Protective effect of L-carnitine versus amifostine against cisplatin-induced nephrotoxicity in rats
Department of Medical Oncology, Faculty of Medicine, Trakya University, Edirne, Turkey. Medical Oncology
(Impact Factor: 2.63).
12/2010; 28 Suppl 1(S1):S690-6. DOI: 10.1007/s12032-010-9746-2
We aimed to compare the protective effect of L-carnitine (CAR) and amifostine (AMF) against cisplatin (CDDP)-induced nephrotoxicity through biochemical markers and histopathological evaluation. Fifty-seven Wistar albino male rats were randomly classified into six groups, which were AMF+CDDP (n = 11; 200 mg/kg AMF 30 min prior to 7 mg/kg CDDP), CAR+CDDP (n = 11; 300 mg/kg CAR 30 min prior to 7 mg/kg CDDP), CDDP (n = 11; 1 mL/kg isotonic saline 30 min prior to 7 mg/kg CDDP), AMF (n = 8; 200 mg/kg AMF alone), CAR (n = 8; 300 mg/kg CAR alone), and control (n = 8; 1 mL/kg isotonic saline alone). All drugs were given intraperitoneally. Five days after medication, animals were killed, and samples of blood and kidney tissues were collected for biochemical and histopathological evaluation. The serum urea level was highest in AMF+CDDP group among CDDP-applied groups without statistical significance (median, range: 88, 56-21 mg/dL; P > 0.05). There was no statistical significance among CDDP-applied groups in terms of creatinine level (P > 0.05). In the AMF+CDDP group, the median glomerular, tubular, and tubulointerstitial inflammatory damage scores were significantly higher than the other CDDP-applied groups (P < 0.001). The difference between CAR+CDDP and CDDP groups was not statistically significant in terms of renal damage scores. AMF+CDDP group had significantly higher median total nephrotoxicity score than all the other groups (P < 0.001). To conclude, AMF or CAR has no protective effect on CDDP-induced nephrotoxicity. Furthermore, our findings suggest that application of AMF before CDDP may enhance CDDP-induced nephrotoxicity histopathologically.
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- "There are many experimental studies reporting the protective effect of carnitine against the toxicity of irradiation and antineoplastic agents including doxorubicin and cisplatin (23,24,25,26,27,28,29,30,31,32). In the studies investigating the potential renoprotective effect of carnitine against cisplatin-induced nephrotoxicity, it has been demonstrated that carnitine successfully prevented renal dysfunction and injury (23,24,25) But, a recent study concludes that neither carnitine nor amifostin has protective effect against cisplatin induced nephrotoxicity (33). Carnitine doses of 100-500 mg/kg were used in various types of experimental studies (23). "
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ABSTRACT: Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake.
Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1) Control (saline; 5 ml/kg intraperitoneally); 2) L-carnitine (CAR; 300 mg/kg intraperitoneally); 3) Amifostine (AMI; 200 mg /kg intraperitoneally); 4) Cisplatin (CIS;7 mg/kg intraperitoneally); 5) Cisplatin plus L-carnitine (CIS + CAR); 6) Cisplatin plus amifostine (CIS + AMI). L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g) was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA) and reduced glutathione (GSH) in kidney tissue homogenates.
Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01), in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002). A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue.
Conclusion: The results showed that L-carnitine significantly attenuates the cisplatin-induced nephrotoxicity as amifostin.
Conflict of interest:None declared.
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Ablative radioiodine-131 ((131)I) therapy is used in the standart treatment procedure of thyroid carcinoma and procedures using (131)I represent the majority of Nuclear Medicine therapeutic procedures. The principal route of (131)I excretion after the administration of (131)I is the urine. Amifostine is an organic thiophosphate ester prodrug and the kidney concentrations of the active metabolite WR-1065 are about 100 times higher than tumour concentrations. To our knowledge, there is no published data in literature presenting acute effect of radioiodine on renal tissue during high dose I-131 radioiodine treatment (RIT). Additionally, it is not known whether amifostine takes role in this process.
Materials and methods:
In this study, 50 healthy female Wistar albino rats, weighing 200-250 g and averaging 16 weeks old were utilised. The rats were randomly divided into ten groups. 1- Sham group (n=5), 2- Amifostine group (n=5): rats pretreated with 1 cc amifostine (200 mg/kg) by intraperitoneal injection, 3- Radioactive iodine first day group (RI-1) (n=5): rats treated with 1 cc oral 185 MBq radioactive iodine-131 and sacrification performed after 1(st) day, 4- Amifostine + Radioactive iodine first day group (A+RI-1) (n=5): rats pretreated with amifostine (200 mg/kg) by intraperitoneal injection and rats treated with 5mCi radioactive iodine-131 and sacrification performed after 1(st) day. 5- Radioactive iodine third day group (RI-3) (n=5), 6- Amifostine + Radioactive iodine third day group (A+RI-3) (n=5), 7- Radioactive iodine fifth day group (RI-5) (n=5), 8- Amifostine + Radioactive iodine fifth day group (A+RI-5) (n=5), 9- Radioactive iodine seventh day group (RI-7) (n=5) and 10- Amifostine + Radioactive iodine seventh day group (A+RI-7) (n=5). The renal cast formation and tubular damage are evaluated by a pathologist in a blinded manner.
Ablative radioiodine-131 therapy induced renal tubular damage was significantly higher in the radioactive iodine fifth day group (RI-5) when compared with the Sham group (p=0.01) and Amifostine group (p=0.01).
A marked ablative radioiodine-131 induced renal toxicity was seen at fifth day of the therapy after a single RIT application and the main histopathological change was tubular damage. Amifostine have protective effects against ablative radioiodine-131 therapy and this effect is significant at fifth day of the therapy.
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