Protective effect of fosfomycin against renal accumulation of aminoglycoside antibiotics

Male Wistar rats received 20 mg/kg/day of amikacin (AMK) with or without 200 mg/kg/day of fosfomycin (FOM) for 5 days. Accumulation of AMK in renal lysosome-containing fraction was inhibited by FOM. FOM was reported to interfere with the nephrotoxic properties of aminoglycosides. Our observation supports the finding.     

葡甲胺对顺铂所致大鼠肾毒性的预防作用

目的　研究葡甲胺 (N MG)对顺铂 (CDDP)所致大鼠肾毒性的预防作用及其可能机制。方法　大鼠1次腹腔注射 5mg/kgCDDP动物模型 ,于CDDP处理前 1h经口给予N MG预处理。检测指标包括血尿素氮BUN、尿蛋白、尿铂 (Pt) ,肾组织匀浆中NOS、NO、MDA、SOD及肾组织Pt含量 ,同时观察抗肿瘤活性。结果　给药后第 3、5天N MG预处理组可明显预防CDDP所致大鼠肾功能损害 ,降低肾组织中NOS、NO、及MDA含量 ,增加SOD活性 (P <0 0 5或P <0 0 1)。另外 ,给药后第 3天尿Pt(0 .42 5 μg/mgCr)排泄量非常显著地高于CDDP组(0 2 45 μg/mgCr,P <0 0 1) ,肾组织Pt含量于给药后第 3、5天显著低于CDDP组 (P <0 0 5 )。N MG预处理对荷瘤小鼠的肿瘤抑制率与CDDP组无显著性差异。结论　N MG预处理能明显预防CDDP所致大鼠的肾损害 ,其预防作用机制可能是N MG促进Pt经尿排出 ,并减少了肾组织Pt蓄积 ,从而CDDP产生的自由基减少 ,脂质过氧化程度减轻。N MG对CDDP抗肿瘤活性无明显影响。     

Use of cultured renal epithelial cells for the study of cisplatin toxicity

The nephrotoxicity of cisplatin was evaluated in an in vitro system with an established cell line of normal rat kidney, NRK-52E. Leakage of enzymes from the cells into the culture medium increased when they were exposed to 1 microM of cisplatin for 72 hr. The level of lipid peroxides increased in the cells after 48 hr of exposure to cisplatin; the increase was more rapid than the enzyme leakage. This culture system can be used to evaluate drug-induced nephrotoxicity and its mechanism.     

Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin

Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK₁). Viability of LLC-PK₁ cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100–400 μM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10–25 μM and reaching a plateau between 50 and 100 μM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100–500 μM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 μM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role. Received: 26 January 1998 / Accepted: 16 March 1998     

Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats

The nephrotoxicity of vancomycin and cisplatin and the protective effects of fosfomycin and imipenem-cilastatin on renal function have been studied in rats. The renal clearance of vancomycin after the induction of renal dysfunction was also evaluated by calculating the glomerular filtration rate (GFR) and its secretory clearance. Plasma concentrations of creatinine and urea nitrogen increased dose-dependently after vancomycin injection. No such increases were observed after co-treatment with fosfomycin or imipenem-cilastatin. Changes of N-acetyl-beta-D-glucosaminidase activity in the urine of vancomycin-treated rats were not remarkable compared with those in cisplatin-treated animals. The reduced renal clearance of vancomycin in rats with acute renal failure induced by vancomycin was because of a decrease in both GFR and secretory clearance. However, the changes in GFR and secretory clearance were not proportional-the change in GFR was more pronounced than that of secretory clearance in the experimental groups. In addition, the renal clearance of vancomycin was maintained at the control level after co-administration of fosfomycin or imipenem-cilastatin with vancomycin. These results suggest that vancomycin impairs glomerular filtration more markedly than renal tubular function as compared with cisplatin. Co-administration with fosfomycin or imipenem-cilastatin confers significant protection against the nephrotoxic effects of vancomycin.     

大黄素对顺铂所致人胚肺成纤维细胞毒性的作用

目的　从细胞水平研究大黄素对顺铂引起人胚肺成纤维细胞毒性的效应。方法　采用MTT法检测细胞毒性 ,荧光法检测细胞氧化性损伤。结果　WI 3 8细胞经大黄素和顺铂同时处理 2 2h后 ,大黄素 (3 0mg L)可明显减轻顺铂引起的细胞毒性 ,其IC50 值由 (16± 3 )mg L增加至 (3 4± 6)mg/L ;可使顺铂引起的细胞内氧自由基水平和细胞内脂质过氧化物水平的升高更加明显 ,使顺铂引起的还原性谷胱甘肽含量的下降更加明显。结论　大黄素可对抗顺铂所致WI 3 8细胞毒性 ,但它不能减少顺铂对细胞的氧化性损伤作用 ,大黄素的预防作用与抗氧化机制无关。     

An effect of fosfomycin on the pharmacokinetics of amikacin

The effect on amikacin pharmacokinetics by fosfomycin previously or simultaneously administered via the intraperitoneal, intramuscular, or oral route was studied in the rats. Absorption of amikacin from the peritoneal cavity was prolonged by co-administered fosfomycin. High serum fosfomycin levels prevented renal lysosomal accumulation of amikacin, possibly because of the interference of urinary fosfomycin with the endocytosis of proximal tubular cells. These characteristics may explain the effect of fosfomycin in protecting against amikacin nephrotoxicity.     

Effects of silymarin-loaded amphiphilic chitosan polymeric micelles on the renal toxicity and anticancer activity of cisplatin

This research aimed to evaluate the effects of silymarin (SM)-loaded polymeric micelles (PMs) on the renal toxicity and anticancer activity of cisplatin. Amphiphilic chitosan derivatives were employed to develop SM-loaded PMs. The permeation across an intestinal membrane, cytotoxicity, and renal toxicity of cisplatin during the treatment were evaluated. The SM-loaded PMs had small particle sizes (326–336?nm), negative surface charge, high entrapment efficiency (47–70%), and demonstrated pH-sensitive release. Rapid drug release was obtained at pH 7.4 (81–87% in 4?h). The SM-loaded PMs exhibited higher flux than free SM. Moreover, the pretreatment of SM (50–100?μg/mL)-loaded PMs increased the killing efficacy of cisplatin on the cancer cells. The renoprotective effect was witnessed (p?<?0.05) on the cells pretreated with SM-loaded benzyl-functionalized succinyl chitosan (BSC) PMs compared with those treated with only cisplatin, which the % cell viability increased from 29% to 82% and 96% for the PMs with SM concentration of 50 and 100?μg/mL, respectively. Moreover, the reduction in cell apoptosis and necrosis induced by cisplatin has been observed. In conclusion, SM-loaded BSC PMs could improve the bioavailability of SM, enhance the therapeutic effect, and protect renal damage during the treatment with cisplatin.     

The clinical effect of fosfomycin on cystitis

Fosfomycin (FOM) is an antibiotic which inhibits phospho(enol)pyruvic acid transferase. Fifty-five patients with cystitis were treated with the drug for 7 days, at oral doses of 1 g for 3 times a day. Adult females under 70 years of age, visiting the clinic within 2 weeks after the onset, were classified as cases with typical simple cystitis with confirming the bladder irritability, pyuria and bacteriuria. The treatment was effective for 95.0% of these cases. Two cases with atypical cystitis caused by Klebsiella pneumoniae poorly responded to the drug.     

Stimulatory effect of cisplatin on production of lipid peroxidation in renal tissues

Cisplatin (cis-diamminedichloroplatinum II), an anticancer chemotherapeutic agent with the dose-limiting side effect of nephrotoxicity, caused a statistically significant increase in lipid peroxidation, monitored by measuring the production of malondialdehyde, in rat kidney 72 hr after injection. Treatment of rats beforehand with the antioxidant alpha-tocopherol or N-N'-diphenyl-p-phenylenediamine (DPPD) effectively decreased such peroxidation. DPPD was a more effective inhibitor than alpha-tocopherol, since it is known for its ability to scavenge free radicals more powerfully. The ability of renal cortical slices to accumulate p-aminohippurate (PAH) was examined as a biochemical parameter that would change in nephrotoxicity. The ability to accumulate PAH by the incubated slices decreased 72 hr after administration of cisplatin. The pretreatment with DPPD prevented the decrease in PAH accumulation in the slices from rats treated with cisplatin. Structural changes of the renal proximal tubule caused by cisplatin, analyzed in a transmission electron microscope, were also prevented by the pretreatment with DPPD. The results suggest that cisplatin affects renal tissues in which free radicals generated by cisplatin may interact with membrane lipids to cause the production of lipid peroxidation, which affects both cellular structure and function.     

谷胱甘肽对顺铂致大鼠肾小管上皮细胞毒性的影响

目的 探讨顺铂对不同年龄大鼠肾小管上皮细胞的毒性及谷胱甘肽(GSH)对其影响。方法 从不同年龄的雄性大鼠分离的肾小管上皮细胞接种于96孔培养板，培养24h后加入一系列浓度的顺铂，或在加入顺铂前16和4h。分别加入GSH合成抑制剂：BSO和GSH的前体物半胱氨酸，再培养24h后用MTT方法检测细胞存活率。结果 顺铂对5、2月龄和3周龄大鼠肾小管上皮细胞半数抑制浓度(IC50)分别为243．42、178．16和159．06μmol／L；BSO能使3组IC50分别降低到1．62、1．30和1．47μmol／L，而半胱氨酸则可使3组IC50均大于5000μmol／L。结论 顺铂对不同年龄大鼠肾小管上皮细胞均具有明显的毒性，BSO和半胱氨酸可分别增强和减弱顺铂的毒性，间接证明细胞内GSH对顺铂所致大鼠肾小管上皮细胞毒性有保护作用。     

顺铂药效和毒性作用的依时特征

目的:探索顺铂药效和毒性依时特征.方法:通过监测S180实体瘤小鼠的瘤重、外周血尿素氮和LD50评价昼夜不同时间顺铂给药的反应.结果:顺铂凌晨2:00给药作用强、毒性大,晚上18:00给药毒性小,作用弱.结论:顺铂的药效和毒性反应同步运行,对于小鼠晚上给药不良反应小,提示顺铂临床用药应避开毒性反应最大的时间.     

Vitamin C suppresses the cisplatin toxicity on blood platelets

The effects of vitamin C on the oxidative stress in blood platelets induced by cisplatin were studied. In the presence of vitamin C we measured in blood platelets the production of thiobarbituric acid reactive substances (TBARS), the generation of superoxide radicals (O2*-), other reactive oxygen species (H2O2, singlet oxygen and organic radicals) and catalase activity. Vitamin C at a low concentration (0.1 mM), like cisplatin (20 microM), induced blood platelet oxidative stress: an increase of TBARS, chemiluminescence and generation of superoxide radicals. After treatment of blood platelets with vitamin C at a high concentration (3 mM), chemiluminescence (p>0.05), the levels of O2*- (p<0.01) and TBARS (p<0.002) were reduced. We have shown that vitamin C at a high concentration (3 mM) had a protective effect against oxidative stress in platelets caused by cisplatin (20 microM). It diminished platelet lipid peroxidation and reactive oxygen species generation induced by cisplatin. In the presence of vitamin C, the catalase activity was suppressed.     

卡维地洛对顺铂致大鼠急性肾衰竭的预防作用

目的观察卡维地洛对顺铂致大鼠急性肾衰竭的影响,并初步探讨其作用机制。方法Wistar大鼠给予卡维地洛5,15和30mg.kg-1,ig,每日1次,连续6d,于d3单次ip顺铂10mg.kg-1。于d6测定血清尿素氮(BUN)和肌酐(SCr)含量,尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)活性,肾组织丙二醛(MDA)含量、超氧化物歧化酶(SOD)及谷胱甘肽过氧化物酶(GSH-Px)活性;苏木素-伊红染色观察肾脏病理改变。结果顺铂组大鼠血清BUN和SCr含量升高,尿NAG活性升高,肾组织MDA水平增加,SOD和GSH-Px水平降低,肾脏病理改变明显。预先给予卡维地洛5和15mg.kg-1可明显逆转上述改变,但加大剂量至30mg.kg-1时效应反而降低。结论在一定剂量范围内,卡维地洛可能通过减少活性氧产生,增加抗氧化酶活性而减轻顺铂所致急性肾衰竭。     

Toxic effects of systemic cisplatin on rat eyes and the protective effect of hesperidin against this toxicity

Context: In the present study, cisplatin (CP) induced eye toxicity and the beneficial effect of hesperidin (HP) was investigated.

Methods: Twenty-eight rats were equally divided into four groups; the first group was kept as control. In the second and third group, CP and HP were given at the doses of 7?mg/kg and 50?mg/kg/d, respectively. In the fourth group, CP and HP were given together at the same doses. Tissue samples were collected on day 14 of CP treatment.

Results: The results demonstrated that CP caused a significant increase in thiobarbituric acid reactive substances (TBARS) levels and decrease of glutathione levels and antioxidant enzyme activity (catalase, superoxide dismutase and glutathione peroxidase) in eye tissues compared to other groups, HP prevented these effects of CP. Besides, CP led to histopathological damage in the retina and cornea. On the other hand, HP treatment prevented histopathological effects of CP.

Conclusion: CP had severe dose-limiting toxic effects and HP treatment can be beneficial against the toxic ocular effects of CP. Thus, it appears that co-administration of HP with CP may be a useful approach to attenuate the negative effects of CP on the eye.     

In vivo toxicity of cisplatin and carboplatin on the Leydig cell function and effect of the human choriogonadotropin

In order to characterize the respective toxicity of cisplatin (CDDP) and carboplatin (CBDCA) on the male reproductive system, we have investigated their in vivo effects on the steroidogenesis function of rat leydig cells. Animals were treated at the respective LD50 of platin compounds, and we analyzed plasmatic testosterone level, microsomal cytochrome P-450 and platinum concentrations in the testis. CDDP induces a dramatic change in both the testosterone level and the microsomal cytochrome P-450 concentration. In contrast, CBDCA was found to be less toxic than CDDP, probably due to its different accumulation at the testis level. We also investigated the potential action of human chorionic gonadotropin which allows a full restoration of the steroidogenesis function.     

Preventive effect of flavangenol on ischemia/reperfusion-induced acute renal failure in rats

The effects of flavangenol on ischemia/reperfusion-induced acute renal failure (ARF) in rats were examined. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured. Renal function in ARF rats markedly decreased at 1 d after reperfusion. Pre-ischemic treatment with flavangenol (3-30 mg/kg, i.v.) attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damage, such as tubular necrosis and proteinaceous casts in tubuli, which were also significantly suppressed by the administration of flavangenol. These findings suggest that flavangenol supplementation may be a promising candidate for treatments to improve the ischemia/reperfusion-induced renal injury.     

Preventive effect of L-carnosine on ischemia/reperfusion-induced acute renal failure in rats

We investigated the effect of L-carnosine (beta-alanyl-L-histidine) on ischemic acute renal failure in rats. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated acute renal failure rats markedly decreased at 1 day after reperfusion. Pre-ischemic treatment with L-carnosine dose-dependently (1, 10 microg/kg, i.v.) attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated acute renal failure rats revealed severe renal damage, which was significantly suppressed by pre-treatment with L-carnosine, at each dose given. In untreated acute renal failure rats, norepinephrine concentrations in renal venous plasma remarkably increased within 2 min after reperfusion and thereafter rapidly decreased. Pre-ischemic treatment with L-carnosine at a dose of 10 microg/kg significantly depressed the elevated norepinephrine level. On the other hand, although the higher dose of L-carnosine given 5 min after reperfusion tended to ameliorate the renal dysfunction after reperfusion, the improvement was moderate compared with those seen in pre-ischemic treatment. These results indicate that L-carnosine prevents the development of ischemia/reperfusion-induced renal injury, and the effect is accompanied by suppression of the enhanced norepinephrine release in the kidney immediately after reperfusion. Thus, the preventing effect of L-carnosine on ischemic acute renal failure is probably through the suppression of enhanced renal sympathetic nerve activity induced by ischemia/reperfusion.     

The deleterious effect of buthionine sulfoximine, a glutathione-depleting agent, on the cisplatin toxicity in mice

Pretreatment of buthionine sulfoximine (500 mg/kg, i.p., BSO), a potent glutathione-depleting agent, markedly increased the lethality and nephrotoxicity of cisplatin. These results suggest that a reactive electrophilic intermediate may be involved in the mechanism of cisplatin nephrotoxicity and moreover, that renal glutathione may play a protective role against cisplatin-induced nephrotoxicity.