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Osamu Nagata - One of the best experts on this subject based on the ideXlab platform.
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Study on species differences in nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor
Archives of Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Osamu NagataAbstract:To clarify the toxicological aspects of FYX-051, a xanthine Oxidoreductase Inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.
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Study on toxicological aspects of crystal-mediated nephrotoxicity induced by FYX-051, a xanthine Oxidoreductase Inhibitor, in rats.
Drug and Chemical Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Kazuhiko Oba, Osamu NagataAbstract:To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney-related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine Oxidoreductase Inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: ±0.7 ∼ ±0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was −0.6648, 0.7896, −0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: ±0.4 ∼ ±0.7). In F344 rats, the correlation coefficient on histopathology betw...
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Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor, in rats
Drug and Chemical Toxicology, 2010Co-Authors: Naoki Ashizawa, Takeo Shimo, Mitsuyoshi Moto, Koji Matsumoto, Tetsuya Taniguchi, Osamu NagataAbstract:As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine Oxidoreductase Inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume. As a result, the dosing interval of citrate was found to be optimal at 4 hours, but not at 3 or 5 hours, because this treatment completely inhibited intrarenal xanthine deposition. The dose of citrate for the second treatment and the dosing volume were found to be sufficient at 1,500 mg/kg and 10 mL/kg, respectively. Subsequently, a 4-week study by simultaneous treatment at 3 mg/kg of FYX-051 and citrate (2,000 mg/kg) + citrate (1,500 mg/kg), under the improved conditions, revealed that renal lesions could be drastically inhibited. Thus, the present study demonstrated that the interval of two citrate treatments is pivotal and indicated that the improved model would be useful for the mechanistic study of FYX-051-induced urinary bladder carcinogenesis because of an easier treatment method than our previous model.
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Discovery of 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051-a xanthine Oxidoreductase Inhibitor for the treatment of hyperuricemia
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Takahiro Sato, Naoki Ashizawa, Takashi Iwanaga, Koji Matsumoto, Hiroshi Nakamura, Inoue Tsutomu, Osamu NagataAbstract:Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine Oxidoreductase (XOR) Inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR Inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-Inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.
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FYX-051, a xanthine Oxidoreductase Inhibitor, induces nephropathy in rats, but not in monkeys.
Toxicologic Pathology, 2009Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Koji Matsumoto, Osamu NagataAbstract:The present studies were performed to investigate the possible mechanism of marked species differences on nephropathy found in the long-term toxicity study of FYX-051, a xanthine Oxidoreductase Inhibitor. In the twenty-six-week dose toxicity study in the rat, in which FYX-051 was administered by oral gavage at 0.04, 0.2, and 1 mg/kg, xanthine-mediated nephropathy was seen only at 1 mg/kg, despite the presence of xanthine crystals in urine at 0.2 mg/kg and more; however, in the fifty-two-week dose toxicity study in the monkey, in which FYX-051 was administered by oral gavage at 30, 100, and 300 mg/kg, no toxicities were seen, even at 300 mg/kg. These outcomes showed there would be 1500-fold or more differences in the mode of intrarenal xanthine deposition between rats and monkeys. Thus we performed the mechanistic study, and the following outcomes were obtained. First, the amount of urinary purine metabolites was thirty-fold higher in rats than in monkeys. Second, urinary xanthine solubility was sixfold higher in monkeys than in rats. Third, exposure levels of FYX-051 were five-fold higher in rats than in monkeys. Therefore, the present study indicated that the combined effects of purine metabolism, urinary xanthine solubility, and toxicokinetics would contribute to species difference si n nephropathy, that is, absence of xanthine-mediated nephropathy in monkeys even at the highest dose of FYX-051.
Takashi Iwanaga - One of the best experts on this subject based on the ideXlab platform.
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Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel xanthine Oxidoreductase Inhibitor.
Journal of Pharmacy and Pharmacology, 2015Co-Authors: Tetsuya Taniguchi, Naoki Ashizawa, Takashi Iwanaga, Koji Matsumoto, Kazuhiro SaitohAbstract:Objectives The aim of this study was to establish the rat model for evaluating hypouricemic effects by some uricosuric agents. Methods Rats were made hyperuricemic by subcutaneous administration of potassium oxonate, a uricase Inhibitor, or made hypouricemic by oral administration of topiroxostat, a xanthine Oxidoreductase Inhibitor. Furthermore, rats were co-treated with topiroxostat and inosine, a urate precursor. In each condition, hypouricemic effects by uricosuric agents were examined. Key findings In potassium oxonate-treated rats, treatment with uricosuric agents such as FYU-981, F12859 and probenecid showed no hypouricemic effect. On the other hand, in topiroxostat-treated rats, uricosuric agents remarkably lowered plasma urate level compared with topiroxostat treatment alone, with a dose dependency of 30 and 100 mg/kg for FYU-981 and F12859 each. The decrease in the plasma urate level observed in the topiroxostat-treated rats disappeared by further co-treatment with inosine. Conclusions Effects of uricosuric agents on the plasma urate level in rats were sensitive to the rate of urate formation. Induction of slower urate formation by topiroxostat provides valuable model for evaluation of hypouricemic effects by uricosuric agents in rats.
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Xanthine crystals induced by topiroxostat, a xanthine Oxidoreductase Inhibitor, in rats, cause transitional cell tumors
Archives of Toxicology, 2014Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Koji Matsumoto, Kazuhiro SaitoAbstract:The present study was performed to elucidate the underlying mechanism of transitional cell tumors found in the carcinogenicity testing of topiroxostat, a xanthine Oxidoreductase Inhibitor, in which topiroxostat was orally given to F344 rats at 0.3, 1, and 3 mg/kg for 2 years. In the urinary bladder, transitional cell papillomas and/or carcinomas were seen in males receiving 0.3, 1, and 3 mg/kg (1/49, 3/49, and 10/50, respectively). In the kidney, transitional cell papillomas and/or carcinomas in the pelvis were seen in 2/50 males and 1/50 females receiving 3 mg/kg. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. As for sex differences of urinary bladder tumors, the BrdU labeling index for epithelial cells of the urinary bladder by 5-week oral treatment with topiroxostat at 10 mg/kg to F344 rats was increased in males only, showing consistency with histopathological findings. Therefore, the present study indicates that transitional cell tumors induced by topiroxostat in rats were due to physical stimulation to transitional cells of xanthine crystals/calculi and provides that other factors were not implicated in this tumorigenesis. Furthermore, the present study suggests that such tumors do not predict for humans since topiroxostat-induced xanthine deposition is a rodent-specific event.
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Study on species differences in nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor
Archives of Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Osamu NagataAbstract:To clarify the toxicological aspects of FYX-051, a xanthine Oxidoreductase Inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.
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Discovery of 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051-a xanthine Oxidoreductase Inhibitor for the treatment of hyperuricemia
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Takahiro Sato, Naoki Ashizawa, Takashi Iwanaga, Koji Matsumoto, Hiroshi Nakamura, Inoue Tsutomu, Osamu NagataAbstract:Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine Oxidoreductase (XOR) Inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR Inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-Inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.
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FYX-051, a xanthine Oxidoreductase Inhibitor, induces nephropathy in rats, but not in monkeys.
Toxicologic Pathology, 2009Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Koji Matsumoto, Osamu NagataAbstract:The present studies were performed to investigate the possible mechanism of marked species differences on nephropathy found in the long-term toxicity study of FYX-051, a xanthine Oxidoreductase Inhibitor. In the twenty-six-week dose toxicity study in the rat, in which FYX-051 was administered by oral gavage at 0.04, 0.2, and 1 mg/kg, xanthine-mediated nephropathy was seen only at 1 mg/kg, despite the presence of xanthine crystals in urine at 0.2 mg/kg and more; however, in the fifty-two-week dose toxicity study in the monkey, in which FYX-051 was administered by oral gavage at 30, 100, and 300 mg/kg, no toxicities were seen, even at 300 mg/kg. These outcomes showed there would be 1500-fold or more differences in the mode of intrarenal xanthine deposition between rats and monkeys. Thus we performed the mechanistic study, and the following outcomes were obtained. First, the amount of urinary purine metabolites was thirty-fold higher in rats than in monkeys. Second, urinary xanthine solubility was sixfold higher in monkeys than in rats. Third, exposure levels of FYX-051 were five-fold higher in rats than in monkeys. Therefore, the present study indicated that the combined effects of purine metabolism, urinary xanthine solubility, and toxicokinetics would contribute to species difference si n nephropathy, that is, absence of xanthine-mediated nephropathy in monkeys even at the highest dose of FYX-051.
Naoki Ashizawa - One of the best experts on this subject based on the ideXlab platform.
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Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel xanthine Oxidoreductase Inhibitor.
Journal of Pharmacy and Pharmacology, 2015Co-Authors: Tetsuya Taniguchi, Naoki Ashizawa, Takashi Iwanaga, Koji Matsumoto, Kazuhiro SaitohAbstract:Objectives The aim of this study was to establish the rat model for evaluating hypouricemic effects by some uricosuric agents. Methods Rats were made hyperuricemic by subcutaneous administration of potassium oxonate, a uricase Inhibitor, or made hypouricemic by oral administration of topiroxostat, a xanthine Oxidoreductase Inhibitor. Furthermore, rats were co-treated with topiroxostat and inosine, a urate precursor. In each condition, hypouricemic effects by uricosuric agents were examined. Key findings In potassium oxonate-treated rats, treatment with uricosuric agents such as FYU-981, F12859 and probenecid showed no hypouricemic effect. On the other hand, in topiroxostat-treated rats, uricosuric agents remarkably lowered plasma urate level compared with topiroxostat treatment alone, with a dose dependency of 30 and 100 mg/kg for FYU-981 and F12859 each. The decrease in the plasma urate level observed in the topiroxostat-treated rats disappeared by further co-treatment with inosine. Conclusions Effects of uricosuric agents on the plasma urate level in rats were sensitive to the rate of urate formation. Induction of slower urate formation by topiroxostat provides valuable model for evaluation of hypouricemic effects by uricosuric agents in rats.
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Xanthine crystals induced by topiroxostat, a xanthine Oxidoreductase Inhibitor, in rats, cause transitional cell tumors
Archives of Toxicology, 2014Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Koji Matsumoto, Kazuhiro SaitoAbstract:The present study was performed to elucidate the underlying mechanism of transitional cell tumors found in the carcinogenicity testing of topiroxostat, a xanthine Oxidoreductase Inhibitor, in which topiroxostat was orally given to F344 rats at 0.3, 1, and 3 mg/kg for 2 years. In the urinary bladder, transitional cell papillomas and/or carcinomas were seen in males receiving 0.3, 1, and 3 mg/kg (1/49, 3/49, and 10/50, respectively). In the kidney, transitional cell papillomas and/or carcinomas in the pelvis were seen in 2/50 males and 1/50 females receiving 3 mg/kg. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. As for sex differences of urinary bladder tumors, the BrdU labeling index for epithelial cells of the urinary bladder by 5-week oral treatment with topiroxostat at 10 mg/kg to F344 rats was increased in males only, showing consistency with histopathological findings. Therefore, the present study indicates that transitional cell tumors induced by topiroxostat in rats were due to physical stimulation to transitional cells of xanthine crystals/calculi and provides that other factors were not implicated in this tumorigenesis. Furthermore, the present study suggests that such tumors do not predict for humans since topiroxostat-induced xanthine deposition is a rodent-specific event.
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Mechanism of Urinary Bladder Carcinogenesis Induced by a Xanthine Oxidoreductase Inhibitor, in Rats
Carcinogenesis, 2013Co-Authors: Naoki Ashizawa, Takeo ShimoAbstract:© 2013 Ashizawa and Shimo, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mechanism of Urinary Bladder Carcinogenesis Induced by a Xanthine Oxidoreductase Inhibitor, in Rats
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Study on species differences in nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor
Archives of Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Osamu NagataAbstract:To clarify the toxicological aspects of FYX-051, a xanthine Oxidoreductase Inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.
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Study on toxicological aspects of crystal-mediated nephrotoxicity induced by FYX-051, a xanthine Oxidoreductase Inhibitor, in rats.
Drug and Chemical Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Kazuhiko Oba, Osamu NagataAbstract:To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney-related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine Oxidoreductase Inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: ±0.7 ∼ ±0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was −0.6648, 0.7896, −0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: ±0.4 ∼ ±0.7). In F344 rats, the correlation coefficient on histopathology betw...
Takeo Shimo - One of the best experts on this subject based on the ideXlab platform.
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Xanthine crystals induced by topiroxostat, a xanthine Oxidoreductase Inhibitor, in rats, cause transitional cell tumors
Archives of Toxicology, 2014Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Koji Matsumoto, Kazuhiro SaitoAbstract:The present study was performed to elucidate the underlying mechanism of transitional cell tumors found in the carcinogenicity testing of topiroxostat, a xanthine Oxidoreductase Inhibitor, in which topiroxostat was orally given to F344 rats at 0.3, 1, and 3 mg/kg for 2 years. In the urinary bladder, transitional cell papillomas and/or carcinomas were seen in males receiving 0.3, 1, and 3 mg/kg (1/49, 3/49, and 10/50, respectively). In the kidney, transitional cell papillomas and/or carcinomas in the pelvis were seen in 2/50 males and 1/50 females receiving 3 mg/kg. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. As for sex differences of urinary bladder tumors, the BrdU labeling index for epithelial cells of the urinary bladder by 5-week oral treatment with topiroxostat at 10 mg/kg to F344 rats was increased in males only, showing consistency with histopathological findings. Therefore, the present study indicates that transitional cell tumors induced by topiroxostat in rats were due to physical stimulation to transitional cells of xanthine crystals/calculi and provides that other factors were not implicated in this tumorigenesis. Furthermore, the present study suggests that such tumors do not predict for humans since topiroxostat-induced xanthine deposition is a rodent-specific event.
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Mechanism of Urinary Bladder Carcinogenesis Induced by a Xanthine Oxidoreductase Inhibitor, in Rats
Carcinogenesis, 2013Co-Authors: Naoki Ashizawa, Takeo ShimoAbstract:© 2013 Ashizawa and Shimo, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mechanism of Urinary Bladder Carcinogenesis Induced by a Xanthine Oxidoreductase Inhibitor, in Rats
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Study on species differences in nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor
Archives of Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Takashi Iwanaga, Osamu NagataAbstract:To clarify the toxicological aspects of FYX-051, a xanthine Oxidoreductase Inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.
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Study on toxicological aspects of crystal-mediated nephrotoxicity induced by FYX-051, a xanthine Oxidoreductase Inhibitor, in rats.
Drug and Chemical Toxicology, 2011Co-Authors: Takeo Shimo, Naoki Ashizawa, Mitsuyoshi Moto, Kazuhiko Oba, Osamu NagataAbstract:To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney-related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine Oxidoreductase Inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: ±0.7 ∼ ±0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was −0.6648, 0.7896, −0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: ±0.4 ∼ ±0.7). In F344 rats, the correlation coefficient on histopathology betw...
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Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine Oxidoreductase Inhibitor, in rats
Drug and Chemical Toxicology, 2010Co-Authors: Naoki Ashizawa, Takeo Shimo, Mitsuyoshi Moto, Koji Matsumoto, Tetsuya Taniguchi, Osamu NagataAbstract:As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine Oxidoreductase Inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume. As a result, the dosing interval of citrate was found to be optimal at 4 hours, but not at 3 or 5 hours, because this treatment completely inhibited intrarenal xanthine deposition. The dose of citrate for the second treatment and the dosing volume were found to be sufficient at 1,500 mg/kg and 10 mL/kg, respectively. Subsequently, a 4-week study by simultaneous treatment at 3 mg/kg of FYX-051 and citrate (2,000 mg/kg) + citrate (1,500 mg/kg), under the improved conditions, revealed that renal lesions could be drastically inhibited. Thus, the present study demonstrated that the interval of two citrate treatments is pivotal and indicated that the improved model would be useful for the mechanistic study of FYX-051-induced urinary bladder carcinogenesis because of an easier treatment method than our previous model.
S. N. Cherenkevich - One of the best experts on this subject based on the ideXlab platform.
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Phenolic antioxidant TS-13 regulating ARE-driven genes induces tumor cell death by a mitochondria-dependent pathway
Biophysics, 2015Co-Authors: G. G. Martinovich, I. V. Martinovich, N. K. Zenkov, E. B. Menshchikova, N. V. Kandalintseva, S. N. CherenkevichAbstract:Effects of water-soluble phenolic antioxidant sodium 3-(3′-tert-butyl-4′-hydroxyphenyl)-propyl thiosulfonate (TS-13), potassium 3,5-dimethyl-4-hydroxybenzyl thioethanoate (BEP-11-K), and potassium 3-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)-propionate (potassium phenosan) on the proliferative activity of tumor cells and the role of redox-dependent and calcium-dependent signaling mechanisms in realization of tumor cell response to antioxidants were studied. Potassium phenosan and BEP-11-K were found to stimulate proliferation, whereas the ARE-inducing phenolic antioxidant TS-13 inhibited tumor cell growth in culture. The rate of tumor cell growth depended on the rate of intracellular reactive oxygen species production and was suppressed by apocynin (a NADPH oxidase Inhibitor) and antimycin A (an ubiquinol-cytochrome c Oxidoreductase Inhibitor). The action of TS-13 on tumor cells was accompanied by a transient increase in the intracellular production of reactive oxygen species and the intracellular calcium concentration, whereas cell incubation with potassium phenosan and BEP-11-K did not influence the level of reactive oxygen species and intracellular calcium ions. Cyclosporin A blocked the Inhibitory effect of TS-13. Thus, it can be reasonably speculated that phenolic antioxidant TS-13 triggers mitochondria-dependent apoptosis in tumor cells by opening mitochondrial permeability transition pores.
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Phenolic antioxidant TS-13 regulating ARE-dependent genes induces tumor cell death by mitochondria-dependent pathway
Biofizika, 2015Co-Authors: G. G. Martinovich, I. V. Martinovich, N. K. Zenkov, N. V. Kandalintseva, E B Men'shikova, S. N. CherenkevichAbstract:Effects of water-soluble phenolic antioxidant sodium 3-(3'-tret-butyl-4'-hydroxyphenyl)-propyl thiosulfonate (TS-13), potassium 3,5-dimethyl-4-hydroxybenzyl thioetanoate (BEP-11-K) and potassium 3-(3',5'-ditretbutyl-4'-hydroxyphenyl)-propionate (potassium phenosan) on tumor cells proliferative activity and the role of redox-dependent and calcium-dependent signaling mechanisms in realization of tumor cell response to the antioxidant action were studied. Potassium phenosan and BEP-11-K were found to stimulate proliferation and ARE-inducing phenolic antioxidant TS-13 was found to inhibit tumor cell growth in culture. The tumor cell growth rate depended on the rate of intracellular reactive oxygen species production and was decreased by apocynin (a NADPH-oxidase Inhibitor) and antimycin A (an ubiquinol-cytochrome c Oxidoreductase Inhibitor). TS-13 action on tumor cells was accompanied by a transient increase in intracellular reactive oxygen species production and the intracellular calcium concentration, whereas cell incubation with potassium phenosan and BEP-11-K did not influence the reactive oxygen species level and intracellular calcium ions. Cyclosporine A blocked the Inhibitory effect of TS-13. Thus, it can be reasonably speculated that phenolic antioxidant TS-13 starts mitochondria-dependent apoptosis in tumor cells by the opening of permeability transition pores.
