic examination of perfusion-fixed kidneys from cyclosporine-treated rats revealed focal areas of tubular atrophy and interstitial fibrosis in the outer cortex and a generalized increase in interstitial cells in the outer medulla. No areas of acute tubular necrosis were identified. The effect of this dose of cyclosporine on renal hemodynamics was examined in conscious restrained rats. Renal blood flow, measured by microsphere injection, was 70% of control after four daily doses and remained near this level after eight daily doses. The glomerular filtration rate, measured by iodothalamate clearance, was 70% of control after four doses but fell to 34% of control after eight doses. [3H]Thymidine incorporation into renal DNA was used as a sensitive index of renal cell proliferation after cyclosporine administration (100 mg/kg/day). [3H]Thymidine incorporation was increased over control 3-fold in the outer cortex, 7-fold in the inner cortex and 11-fold in the medullary-papillary regions of the kidney after eight daily doses of cyclosporine. Histoautoradiographic examination of renal sections revealed an increase in the number of labeled nuclei in all three regions of the kidney from rats treated with cyclosporine. Morphometric analysis demonstrated that the majority of proliferating cells were located in the interstitium and not in renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of calcium channel agonists on renin release from rat kidney cortical slices

Inhibitory effects of calcium channel agonists such as Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate] and CGP 28392 [ethyl-4-(2-difluoromethoxyphenyl)-1,4,5,7-tetrahydro-2-methyl- 5-oxofuro-(3,4-b)-pyridine-3-carboxylate] on renin release were investigated, using rat kidney cortical slices. Bay K 8644 or CGP 28392 alone had no effect on renin release from the slices, whereas both compounds produced a concentration-dependent inhibition of the release in the presence of 15 mM potassium. The Bay K 8644-induced inhibitory action was more effective and potent than that seen with CGP 28392. Bay K 8644 caused a leftward shift of the dose-response curve of the potassium-induced decrease in renin release. In contrast, the dose-response relationships of the release to norepinephrine and methoxamine were not affected by Bay K 8644. The combination of the maximum effective doses of calcium channel agonists and norepinephrine exerted an apparent additive effect on the release of renin. The inhibitory effects of Bay K 8644 and CGP 28392 were attenuated in the presence of decreased extracellular calcium concentrations. Nifedipine and verapamil elicited a blocking action on the inhibition of renin release by Bay K 8644 or CGP 28392, in a concentration-dependent manner. Calmodulin antagonists, such as trifluoperazine and calmidazolium suppressed significantly the decreasing effect of Bay K 8644 or CGP 28392 on renin release from the slices.(ABSTRACT TRUNCATED AT 250 WORDS)     

The protective effect of eugenol against gentamicin-induced nephrotoxicity and oxidative damage in rat kidney

Gentamicin (GM) is an effective aminoglycoside antibiotic against life-threatening Gram-negative bacteria. However, a major complication of therapeutic doses of GM is nephrotoxicity, which is believed to be related to the generation of reactive oxygen species. The present study was therefore aimed to investigate the protective effect of eugenol, a phenolic antioxidant, on GM-induced nephrotoxicity in Sprague-Dawley rats. Intramuscular injection of rats with GM (80 mg/kg body weight/day) for six consecutive days induced marked acute renal failure, manifested by a sharp significant increase in serum urea and creatinine levels, along with a significant depletion of serum potassium level, compared to normal controls. GM-induced renal dysfunction was attributable to enhanced oxidative stress, as revealed by decreased superoxide dismutase and catalase activities, glutathione depletion and increased lipid peroxidation. Furthermore, kidney lactate dehydrogenase activity, as an indicator of hypoxia, was significantly increased by GM administration. Eugenol (100 mg/kg body weight, per os) administered four days before and six days concurrently with GM (80 mg/kg body weight, i.m.) restored normal renal functions and suppressed GM-induced oxidative stress and hypoxia. Light microscopical examination of the renal tissues of GM-treated animals demonstrated severe tubular necrosis at the cortex and increased cellular inflammatory processes. However, these alterations were considerably reduced with eugenol coadministration. In conclusion, eugenol ameliorates GM-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense.     

The protective effect of melatonin on cisplatin nephrotoxicity

Regarding the mechanisms of cisplatin (CP) nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione and production of lipid peroxide) is noticeable. This investigation elucidates the role of the antioxidant system in CP-induced nephrotoxicity and the nephroprotection by melatonin. Balb/c mice were injected i.p. with: 1) vehicle control; 2) a single dose of 6.5 mg/kg cisplatin, CP group; 3) melatonin in a dose of 10 mg/kg for 5 days after CP injection, CP-M group; 4) melatonin (10 mg/kg) for 5 days before and after CP injection, M-CP-M group; 5) melatonin in a dose of 10 mg/kg for 5 days, M group. Mice were sacrificed 5 days after CP injection to determine blood urea nitrogen (BUN) and serum creatinine. Renal lipid peroxidation (LP) and glutathione (GSH) levels were evaluated in kidney homogenates. Cisplatin administration resulted in increased LP, BUN and serum creatinine levels and decreased GSH levels, whereas melatonin reversed these effects. Morphological kidney damage was apparent in the CP group. Mentioned degeneration was moderate in the CP-M group, whereas morphological findings of the M-CP-M group implied a well preserved kidney tissue. When M was administered alone, it didn't cause any significant change in biochemical parameters. Both C and M groups exhibited similar biochemical and morphological findings in light and transmission electron microscope observation. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with CP.     

丙泊酚预处理对谷氨酸损伤大鼠脑组织的保护作用研究

目的 探讨丙泊酚预处理对谷氨酸(Glu)损伤大鼠脑组织的保护作用.方法 取出生10～ 15 dSD大鼠脑皮质切片进行培养,观察脑片形态学变化.将脑皮质切片分为空白对照组、Glu损伤组(1 mmol/L Glu 作用0.5 h)及丙泊酚预处理组(损伤前给予20 mg/L丙泊酚作用24 h),每组12个样本.镜下观察各组脑皮质切片的细胞病理改变及超微结构变化,计算乳酸脱氢酶(LDH)漏出率,免疫组化法检测胶质纤维酸性蛋白(GFAP)阳性表达并计数.结果 培养的脑皮质切片细胞形态完整、存活良好.苏木素-伊红(HE)染色、电镜及LDH检测结果显示:Glu损伤组脑皮质切片中神经元细胞损伤严重,形态不规则,胶质细胞增生、水肿,LDH漏出率较空白对照组明显增高[(68.5±2.0)％比(16.0±2.5)％,P＜0.01];丙泊酚预处理组脑皮质切片神经元细胞损伤减轻,细胞形态恢复,LDH漏出率较Glu损伤组明显减少[(38.5±2.4)％比(68.5±2.0)％,P＜0.05].免疫组化检测结果显示:Glu损伤组胶质细胞胞体肿胀,突起数量增多,GFAP阳性反应强,阳性细胞数量(个/HP)较空白对照组显著增多(50±5比10±3,P＜0.01);丙泊酚预处理组胶质细胞形态有所恢复,细胞突起细长,GFAP阳性反应减弱,阳性细胞数量较Glu损伤组明显减少(30±4比50±5,P＜0.05).结论 丙泊酚预处理对Glu损伤的SD大鼠脑皮质神经元具有保护作用.     

Chemical induction of p-aminohippuric acid transport in renal cortical slices from adult and immature rabbits

Fourteen-day-old and adult rabbits received procaine penicillin G (PEN), 450,000 U/kg s.c., every 12 hours for a total of four doses or phenobarbital-Na (PHB), 40 mg/kg i.p., once daily for 3 days, or 3-methylcholanthrene (3MC), to 20 mg/kg i.p., once daily for 3 days. Twenty-four hours after the final treatment the animals were killed and the kidneys were removed for analysis of enzymatic activities and p-aminohippuric acid (PAH) transport capability. PEN, PHB and 3MC had no effect on PAH transport in slices from adult rabbits but significantly increased PAH transport in slices from 14-day-old rabbits. Aryl hydrocarbon hydroxylase activity was enhanced in both adult and 2-week rabbit kidneys by 3MC while biphenyl-4-hydroxylase activity was enhanced in 2-week and adult rabbit kidneys by PHB. Epoxide hydratase was unaffected by all three treatments. 3MC increased gluthione-S-aryltransferase (ligandin) activity in 2-week but not adult kidneys. Induction of PAH transport in 14-day-old rabbits does not appear to be related to stimulation of microsomal enzymes or glutathione-S-aryltransferase activity in the kidney. Although they are not considered to be substrates for renal organic anion transport, PHB and 3MC resemble PEN in their ability to induce PAH transport in renal cortex of immature but not adult rabbits.     

The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats

The effect of coadministration of fosfomycin (FOM) on glycopeptide antibiotic-induced nephrotoxicity for 3 days was investigated in rats. To induce nephrotoxicity in a short time, gentamicin (GM) was also coadministered. In the present study, FOM decreased glycopeptide antibiotic-induced nephrotoxicity as shown by reduced urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) as well as fewer histopathological signs of nephrotoxicity in the groups treated with the combination of glycopeptide and FOM as compared with a glycopeptide alone. In addition, the higher the dose of FOM, the more it decreased urinary NAG levels, suggesting that the role of FOM in alleviating nephrotoxicity is dose dependent. The accumulation of teicoplanin and vancomycin was significantly lower in the renal cortex of rats treated with the combination of glycopeptide antibiotics and FOM as compared with glycopeptide antibiotics alone (P < 0.05). In conclusion, the concomitant administration of FOM and glycopeptide antibiotics may help to achieve a chemotherapeutic stra-tegy that reduces the nephrotoxic effects of glycopeptide antibiotics. Received: October 13, 2000 / Accepted: August 26, 2001