RESUMEN
The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.
Asunto(s)
Deferoxamina/uso terapéutico , Cardiopatías/prevención & control , Hepatopatías/prevención & control , Insuficiencia Renal/prevención & control , Análisis de Varianza , Animales , Quelantes/efectos adversos , Quelantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas , Deferoxamina/efectos adversos , Doxorrubicina , Corazón/efectos de los fármacos , Cardiopatías/inducido químicamente , Cardiopatías/patología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Hepatopatías/patología , Masculino , Ratas , Ratas Wistar , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/patologíaRESUMEN
The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.
Asunto(s)
Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Desoxicitidina/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Riñón/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Platino (Metal)/metabolismo , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Desoxicitidina/análogos & derivados , Interacciones Farmacológicas , Glutatión/efectos de los fármacos , Glutatión/metabolismo , Riñón/patología , Peroxidación de Lípido/fisiología , Masculino , Ratas , Ratas Wistar , GemcitabinaRESUMEN
BACKGROUND: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. METHODS: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. RESULTS: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. CONCLUSIONS: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.
Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Diabetes Mellitus Experimental/tratamiento farmacológico , Enfermedades Renales/inducido químicamente , Animales , Área Bajo la Curva , Creatinina/sangre , Masculino , Conejos , Urea/sangreRESUMEN
This study aimed to evaluate the protective effect of rebamipide (free radical scavenger) against the nephrotoxic effect induced by cisplatin in normal rats. Twenty-four male Wister albino rats were divided equally into four groups: control, rebamipide, cisplatin and cisplatin plus rebamipide-treated groups. Nephrotoxicity was induced with single intravenous (i.v.) cisplatin dose of 6 mg kg(-1)and measured through the estimation of kidney weight, serum albumin (Alb), serum creatinine (Cr), blood urea nitrogen (BUN), kidney glutathione (GSH) and malondialdehyde (MDA) production. In the cisplatin-treated group the kidney weight as a percent of the total body weight, serum Alb, serum Cr, BUN, GSH content and MDA amount were: 0.61+/-0.054%, 2.84+/-0.24 g dl(-1), 2.99+/-0.10 mg dl(-1), 147.08+/-7.46 mg dl(-1), 3.11+/-0.238 micromol g(-1)and 1449. 09+/-127.36 nmol g(-1), respectively. All the previous changes were significantly (P<0.01) different from the corresponding values in the control group. In addition, histopathological examination of the kidney tissue revealed degenerative cellular material and apoptotic tubular cells were seen in the renal tubules. Rebamipide treatment (140 mg kg(-1), i.p.) for 1 week ameliorated all the previous changes and the results recorded for the cisplatin plus rebamipide-treated group were: 0.45+/-0.035%, 4.17+/-0.091 g dl(-1), 1.37+/-0.209 mg dl(-1), 72.25+/-5.14 mg dl(-1), 5.063+/-0.269 micromol g(-1)and 560.23+/-21.98 nmol g(-1)for the previous tests, respectively. Furthermore, significant improvement in the kidney histopathology was observed. The results of this study clearly revealed that rebamipide protected the kidney against the nephrotoxic effect of cisplatin. These results suggest that lipid peroxidation is not the only mechanism by which cisplatin induced nephrotoxicity. More investigations are needed to confirm the effect of rebamipide and at the same time to elucidate the exact mechanism by which cisplatin induces nephrotoxicity.
Asunto(s)
Alanina/análogos & derivados , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Depuradores de Radicales Libres/farmacología , Riñón/efectos de los fármacos , Quinolonas/farmacología , Alanina/farmacología , Animales , Glutatión/análisis , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratas , Ratas WistarRESUMEN
The pharmacokinetics of two commonly used anticancer drugs, methotrexate (MTX) and 5-fluorouracil (5-FU), were investigated in normal and bilharzial-infested mice. Liver glucose-6-phosphatase activity and antipyrine clearance were used as parameters of liver function. Liver glucose-6-phosphatase activity was significantly reduced in bilharzial-infested mice compared with the normal controls. Bilharzial infestation caused a significant reduction in the elimination (beta) and clearance rate (Cl) of antipyrine, whereas its elimination half-life (t1/2 beta) was increased in comparison with the normal controls. A similar pattern was also obtained after MTX and 5-FU administration in bilharzial mice, compared to controls. These results indicate that hepatic bilharziasis causes a significant reduction in the hepatic clearance and elimination of MTX and 5-FU, whereas their areas under the concentration-time curve were significantly increased. These findings may have to be considered in the treatment of bilharzial cancer patients.