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痛风康宁片对高尿酸血症的预防作用及机制研究

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目的 采用多种实验模型评价痛风康宁片(TKT)对高尿酸血症的预防作用并研究其作用机制.方法 采用ig酵母膏联合ip氧嗪酸钾法制备大鼠高尿酸血症模型,酵母膏(20g·kg-1)连续ig7d,且于ig酵母膏第5天开始给药,设置对照组、模型组和TKT低、中、高(0.58、1.15、2.30 g·kg-1)组和苯溴马隆27 mg·kg-1组,对照及模型组给予等容量0.5%CMC-Na,每天ig给药1次,给药第3天(即ig酵母膏第7天),ip注射氧嗪酸钾200 mg·kg-1造模.检测注射氧嗪酸钾后2、4 h的血清尿酸浓度、尿量、尿液中尿酸排出量及肾脏中尿酸盐转运体1(URAT1)、有机阴离子转运体1(OAT1)、OAT3抗体表达,评价TKT对大鼠高尿酸血症的预防作用;采用次黄嘌呤诱导小鼠高尿酸血症模型,设置对照组、模型组和TKT低、中、高剂量(0.83、1.66、3.33 g·kg-1)组及苯溴马隆39 mg·kg-1组,每天ig给药1次,连续给药5 d,对照及模型组给予等容量0.5%CMC-Na,检测血尿酸、尿酸酶及黄嘌呤氧化酶(XOD)含量,评价TKT对小鼠高尿酸血症的预防作用;采用大鼠水负荷模型,设置对照组和TKT低、中、高(0.58、1.15、2.30 g·kg-1)组及氢氯噻嗪27 mg·kg-1组,每天ig给药1次,连续给药3d,对照组给予等容量0.5%CMC-Na,通过检测给药后1、2、3、4、5 h的尿量及给药后5 h内总尿量,评价TKT对大鼠的利尿作用.结果 与模型组比较,TKT(0.58、1.15、2.30 g·kg-1)能明显降低大鼠血清尿酸浓度(P<0.05、0.01),明显增加尿酸排出量(P<0.05、0.01),明显增加肾脏OAT1的表达(P<0.05、0.01),1.15、2.30g·kg-1 能明显减少肾脏URAT1的表达(P<0.05、0.01);TKT(1.66、3.33 g·kg-1)能明显降低小鼠血清尿酸浓度(P<0.05、0.01),TKT(0.83、1.66、3.33 g·kg-1)能明显增加尿酸酶含量(P<0.05、0.01);TKT(0.58、1.15、2.30 g·kg-1)能明显增加给药后不同时间点的尿量(P<0.05、0.01),明显增加给药后5 h总尿量(P<0.05、0.01).结论 TKT通过促进尿酸分泌、抑制尿酸重吸收及利尿作用,使血清尿酸浓度明显降低、尿尿酸排出量明显增加,显示对实验性高尿酸血症有明显的预防作用.
Study on prophylactic effects and mechanism of Tongfeng Kangning Tables on hyperuricemia
Objective To evaluate of Tongfeng Kangning Tables(TKT)in the prophylactic effect and mechanism study of hyperuricemia in various experimental models.Methods A rat model of hyperuricemia was established using ig administration yeast extract in combination with ip potassium oxonate.Yeast extract(20 g·kg-1)was ig administered for seven consecutive days,and drug administration initiated on the 5th d of yeast extract gavage,groups included a control group,a model group,low,medium,and high dose TKT groups(0.58,1.15,2.30 g·kg-1),and a benzbromarone 27 mg·kg-1 group,the control and model groups received an equal volume of 0.5%CMC-Na daily via ig administration.On the 3rd d of drug administration(the 7th d of ig yeast extract),potassium oxonate at 200 mg·kg-1 was ip injected to induce the model.The preventive effect and mechanism of action of TKT on rat hyperuricemia were evaluated by measuring serum uric acid concentrations,urine volume,uric acid excretion in urine,at 2 h and 4 h post-injection of potassium oxonate,and the expression of URAT1,OAT1,and OAT3 antibodies in the kidneys on the 4th d of drug administration.A mice model of hyperuricemia was induced with hypoxanthine,groups consisted of control group,model group,low-,mid-,and high-dose TKT groups(0.83,1.66,3.33 g·kg-1),and a benzbromarone 39 mg·kg-1 group.These were orally administered once daily for 5 d,with control and model groups receiving an equivalent volume of 0.5%CMC-Na,the preventive effect of TKT against hyperuricemia in mice was assessed through measurements of blood uric acid levels,uricase,and XOD content.A water load model in rats was employed with groups including a control group,low,medium,and high dose TKT groups(0.58,1.15,2.30 g·kg-1),and hydrochlorothiazide 27 mg·kg-1 group.Each group was administered their respective treatments orally once daily for 3 d,while the control group received an equal volume of 0.5%CMC-Na.The diuretic effect of TKT in rats was evaluated by measuring urine volume at 1,2,3,4,and 5 h post-administration,as well as the total urine output within the first 5 h.Results Compared with the model group,TKT groups were significantly reduced serum uric acid(P<0.05,0.01),increased the excretion of uric acid in urine,significantly increased the expression of organic anion transporter 1(OAT1)and decreased urate transporter 1(URAT1)in rats kidney(P<0.05,0.01).TKT 1.66 and 3.33 g·kg-1 could significantly reduce serum uric acid(P<0.05,0.01),0.83,1.66 and 3.33 g·kg-1 increased the uricase level in mice(P<0.05,0.01).TKT 0.58,1.15,and 2.30 g·kg-1 could obviously increase the urine volume at different time points and the total urine volume from 1 to 5 h after administration(P<0.05,0.01).Conclusion TKT reduced the concentration of serum uric acid and increased the excretion of urinary uric acid by promoted the excretion of uric acid,inhibited its reabsorption,and diuretic actions,which demonstrated significant prophylactic efficacy in experimental hyperuricemia.

Tongfeng Kangning Tableshyperuricemiablood uric acidurinary uric acidURAT1OAT1

姜溪、只德广、赵秀义、陈芙蓉、董坚强、岳南

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天津天诚新药评价有限公司,天津 300462

天津市药代动力学和药效动力学重点实验室,天津 300462

天津市新药非临床评价技术工程中心,天津 300462

药物成药性评价与系统转化全国重点实验室,天津 300462

天津市凯文生物科技有限公司,天津 300384

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痛风康宁片 高尿酸血症 尿酸 尿酸盐转运体1 有机阴离子转运体1

2024

药物评价研究
天津药物研究院 中国药学会

药物评价研究

CSTPCD北大核心
影响因子:1.199
ISSN:1674-6376
年,卷(期):2024.47(7)
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