非布索坦治疗痛风的系统评价
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摘要
目的系统评价非布索坦治疗痛风的疗效与安全性。
方法检索PubMed、EMBASE、CBM、CNKI、VIP、Cochrane图书馆,检索无语种限制,时间截止到2009年12月,纳入非布索坦治疗痛风的随机对照试验,进行质量评价,运用Revman5.0软件进行Meta分析。
结果共纳入4个随机对照试验,共3073例痛风并高尿酸血症患者,其中非布索坦组2647例,对照组426例。Meta分析结果显示:在疗效方面,非布索坦与安慰剂相比,①血尿酸:非布索坦能更有效降低血尿酸[P<0.00001,RR=112.14,95%CI(35.03,359.03)],血尿酸较基线水平改善[P<0.00001,SMD=-48.96,95%CI(-56.80,-41.11)];②痛风发作:合用预防痛风急性发作药物治疗期间非布索坦组痛风急性发作的发生率高于安慰剂对照组[P<0.00001,RR=1.74,95%CI(1.41,2.14)],停用预防痛风急性发作药物治疗后两组痛风急性发作的发生率无显著性差异[P=0.52,RR=1.04,95%CI(0.92,1.18)]。非布索坦与别嘌醇相比,①血尿酸:能更有效降低血尿酸[P<0.00001,RR=2.55,95%CI(2.32,2.80)],血尿酸较基线水平改善[P<0.00001,SMD=-19.00,95%CI(-23.71,-14.30)];②痛风发作:合用预防痛风急性发作药物治疗期间非布索坦组痛风急性发作的发生率高于别嘌醇对照组[P=0.0010,RR=1.44,95%CI(1.16,1.78)],停用预防痛风急性发作药物治疗后两组痛风急性发作的发生率无显著性差异[P=0.60,RR=1.02,95%CI(0.95,1.10)];③痛风石:两组痛风石缓解情况无显著性差异。有一研究报道患有痛风石的患者长期使血尿酸达标,痛风石的大小和数量较前减少,痛风石完全消失的比例增加。安全性方面,大部分不良反应的程度为轻度至中度,各组的不良反应发生率无显著性差异。非布索坦最常见不良反应为腹泻、头痛、恶心、背痛、眩晕、皮疹、肝功能异常等。非布索坦组严重不良反应在数量上多于安慰剂组,但是没有统计学上的显著性差异。
结论现有临床证据显示,非布索坦较别嘌醇能更有效的降低血尿酸,不良反应相对较轻。
Objective To systemically review and investigate the eficacy and safety of febuxostat for gout.
Methods To search PubMed、EMBASE、CENTRAL、CBM、CNKI、VIP,The search was concluded in December,2009. The quality of randomized controlled trials assessing febuxostat for gout was evaluated.And the extracted data were calculated by the Cochrane Collaboration's software RevMan 5.0.
Result Four trials involving 3073 participants with hyperuricemia and gout. There were 2647 participants in febuxostat groups and 426 participants in control groups.The results of Meta-analysis showed: febuxostat was more effective than placebo in reducing serum urate,the effect sizes was [P<0.00001,RR=112.14,95%CI(35.03,359.03)],serum urate improvement compared with baseline[P<0.00001,SMD=-48.96,95%CI(-56.80,-41.11)]. When gout flare prophylaxis was provided, greater proportions of subjects receiving febuxostat required treatment for gout flares compared with those receiving placebo[P< 0.00001, RR=1.74, 95%CI (1.41,2.14)]. After the prophylaxis period , there were no statistically significant differences in the proportion of subjects requiring treatment for gout flares observed between the febuxostat groups and placebo groups[P=0.52 , RR=1.04 , 95%CI(0.92 , 1.18)]. Compared with allopurinol, febuxostat was more effective than allopurinol in reducing serum urate [P<0.00001,RR=2.55,95%CI(2.32,2.80)], serum urate improvement compared with baseline [P<0.00001,SMD=-19.00,95%CI(-23.71,-14.30)]. When gout flare prophylaxis was provided, greater proportions of subjects receiving febuxostat required treatment for gout flares compared with those receiving allopurinol[P=0.0010,RR=1.44,95%CI(1.16,1.78)]. After the prophylaxis period,there were no statistically significant differences in the proportion of subjects requiring treatment for gout flares observed between the febuxostat groups and allopurinol groups[P=0.60,RR=1.02,95%CI(0.95,1.10)]. No significant differences in the number and size of tophi were observed between treatment groups. Among subjects with tophi, longterm maintenance of the goal serum urate range was accompanied by reductions in the areas of index tophi and and in the number of tophi and by the proportion of index tophi undergoing complete resolution. Most adverse events were mild to moderate in severity. The incidence of adverse events was similar in each group. The most frequently reported adverse events were diarrhea, headache, nausea, back pain, dizziness, skin rash, abnormal liver function and so on. The incidence of serious adverse events was numerically higher with febuxostat than with placebo, but the difference between treatments was not statistically significant.
Conclusions Current evidence demonstrates that febuxostat is efficacy in lowering serum urate. Adverse reactions of its is relatively slighter.
方法检索PubMed、EMBASE、CBM、CNKI、VIP、Cochrane图书馆,检索无语种限制,时间截止到2009年12月,纳入非布索坦治疗痛风的随机对照试验,进行质量评价,运用Revman5.0软件进行Meta分析。
结果共纳入4个随机对照试验,共3073例痛风并高尿酸血症患者,其中非布索坦组2647例,对照组426例。Meta分析结果显示:在疗效方面,非布索坦与安慰剂相比,①血尿酸:非布索坦能更有效降低血尿酸[P<0.00001,RR=112.14,95%CI(35.03,359.03)],血尿酸较基线水平改善[P<0.00001,SMD=-48.96,95%CI(-56.80,-41.11)];②痛风发作:合用预防痛风急性发作药物治疗期间非布索坦组痛风急性发作的发生率高于安慰剂对照组[P<0.00001,RR=1.74,95%CI(1.41,2.14)],停用预防痛风急性发作药物治疗后两组痛风急性发作的发生率无显著性差异[P=0.52,RR=1.04,95%CI(0.92,1.18)]。非布索坦与别嘌醇相比,①血尿酸:能更有效降低血尿酸[P<0.00001,RR=2.55,95%CI(2.32,2.80)],血尿酸较基线水平改善[P<0.00001,SMD=-19.00,95%CI(-23.71,-14.30)];②痛风发作:合用预防痛风急性发作药物治疗期间非布索坦组痛风急性发作的发生率高于别嘌醇对照组[P=0.0010,RR=1.44,95%CI(1.16,1.78)],停用预防痛风急性发作药物治疗后两组痛风急性发作的发生率无显著性差异[P=0.60,RR=1.02,95%CI(0.95,1.10)];③痛风石:两组痛风石缓解情况无显著性差异。有一研究报道患有痛风石的患者长期使血尿酸达标,痛风石的大小和数量较前减少,痛风石完全消失的比例增加。安全性方面,大部分不良反应的程度为轻度至中度,各组的不良反应发生率无显著性差异。非布索坦最常见不良反应为腹泻、头痛、恶心、背痛、眩晕、皮疹、肝功能异常等。非布索坦组严重不良反应在数量上多于安慰剂组,但是没有统计学上的显著性差异。
结论现有临床证据显示,非布索坦较别嘌醇能更有效的降低血尿酸,不良反应相对较轻。
Objective To systemically review and investigate the eficacy and safety of febuxostat for gout.
Methods To search PubMed、EMBASE、CENTRAL、CBM、CNKI、VIP,The search was concluded in December,2009. The quality of randomized controlled trials assessing febuxostat for gout was evaluated.And the extracted data were calculated by the Cochrane Collaboration's software RevMan 5.0.
Result Four trials involving 3073 participants with hyperuricemia and gout. There were 2647 participants in febuxostat groups and 426 participants in control groups.The results of Meta-analysis showed: febuxostat was more effective than placebo in reducing serum urate,the effect sizes was [P<0.00001,RR=112.14,95%CI(35.03,359.03)],serum urate improvement compared with baseline[P<0.00001,SMD=-48.96,95%CI(-56.80,-41.11)]. When gout flare prophylaxis was provided, greater proportions of subjects receiving febuxostat required treatment for gout flares compared with those receiving placebo[P< 0.00001, RR=1.74, 95%CI (1.41,2.14)]. After the prophylaxis period , there were no statistically significant differences in the proportion of subjects requiring treatment for gout flares observed between the febuxostat groups and placebo groups[P=0.52 , RR=1.04 , 95%CI(0.92 , 1.18)]. Compared with allopurinol, febuxostat was more effective than allopurinol in reducing serum urate [P<0.00001,RR=2.55,95%CI(2.32,2.80)], serum urate improvement compared with baseline [P<0.00001,SMD=-19.00,95%CI(-23.71,-14.30)]. When gout flare prophylaxis was provided, greater proportions of subjects receiving febuxostat required treatment for gout flares compared with those receiving allopurinol[P=0.0010,RR=1.44,95%CI(1.16,1.78)]. After the prophylaxis period,there were no statistically significant differences in the proportion of subjects requiring treatment for gout flares observed between the febuxostat groups and allopurinol groups[P=0.60,RR=1.02,95%CI(0.95,1.10)]. No significant differences in the number and size of tophi were observed between treatment groups. Among subjects with tophi, longterm maintenance of the goal serum urate range was accompanied by reductions in the areas of index tophi and and in the number of tophi and by the proportion of index tophi undergoing complete resolution. Most adverse events were mild to moderate in severity. The incidence of adverse events was similar in each group. The most frequently reported adverse events were diarrhea, headache, nausea, back pain, dizziness, skin rash, abnormal liver function and so on. The incidence of serious adverse events was numerically higher with febuxostat than with placebo, but the difference between treatments was not statistically significant.
Conclusions Current evidence demonstrates that febuxostat is efficacy in lowering serum urate. Adverse reactions of its is relatively slighter.
引文
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1.施桂英.走出痛风性关节炎诊断和治疗的误区.中华全科医师杂志, 2006,5:519-522.
2. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2006,65:1312-24.
3. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum, 2004,51:321-5.
4. Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout. J Rheumatol, 2001,28:577-80.
5. Perez-Ruiz F, Atxotegi J, Hernando I, et al. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum, 2006,55:786-90.
6. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum, 2002,47:356-60.
7. Choy G. An update on the treatment options for gout and calcium pyrophosphate deposition. Expert Opin Pharmacother, 2005,6:2443-53.
8. Keith MP, Gilliland WR. Updates in the management of gout. Am J Med, 2007,120:221-4.
9. Massey V, Komai H, Palmer G, et al. On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines. J Biol Chem, 1970,245:2837-44.
10. Horiuchi H, Ota M, Nishimura S, et al. Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice. Life Sci, 2000,66:2051-70.
11. Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother, 1993,27:337-43.
12. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med, 1984,76:47-56.
13. Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum, 1986,29:82-7.
14. Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci, 2005,76:1835-47.
15. Horiuchi H, Ota M, Kobayashi M, et al. A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol, 1999,104:307-19.
16. Adenuric Summary of Product Characteristics accessed at http://www.emea. europa.eu/humandocs/PDFs/EPAR/adenuric/H-777-PI-en.pdf,(date last acc- essed 8th April 2009).
17. Khosravan R, Grabowski B, Wu JT, et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol, 2008,65:355-63.
18. Khosravan R, Grabowski BA, Mayer MD, et al. The effect of mild andmoderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol, 2006,46:88-102.
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24. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum, 2008,59:1540-8.
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1.施桂英.走出痛风性关节炎诊断和治疗的误区.中华全科医师杂志, 2006,5:519-522.
2. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2006,65:1312-24.
3. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum, 2004,51:321-5.
4. Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout. J Rheumatol, 2001,28:577-80.
5. Perez-Ruiz F, Atxotegi J, Hernando I, et al. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum, 2006,55:786-90.
6. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum, 2002,47:356-60.
7. Choy G. An update on the treatment options for gout and calcium pyrophosphate deposition. Expert Opin Pharmacother, 2005,6:2443-53.
8. Keith MP, Gilliland WR. Updates in the management of gout. Am J Med, 2007,120:221-4.
9. Massey V, Komai H, Palmer G, et al. On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines. J Biol Chem, 1970,245:2837-44.
10. Horiuchi H, Ota M, Nishimura S, et al. Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice. Life Sci, 2000,66:2051-70.
11. Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother, 1993,27:337-43.
12. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med, 1984,76:47-56.
13. Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum, 1986,29:82-7.
14. Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci, 2005,76:1835-47.
15. Horiuchi H, Ota M, Kobayashi M, et al. A comparative study on the hypouricemic activity and potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol, 1999,104:307-19.
16. Adenuric Summary of Product Characteristics accessed at http://www.emea. europa.eu/humandocs/PDFs/EPAR/adenuric/H-777-PI-en.pdf,(date last acc- essed 8th April 2009).
17. Khosravan R, Grabowski B, Wu JT, et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol, 2008,65:355-63.
18. Khosravan R, Grabowski BA, Mayer MD, et al. The effect of mild andmoderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol, 2006,46:88-102.
19. Mayer MD, Khosravan R, Vernillet L, et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther, 2005,12:22-34.
20. Khosravan R, Kukulka MJ, Wu JT, et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol, 2008,48:1014-24.
21. Osada Y, Tsuchimoto M, Fukushima H, et al. Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents. Eur J Pharmacol, 1993,241:183-8.
22. Komoriya K, Osada Y, Hasegawa M, et al. Hypouricemic effect of allopurinol and the novel xanthine oxidase inhibitor TEI-6720 in chimpanzees. Eur J Pharmacol, 1993,250:455-60.
23. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum, 2005,52:916-23.
24. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum, 2008,59:1540-8.
25. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med, 2005,353:2450-61.
26. Schumacher HR Jr. Presentati on at ACR /ARHP 68 th annual scientific meeting[C]. San Ant onio, 2004: 10, 16 - 21.
27. Schumacher HR Jr, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford), 2009,48:188-94.
28. Khosravan R, Grabowski BA, Wu JT, et al. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet, 2006,45:821-41.