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Hiroshi Koga - One of the best experts on this subject based on the ideXlab platform.
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studies on Uricosuric diuretics iii substituted 1 3 dioxolo 4 5 f 1 2 benzisoxazole 6 carboxylic acids and 1 3 dioxolo 4 5 g 1 2 benzisoxazole 7 carboxylic acids
Chemical & Pharmaceutical Bulletin, 1992Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Bunya Aoki, Hiroshi KogaAbstract:A series of substituted 1, 3-dioxolo[4, 5-f]-1, 2-benzisoxazole-6-carboxylic acids 13 and 1, 3-dioxolo[4, 5-g]-1, 2-benzisozazole-7-carboxylic acids 14 were synthesized and evaluated for diuretic and Uricosuric activities in rats. Most of the benzisoxazole derivatives 13 and 14 showed potent diuretic activities. Moderate Uricosuric activities were also found in 14a, 14b, and 14f.
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A selective Uricosuric action of AA-193 in rats. Comparison with its effect on PAH secretion in vivo and in vitro.
Naunyn-Schmiedeberg's archives of pharmacology, 1991Co-Authors: Takashi Dan, Etsuro Onuma, Haruko Tanaka, Hiroshi KogaAbstract:We evaluated the Uricosuric action of AA-193 by comparing it with the effect on PAH secretion in rats, using in vivo and in vitro techniques. The i.v. administration of AA-193 elevated the fractional excretion of urate (FEurate) significantly in a dose-dependent manner at doses from 0.1 to 10 mg/kg. Only at the highest dose of 10 mg/kg did AA-193 cause a momentary decrease in FEPAH. On the other hand, tienilic acid and probenecid reduced FEPAH at Uricosuric effective doses. To compare the inhibitory effects of Uricosurics on urate reabsorption and PAH secretion more directly, we investigated the effects of Uricosurics on the OH− gradient-dependent urate uptake in brush border membrane vesicles and the net PAH accumulation in cortical slices. The relation between the affinity of Uricosuric drug for urate and PAH transporters corresponds well with the difference between the effect on FEurate and that on FEPAH. The relative affinity of AA-193 for the urate uptake is 83-fold greater than that for the PAH accumulation.
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Studies on Uricosuric diuretics. II: Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids
Chemical & pharmaceutical bulletin, 1991Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Aoki Bunya, Hiroshi KogaAbstract:A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids 9 and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids 12 were synthesized and evaluated for Uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives 9 showed Uricosuric and only weak diuretic activities, whereas the benzoxazoles 12 exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (9b, AA-193) was found to be a potent Uricosuric agent without diuretic activity and was selected for further development.
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Uricosurics inhibit urate transporter in rat renal brush border membrane vesicles
European journal of pharmacology, 1990Co-Authors: Takashi Dan, Hiroshi KogaAbstract:It has been proposed that a urate-anion exchanger system in brush border membrane vesicles (BBMV), which mediates hydroxyl ion (OH-) gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption would inhibit the transport of urate into the cell by blocking the urate-anion exchanger. To confirm this hypothesis, we investigated the inhibitory effects of well-known Uricosuric drugs on the OH-/urate exchange in BBMV. The rank order of potency was benzbromarone greater than tienilic acid greater than sulfinpyrazone greater than probenecid, which is consistent with clinical doses in man. AA-193 (5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carb oxylic acid), an excellent candidate for a Uricosuric, exerted the most potent inhibition on urate uptake (Ki = 0.12 microM). In contrast with that by stilbene disulfonates, the inhibition by AA-193 or benzbromarone was reversible.
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Studies on Uricosuric diuretics. I, Syntheses and activities of xanthonyloxyacetic acids and dihydrofuroxanthone-2-carboxylic acids
Chemical & pharmaceutical bulletin, 1990Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Hiroshi KogaAbstract:A series of substituted xanthonyloxyacetic acids (5 and 6), 1, 2-dihydrofuro[2, 3-c]xanthone-2-carboxylic acids (7) and 2, 3-dihydrofuro[3, 2-b]xanthone-2-carboxylic acids (8) were synthesized and tested for diuretic and Uricosuric activities in rats. Most of the xanthon-3-yloxyacetic acids (5) and 7 showed potent diuretic activities, while 8 had lower activities. Uricosuric activities were found in 5c, 5f, 5k, 5m, 5o, 5p, 5r, 7m, 7p and 8q.
Takashi Dan - One of the best experts on this subject based on the ideXlab platform.
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studies on Uricosuric diuretics iii substituted 1 3 dioxolo 4 5 f 1 2 benzisoxazole 6 carboxylic acids and 1 3 dioxolo 4 5 g 1 2 benzisoxazole 7 carboxylic acids
Chemical & Pharmaceutical Bulletin, 1992Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Bunya Aoki, Hiroshi KogaAbstract:A series of substituted 1, 3-dioxolo[4, 5-f]-1, 2-benzisoxazole-6-carboxylic acids 13 and 1, 3-dioxolo[4, 5-g]-1, 2-benzisozazole-7-carboxylic acids 14 were synthesized and evaluated for diuretic and Uricosuric activities in rats. Most of the benzisoxazole derivatives 13 and 14 showed potent diuretic activities. Moderate Uricosuric activities were also found in 14a, 14b, and 14f.
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A selective Uricosuric action of AA-193 in rats. Comparison with its effect on PAH secretion in vivo and in vitro.
Naunyn-Schmiedeberg's archives of pharmacology, 1991Co-Authors: Takashi Dan, Etsuro Onuma, Haruko Tanaka, Hiroshi KogaAbstract:We evaluated the Uricosuric action of AA-193 by comparing it with the effect on PAH secretion in rats, using in vivo and in vitro techniques. The i.v. administration of AA-193 elevated the fractional excretion of urate (FEurate) significantly in a dose-dependent manner at doses from 0.1 to 10 mg/kg. Only at the highest dose of 10 mg/kg did AA-193 cause a momentary decrease in FEPAH. On the other hand, tienilic acid and probenecid reduced FEPAH at Uricosuric effective doses. To compare the inhibitory effects of Uricosurics on urate reabsorption and PAH secretion more directly, we investigated the effects of Uricosurics on the OH− gradient-dependent urate uptake in brush border membrane vesicles and the net PAH accumulation in cortical slices. The relation between the affinity of Uricosuric drug for urate and PAH transporters corresponds well with the difference between the effect on FEurate and that on FEPAH. The relative affinity of AA-193 for the urate uptake is 83-fold greater than that for the PAH accumulation.
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Studies on Uricosuric diuretics. II: Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids
Chemical & pharmaceutical bulletin, 1991Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Aoki Bunya, Hiroshi KogaAbstract:A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids 9 and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids 12 were synthesized and evaluated for Uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives 9 showed Uricosuric and only weak diuretic activities, whereas the benzoxazoles 12 exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (9b, AA-193) was found to be a potent Uricosuric agent without diuretic activity and was selected for further development.
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Uricosurics inhibit urate transporter in rat renal brush border membrane vesicles
European journal of pharmacology, 1990Co-Authors: Takashi Dan, Hiroshi KogaAbstract:It has been proposed that a urate-anion exchanger system in brush border membrane vesicles (BBMV), which mediates hydroxyl ion (OH-) gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption would inhibit the transport of urate into the cell by blocking the urate-anion exchanger. To confirm this hypothesis, we investigated the inhibitory effects of well-known Uricosuric drugs on the OH-/urate exchange in BBMV. The rank order of potency was benzbromarone greater than tienilic acid greater than sulfinpyrazone greater than probenecid, which is consistent with clinical doses in man. AA-193 (5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carb oxylic acid), an excellent candidate for a Uricosuric, exerted the most potent inhibition on urate uptake (Ki = 0.12 microM). In contrast with that by stilbene disulfonates, the inhibition by AA-193 or benzbromarone was reversible.
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Studies on Uricosuric diuretics. I, Syntheses and activities of xanthonyloxyacetic acids and dihydrofuroxanthone-2-carboxylic acids
Chemical & pharmaceutical bulletin, 1990Co-Authors: Haruhiko Sato, Takashi Dan, Etsuro Onuma, Haruko Tanaka, Hiroshi KogaAbstract:A series of substituted xanthonyloxyacetic acids (5 and 6), 1, 2-dihydrofuro[2, 3-c]xanthone-2-carboxylic acids (7) and 2, 3-dihydrofuro[3, 2-b]xanthone-2-carboxylic acids (8) were synthesized and tested for diuretic and Uricosuric activities in rats. Most of the xanthon-3-yloxyacetic acids (5) and 7 showed potent diuretic activities, while 8 had lower activities. Uricosuric activities were found in 5c, 5f, 5k, 5m, 5o, 5p, 5r, 7m, 7p and 8q.
Robert P Hanzlik - One of the best experts on this subject based on the ideXlab platform.
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identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes
Chemical Research in Toxicology, 2012Co-Authors: Yakov M Koen, Scott Ronald Obach, Nadezhda A Galeva, Todd D Williams, Diganta Sarma, Robert P HanzlikAbstract:Tienilic acid (TA) is a Uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some...
Michel Burnier - One of the best experts on this subject based on the ideXlab platform.
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Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients.
Transplantation, 1998Co-Authors: Gianni Minghelli, Charles Seydoux, Jean-jacques Goy, Michel BurnierAbstract:Background. The angiotensin II receptor antagonist losartan is an effective antihypertensive agent with unique Uricosuric properties. This study evaluates the Uricosuric effects of losartan in 10 hypertensive heart transplant patients with hyperuricemia. Methods. The patients were randomized to receive losartan 50 mg once daily and enalapril 20 mg once daily for 4 weeks according to a double-blind crossover design. Office blood pressure, plasma uric acid levels, and urinary uric acid excretion were monitored throughout the study. Results. Plasma uric acid levels decreased significantly after 4 weeks of treatment with losartan (P
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Uricosuric effect of the angiotensin ii receptor antagonist losartan in heart transplant recipients
Transplantation, 1998Co-Authors: Gianni Minghelli, Charles Seydoux, Jean-jacques Goy, Michel BurnierAbstract:Background. The angiotensin II receptor antagonist losartan is an effective antihypertensive agent with unique Uricosuric properties. This study evaluates the Uricosuric effects of losartan in 10 hypertensive heart transplant patients with hyperuricemia. Methods. The patients were randomized to receive losartan 50 mg once daily and enalapril 20 mg once daily for 4 weeks according to a double-blind crossover design. Office blood pressure, plasma uric acid levels, and urinary uric acid excretion were monitored throughout the study. Results. Plasma uric acid levels decreased significantly after 4 weeks of treatment with losartan (P<0.05) but not with enalapril. On day 1 and after 1 month of treatment, a significant increase in uric acid excretion was observed only with losartan. Significant decreases in office systolic and diastolic blood pressures were obtained with enalapril but not with losartan. Conclusions. Losartan effectively lowers plasma uric acid levels in hyperuricemic heart transplant patients.
Yakov M Koen - One of the best experts on this subject based on the ideXlab platform.
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identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes
Chemical Research in Toxicology, 2012Co-Authors: Yakov M Koen, Scott Ronald Obach, Nadezhda A Galeva, Todd D Williams, Diganta Sarma, Robert P HanzlikAbstract:Tienilic acid (TA) is a Uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some...
