- Email: [email protected]
The effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats
J Infect Chemother (2005) 11:14–17 DOI 10.1007/s10156-004-0361-z
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2005
ORIGINAL ARTICLE Yuji Yoshiyama · Kazue Yamaguchi · Kazuhiro Matsuo Minoru Kurokawa · Motoko Kanke
The effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats
Received: July 9, 2004 / Accepted: November 11, 2004
Abstract 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-β-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.
cisplatin-resistant human leukemia cells in one report.5 In preclinical investigations, the antitumor activity of nedaplatin has been similar to or greater than that of cisplatin, with evidence of reduced nephrotoxicity.2,5,6 One of the side-effects of platinum analogues is nephrotoxicity. Nedaplatin is a less toxic alternative to cisplatin, particularly with reference to nephrotoxicity.7–9 It has been reported that fosfomycin (FOM) protects the kidneys by stabilizing the lysosomal membrane and inhibiting drug uptake by renal tubular epithelial cells.10–13 The aim of the present study was to examine the effect of FOM on the nephrotoxicity induced by nedaplatin in rats.
Key words Nedaplatin · Nephrotoxicity · Fosfomycin · Rats
The experimental protocol was approved by the Committee for the Institutional Care and Use of Animals at Kyoritsu University of Pharmacy. Adult male Wistar rats (weighing 160–180 g) were used. The animals were housed in a light-controlled room (lights on from 08:00 to 20:00), at a room temperature of 24 1°C and humidity of 60 10%, for 1 week. They were acclimated for 1 week, and they had free access to food and water throughout the experiment. Nedaplatin (Shionogi, Osaka, Japan) and FOM (Meiji Seika Kaisha, Tokyo, Japan) were used for the treatment. The following doses were chosen based on data from previous studies. For 6-day administration, drugs were administered once daily to the following three groups: group A, nedaplatin 10 mg/kg saline; group B, FOM 0.5 g/kg saline; and group C, nedaplatin 10 mg/kg FOM 0.5 g/kg. FOM was first injected intraperitoneally. After an interval of approximately 30 min to allow FOM to take effect, nedaplatin was injected intraperitoneally on the contralateral side. The rats were randomly assigned to the experimental groups (five rats each) and were housed individually in metabolic cages to collect urine. Urine samples were collected 24 h prior to drug administration and every 24 h
Introduction Nedaplatin (cis-diammine glycolate platinum) is a platinum analogue with a spectrum of antitumor activity similar to that of cisplatin.1,2 The mechanism of cytotoxicity appears to be similar to that of cisplatin and carboplatin (i.e., effects on DNA intrastrand and interstrand cross links).3 In vitro, nedaplatin has demonstrated partial cross-resistance to cisplatin and other platinum compounds in various solid tumors.2,4 However, significant activity was observed against
Y. Yoshiyama (*) · M. Kanke Division of Clinical Pharmacy, Kyoritsu University of Pharmacy, 1-15-30 Shibakoen, Minato-ku 105-8512, Tokyo, Japan Tel./Fax 81-3-5400-2667 e-mail: [email protected] K. Yamaguchi · K. Matsuo · M. Kurokawa Department of Pharmacy, Toho University Omori Hospital, Tokyo, Japan
Materials and methods
15
thereafter. Urine volumes were measured, and the urine samples were centrifuged at 3000 g for 10 min. The N-acetylβ-d-glucosaminidase (NAG) activity of the supernatant was determined, and was expressed as international units per total urine volume collected over 24 h. Urinary NAG activity is one sensitive indicator of nedaplatin-induced nephrotoxicity.14 Under anesthesia, the rats were killed by exsanguination 24 h after the last injection of drugs. Blood samples were collected from the inferior vena cava and then centrifuged, and the serum was frozen (80°C) for the determination of blood urea nitrogen (BUN) and serum creatinine levels. The kidneys were removed for the determination of tissue nedaplatin concentrations. The renal cortical accumulation of nedaplatin was measured by atomic absorption spectrometry. Histopathological samples were prepared for standard hematoxylin-eosin (H&E) and periodic acid Schiff (PAS) staining and were evaluated under a microscope. Sections came from three different regions of the renal cortex of each rat, and five rats per group were used. Statistical analysis of the differences between groups with FOM and without FOM was performed using Student’s t-test. Data on the effects of FOM on urinary NAG levels were first analyzed by analysis of variance, and group comparisons were made using the Fisher protected least significant difference post-hoc test.
Fig. 1. Time course of urinary N-acetyl-β-d-glucosaminidase (NAG) activity in rats treated with nedaplatin 10 mg/kg for 6 days. Nedaplatin was administered without fosfomycin (FOM) and with FOM 0.5 g/kg. Each point represents the mean and SD for five rats.* Significant difference between groups with FOM and without FOM (p 0.05)
Results Urine NAG levels were significantly higher in the group treated with nedaplatin alone than in the groups given FOM alone or nedaplatin with FOM (Fig. 1). In other words, the extent of increase in urine NAG activity was significantly smaller when FOM was given with nedaplatin as compared with nedaplatin alone (p 0.05). The serum creatinine and BUN levels of each group are presented in Fig. 2. Significantly higher levels of serum creatinine and BUN were observed in the group that received nedaplatin alone compared with the groups treated with FOM alone or nedaplatin with FOM. This suggests that the concomitant administration of these two drugs is less toxic than nedaplatin alone. The effects of FOM on the concentration of nedaplatin in the renal cortex are given in Fig. 3. After 6 days of administration, the concentration of nedaplatin was significantly lower in the renal cortex of rats that received the nedaplatin and FOM combination compared with those that received nedaplatin alone (p 0.05). Histopathological analysis of the renal tissue showed tubular necrosis (Fig. 4a), degeneration, vacuolation of proximal tubular cells, and cell infiltration in the interstitum in the group given 10 mg/kg nedaplatin alone. The group that received FOM alone showed no significant change in kidney histology. In contrast, the above abnormalities were significantly reduced, especially the number of necrosed cells, when FOM was administered concomitantly with nedaplatin (Fig. 4b).
Fig. 2. a Serum creatinine levels and b blood urea nitrogen levels in rats treated with nedaplatin 10 mg/kg for 6 days. Conditions were the same as those described in Fig. 1. *p 0.05, FOM() vs FOM()
16
Discussion Data from our laboratory have shown that some antibiotics, including FOM, reduce the nephrotoxic potential of antibiotics when administered concomitantly.15–17 In this study, we investigated the effect of 6-day coadministration of FOM on nedaplatin-induced nephrotoxicity in rats. The study showed that FOM protected against nedaplatin-induced nephrotoxicity, as shown by lower urinary excretion of NAG and lower BUN and serum creatinine levels, as well as fewer histopathological signs of nephrotoxicity in the groups treated with the nedaplatin FOM combination as compared the group treated with nedaplatin alone. Because the ability of FOM to reduce nephrotoxicity is reportedly due to its inhibition of the uptake of concomitantly administered drugs by renal tubular epithelial cells and to its stabilization of lysosomal membranes, we
determined drug concentrations in the renal cortex in this investigation.10,11 During the 6-day experimental period, coadministration of FOM resulted in a significant decrease in drug concentrations in the renal cortex in the groups that received nedaplatin. Thus, the uptake of nedaplatin by the renal cortex was inhibited by FOM. Kurebe et al.18 found that coadministration of FOM with cisplatin in rats resulted in less nephrotoxicity compared with cisplatin monotherapy. They suggested that this was due to the stabilization of lysosomal membranes and to the inhibition of drug uptake by renal tubular epithelial cells. We also demonstrated, in this study, that FOM decreased the incidence of nephrotoxicity induced by nedaplatin. FOM protects against cisplatin-induced nephrotoxicity and does not inhibit tumoricidal activity in vitro,19 and FOM has been used successfully in clinical trials to ameliorate cisplatin-induced nephrotoxicity.20 The use of nephroprotective agents could potentially allow increased doses of cisplatin. The effect of FOM against nedaplatin-induced nephrotoxicity observed in this study might be beneficial in the treatment of patients. There may be several mechanisms involved in the inhibition of nephrotoxicity by FOM. Although the mechanism by which FOM decreases the severity of nedaplatin-induced nephrotoxicity remains unclear, it may be due, at least in part, to a reduction in the accumulation of nedaplatin in the kidney. Further investigations are needed to clarify the mechanism of this effect. In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin while maximizing its therapeutic effectiveness. Acknowledgments The authors express her gratitude to Ms. Rika Hashikura for her assistance in this study.
Fig. 3. Effects of FOM on concentration of nedaplatin in the renal cortex of rats administered nedaplatin 10 mg/kg for 6 days. Conditions were the same as those described in Fig. 1. *p 0.05, FOM() vs FOM()
Fig. 4a,b. Light micrographs of proximal tubular cells in the renal cortex of rats administered with nedaplatin 10 mg/kg for 6 days. a Nedaplatin 10 mg/kg without FOM (arrows indicate tubular necrosis). b Nedaplatin 10 mg/kg with FOM 0.5 g/kg. a and b; PAS stain, 200
a
b
17
References 1. Weiss RB, Christian MC. New cisplatin analogues in development: a review. Drugs 1993;46:360–77. 2. Alberts DS, Fanta PT, Running KL, Adair LP Jr, Garcia DJ, Liu-Stevens R, et al. In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers. Cancer Chemother Pharmacol 1997;39:493–7. 3. Ota K, Oguma T, Shimamura K. Pharmacokinetics of platinum in cancer patients following intravenous infusion of cisdiammine(glycolato)platinum, 254-S. Anticancer Res 1994; 14:1383–8. 4. Fukuda M, Ohe Y, Kanzawa F, Oka M, Hara K, Saijo N. Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin. Anticancer Res 1995;15:393–8. 5. Kobayashi H, Takemura Y, Miyachi H, Ogawa T. Antitumor activities of new platinum compounds, DWA2114R, NK121 and 254-S, against human leukemia cells sensitive to cisplatin. Invest New Drugs 1991;9:313–9. 6. Hirabayashi K, Okada E. Combination chemotherapy with 254-S, ifosfamide, and peplomycin for advanced or recurrent cervical cancer. Cancer 1993;71:2769–75. 7. Taguchi T, Wakui A, Nabeya K, Kurihara M, Isono K, Kakegawa T, et al. A phase II clinical study of cis-diammine glycolato platinum, 254-S, for gastrointestinal cancers. Gan To Kagaku Ryoho (Japanese Journal of Cancer and Chemotherapy) 1992;19:483–8. 8. Fukuda M, Shinkai T, Eguchi K, Sasaki Y, Tamura T, Ohe Y, et al. Phase II study of (glycolate-O,O’) diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer. Cancer Chemother Pharmacol 1990;26:393–6.
9. Adachi S, Ogasawara T, Yamasaki N, Shibahara H, Tsuji Y, Takemura T, et al. A pilot study of nedaplatin and etoposide for recurrent gynecological malignancies. Oncol Rep 1998;5:881–94. 10. Nakamura T, Kokuryo T, Hashimoto Y, Inui K. Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats. J Pharm Pharmacol 1999;51:227–32. 11. Nakamura T, Hashimoto Y, Kokuryo T, Inui K. Effects of fosfomycin and imipenem/cilastatin on nephrotoxicity and renal excretion of vancomycin in rats. Pharm Res 1998;15:734–8. 12. Toyoguchi T, Nakagawa Y. Nephrotoxicity and drug interaction of vancomycin (2). Folia Pharmacol Jpn 1996;107:225–35. 13. Takahashi K, Kanno H. Activities of vancomycin and other antibiotic combinations against methicillin-resistant Staphylococcus aureus. Jpn J Chemother 1995;43:907–18. 14. Yoshiyama Y, Yazaki T, Kanke M, Beauchamp D. Nephrotoxicity of teicoplanin in rats. Jpn J Antibiot 2000;53:1–7. 15. Yoshiyama Y, Yazaki T, Beauchamp D, Kanke M. Protective effect of ceftriaxone against the nephrotoxicity of isepamicin administered once daily in rats. Biol Pharm Bull 1998;21:520–3. 16. Yoshiyama Y, Yazaki T, Wong P, Beauchamp D, Kanke M. The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats. J Infect Chemother 2001;7:243–6. 17. Yazaki T, Yoshiyama Y, Wong P, Beauchamp D, Kanke M. Protective effect of fleroxacin against the nephrotoxicity of isepamicin in rats. Biol Pharm Bull2002;25:516–9. 18. Kurebe M, Niizato T, Sanda M, Sasaki H, Hayasaka H. Preventive effect of fosfomycin on the renal toxicity of cisplatin. Jpn J Antibiot 1985;38:62–8. 19. Olson JJ, Truelson JM, Street N. In vitro interaction of cisplatin and fosfomycin on squamous cell carcinoma cultures. Arch Otolaryngol Head Neck Surg 1994;120:1253–7. 20. Umeki S, Watanabe M, Yagi S, Soejima R. Supplemental fosfomycin and/or steroids that reduce cisplatin-induced nephrotoxicity. Am J Med Sci 1988;295:6–10.
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2005
ORIGINAL ARTICLE Yuji Yoshiyama · Kazue Yamaguchi · Kazuhiro Matsuo Minoru Kurokawa · Motoko Kanke
The effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats
Received: July 9, 2004 / Accepted: November 11, 2004
Abstract 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-β-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.
cisplatin-resistant human leukemia cells in one report.5 In preclinical investigations, the antitumor activity of nedaplatin has been similar to or greater than that of cisplatin, with evidence of reduced nephrotoxicity.2,5,6 One of the side-effects of platinum analogues is nephrotoxicity. Nedaplatin is a less toxic alternative to cisplatin, particularly with reference to nephrotoxicity.7–9 It has been reported that fosfomycin (FOM) protects the kidneys by stabilizing the lysosomal membrane and inhibiting drug uptake by renal tubular epithelial cells.10–13 The aim of the present study was to examine the effect of FOM on the nephrotoxicity induced by nedaplatin in rats.
Key words Nedaplatin · Nephrotoxicity · Fosfomycin · Rats
The experimental protocol was approved by the Committee for the Institutional Care and Use of Animals at Kyoritsu University of Pharmacy. Adult male Wistar rats (weighing 160–180 g) were used. The animals were housed in a light-controlled room (lights on from 08:00 to 20:00), at a room temperature of 24 1°C and humidity of 60 10%, for 1 week. They were acclimated for 1 week, and they had free access to food and water throughout the experiment. Nedaplatin (Shionogi, Osaka, Japan) and FOM (Meiji Seika Kaisha, Tokyo, Japan) were used for the treatment. The following doses were chosen based on data from previous studies. For 6-day administration, drugs were administered once daily to the following three groups: group A, nedaplatin 10 mg/kg saline; group B, FOM 0.5 g/kg saline; and group C, nedaplatin 10 mg/kg FOM 0.5 g/kg. FOM was first injected intraperitoneally. After an interval of approximately 30 min to allow FOM to take effect, nedaplatin was injected intraperitoneally on the contralateral side. The rats were randomly assigned to the experimental groups (five rats each) and were housed individually in metabolic cages to collect urine. Urine samples were collected 24 h prior to drug administration and every 24 h
Introduction Nedaplatin (cis-diammine glycolate platinum) is a platinum analogue with a spectrum of antitumor activity similar to that of cisplatin.1,2 The mechanism of cytotoxicity appears to be similar to that of cisplatin and carboplatin (i.e., effects on DNA intrastrand and interstrand cross links).3 In vitro, nedaplatin has demonstrated partial cross-resistance to cisplatin and other platinum compounds in various solid tumors.2,4 However, significant activity was observed against
Y. Yoshiyama (*) · M. Kanke Division of Clinical Pharmacy, Kyoritsu University of Pharmacy, 1-15-30 Shibakoen, Minato-ku 105-8512, Tokyo, Japan Tel./Fax 81-3-5400-2667 e-mail: [email protected] K. Yamaguchi · K. Matsuo · M. Kurokawa Department of Pharmacy, Toho University Omori Hospital, Tokyo, Japan
Materials and methods
15
thereafter. Urine volumes were measured, and the urine samples were centrifuged at 3000 g for 10 min. The N-acetylβ-d-glucosaminidase (NAG) activity of the supernatant was determined, and was expressed as international units per total urine volume collected over 24 h. Urinary NAG activity is one sensitive indicator of nedaplatin-induced nephrotoxicity.14 Under anesthesia, the rats were killed by exsanguination 24 h after the last injection of drugs. Blood samples were collected from the inferior vena cava and then centrifuged, and the serum was frozen (80°C) for the determination of blood urea nitrogen (BUN) and serum creatinine levels. The kidneys were removed for the determination of tissue nedaplatin concentrations. The renal cortical accumulation of nedaplatin was measured by atomic absorption spectrometry. Histopathological samples were prepared for standard hematoxylin-eosin (H&E) and periodic acid Schiff (PAS) staining and were evaluated under a microscope. Sections came from three different regions of the renal cortex of each rat, and five rats per group were used. Statistical analysis of the differences between groups with FOM and without FOM was performed using Student’s t-test. Data on the effects of FOM on urinary NAG levels were first analyzed by analysis of variance, and group comparisons were made using the Fisher protected least significant difference post-hoc test.
Fig. 1. Time course of urinary N-acetyl-β-d-glucosaminidase (NAG) activity in rats treated with nedaplatin 10 mg/kg for 6 days. Nedaplatin was administered without fosfomycin (FOM) and with FOM 0.5 g/kg. Each point represents the mean and SD for five rats.* Significant difference between groups with FOM and without FOM (p 0.05)
Results Urine NAG levels were significantly higher in the group treated with nedaplatin alone than in the groups given FOM alone or nedaplatin with FOM (Fig. 1). In other words, the extent of increase in urine NAG activity was significantly smaller when FOM was given with nedaplatin as compared with nedaplatin alone (p 0.05). The serum creatinine and BUN levels of each group are presented in Fig. 2. Significantly higher levels of serum creatinine and BUN were observed in the group that received nedaplatin alone compared with the groups treated with FOM alone or nedaplatin with FOM. This suggests that the concomitant administration of these two drugs is less toxic than nedaplatin alone. The effects of FOM on the concentration of nedaplatin in the renal cortex are given in Fig. 3. After 6 days of administration, the concentration of nedaplatin was significantly lower in the renal cortex of rats that received the nedaplatin and FOM combination compared with those that received nedaplatin alone (p 0.05). Histopathological analysis of the renal tissue showed tubular necrosis (Fig. 4a), degeneration, vacuolation of proximal tubular cells, and cell infiltration in the interstitum in the group given 10 mg/kg nedaplatin alone. The group that received FOM alone showed no significant change in kidney histology. In contrast, the above abnormalities were significantly reduced, especially the number of necrosed cells, when FOM was administered concomitantly with nedaplatin (Fig. 4b).
Fig. 2. a Serum creatinine levels and b blood urea nitrogen levels in rats treated with nedaplatin 10 mg/kg for 6 days. Conditions were the same as those described in Fig. 1. *p 0.05, FOM() vs FOM()
16
Discussion Data from our laboratory have shown that some antibiotics, including FOM, reduce the nephrotoxic potential of antibiotics when administered concomitantly.15–17 In this study, we investigated the effect of 6-day coadministration of FOM on nedaplatin-induced nephrotoxicity in rats. The study showed that FOM protected against nedaplatin-induced nephrotoxicity, as shown by lower urinary excretion of NAG and lower BUN and serum creatinine levels, as well as fewer histopathological signs of nephrotoxicity in the groups treated with the nedaplatin FOM combination as compared the group treated with nedaplatin alone. Because the ability of FOM to reduce nephrotoxicity is reportedly due to its inhibition of the uptake of concomitantly administered drugs by renal tubular epithelial cells and to its stabilization of lysosomal membranes, we
determined drug concentrations in the renal cortex in this investigation.10,11 During the 6-day experimental period, coadministration of FOM resulted in a significant decrease in drug concentrations in the renal cortex in the groups that received nedaplatin. Thus, the uptake of nedaplatin by the renal cortex was inhibited by FOM. Kurebe et al.18 found that coadministration of FOM with cisplatin in rats resulted in less nephrotoxicity compared with cisplatin monotherapy. They suggested that this was due to the stabilization of lysosomal membranes and to the inhibition of drug uptake by renal tubular epithelial cells. We also demonstrated, in this study, that FOM decreased the incidence of nephrotoxicity induced by nedaplatin. FOM protects against cisplatin-induced nephrotoxicity and does not inhibit tumoricidal activity in vitro,19 and FOM has been used successfully in clinical trials to ameliorate cisplatin-induced nephrotoxicity.20 The use of nephroprotective agents could potentially allow increased doses of cisplatin. The effect of FOM against nedaplatin-induced nephrotoxicity observed in this study might be beneficial in the treatment of patients. There may be several mechanisms involved in the inhibition of nephrotoxicity by FOM. Although the mechanism by which FOM decreases the severity of nedaplatin-induced nephrotoxicity remains unclear, it may be due, at least in part, to a reduction in the accumulation of nedaplatin in the kidney. Further investigations are needed to clarify the mechanism of this effect. In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin while maximizing its therapeutic effectiveness. Acknowledgments The authors express her gratitude to Ms. Rika Hashikura for her assistance in this study.
Fig. 3. Effects of FOM on concentration of nedaplatin in the renal cortex of rats administered nedaplatin 10 mg/kg for 6 days. Conditions were the same as those described in Fig. 1. *p 0.05, FOM() vs FOM()
Fig. 4a,b. Light micrographs of proximal tubular cells in the renal cortex of rats administered with nedaplatin 10 mg/kg for 6 days. a Nedaplatin 10 mg/kg without FOM (arrows indicate tubular necrosis). b Nedaplatin 10 mg/kg with FOM 0.5 g/kg. a and b; PAS stain, 200
a
b
17
References 1. Weiss RB, Christian MC. New cisplatin analogues in development: a review. Drugs 1993;46:360–77. 2. Alberts DS, Fanta PT, Running KL, Adair LP Jr, Garcia DJ, Liu-Stevens R, et al. In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human ovarian cancers. Cancer Chemother Pharmacol 1997;39:493–7. 3. Ota K, Oguma T, Shimamura K. Pharmacokinetics of platinum in cancer patients following intravenous infusion of cisdiammine(glycolato)platinum, 254-S. Anticancer Res 1994; 14:1383–8. 4. Fukuda M, Ohe Y, Kanzawa F, Oka M, Hara K, Saijo N. Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin. Anticancer Res 1995;15:393–8. 5. Kobayashi H, Takemura Y, Miyachi H, Ogawa T. Antitumor activities of new platinum compounds, DWA2114R, NK121 and 254-S, against human leukemia cells sensitive to cisplatin. Invest New Drugs 1991;9:313–9. 6. Hirabayashi K, Okada E. Combination chemotherapy with 254-S, ifosfamide, and peplomycin for advanced or recurrent cervical cancer. Cancer 1993;71:2769–75. 7. Taguchi T, Wakui A, Nabeya K, Kurihara M, Isono K, Kakegawa T, et al. A phase II clinical study of cis-diammine glycolato platinum, 254-S, for gastrointestinal cancers. Gan To Kagaku Ryoho (Japanese Journal of Cancer and Chemotherapy) 1992;19:483–8. 8. Fukuda M, Shinkai T, Eguchi K, Sasaki Y, Tamura T, Ohe Y, et al. Phase II study of (glycolate-O,O’) diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer. Cancer Chemother Pharmacol 1990;26:393–6.
9. Adachi S, Ogasawara T, Yamasaki N, Shibahara H, Tsuji Y, Takemura T, et al. A pilot study of nedaplatin and etoposide for recurrent gynecological malignancies. Oncol Rep 1998;5:881–94. 10. Nakamura T, Kokuryo T, Hashimoto Y, Inui K. Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats. J Pharm Pharmacol 1999;51:227–32. 11. Nakamura T, Hashimoto Y, Kokuryo T, Inui K. Effects of fosfomycin and imipenem/cilastatin on nephrotoxicity and renal excretion of vancomycin in rats. Pharm Res 1998;15:734–8. 12. Toyoguchi T, Nakagawa Y. Nephrotoxicity and drug interaction of vancomycin (2). Folia Pharmacol Jpn 1996;107:225–35. 13. Takahashi K, Kanno H. Activities of vancomycin and other antibiotic combinations against methicillin-resistant Staphylococcus aureus. Jpn J Chemother 1995;43:907–18. 14. Yoshiyama Y, Yazaki T, Kanke M, Beauchamp D. Nephrotoxicity of teicoplanin in rats. Jpn J Antibiot 2000;53:1–7. 15. Yoshiyama Y, Yazaki T, Beauchamp D, Kanke M. Protective effect of ceftriaxone against the nephrotoxicity of isepamicin administered once daily in rats. Biol Pharm Bull 1998;21:520–3. 16. Yoshiyama Y, Yazaki T, Wong P, Beauchamp D, Kanke M. The effect of fosfomycin on glycopeptide antibiotic-induced nephrotoxicity in rats. J Infect Chemother 2001;7:243–6. 17. Yazaki T, Yoshiyama Y, Wong P, Beauchamp D, Kanke M. Protective effect of fleroxacin against the nephrotoxicity of isepamicin in rats. Biol Pharm Bull2002;25:516–9. 18. Kurebe M, Niizato T, Sanda M, Sasaki H, Hayasaka H. Preventive effect of fosfomycin on the renal toxicity of cisplatin. Jpn J Antibiot 1985;38:62–8. 19. Olson JJ, Truelson JM, Street N. In vitro interaction of cisplatin and fosfomycin on squamous cell carcinoma cultures. Arch Otolaryngol Head Neck Surg 1994;120:1253–7. 20. Umeki S, Watanabe M, Yagi S, Soejima R. Supplemental fosfomycin and/or steroids that reduce cisplatin-induced nephrotoxicity. Am J Med Sci 1988;295:6–10.