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[大学生论坛]:口服血浆激肽释放酶抑制剂,预防遗传性血管神经性水肿

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蓝色的大海 发表于 2019-1-3 22:37:30 | 显示全部楼层 |阅读模式
Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema
口服血浆激肽释放酶抑制剂,预防遗传性血管神经性水肿




Abstract
摘要


Background
Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein–bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks.
背景
遗传性血管神经性水肿是一种危及生命的疾病,由编码C1抑制物(或称C1酯酶抑制剂)的基因突变引起,导致激肽释放酶 - 缓激肽级联过度活跃。BCX7353是一种强有力的口服小分子血浆激肽释放酶抑制剂,具有药代动力学和药效学类型,可有助于预防血管神经性水肿发作。


Methods
In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life.
研究方法
本试验范围为全球各国,分为三个部分,致力于研究BCX7353剂量范围,以安慰剂作对照。我们评估了4剂不同剂量的BCX7353(62.5 mg,125 mg,250 mg和350 mg,每日一剂)在28天内预防血管神经性水肿发作的效果。病人如果患有I型或II型遗传性血管神经性水肿,且该病每月至少发作两次,则将随机分到BCX7353组或安慰剂组。主要疗效研究指标是确诊血管神经性水肿发作的次数。重点次要研究指标包括解剖学定位下的血管神经性水肿发作以及病人的生活质量。


Results
A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups.
研究结果
本试验我们共计对77名患者进行了随机分组,75名患者摄入了BCX7353或安慰剂,72名患者完成了该试验。患者摄入BCX7353,每日剂量在125 mg及以上,其确诊血管神经性水肿发作率显著低于摄入安慰剂的患者。以125mg剂量相比的差异率为73.8%(P <0.001)。125mg和250mg剂量组生活质量评分也有显著改善(P <0.05)。胃肠道不良事件是最常报告的不良事件,以1级为主,尤其是在两个剂量最高的BCX7353组中,情况更为显著。


Conclusions
Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972.)
结论
每日一次口服125mg或更多的BCX7353,遗传性血管神经性水肿的发作率会显著低于服用安慰剂,轻微的胃肠道症状是其主要的副作用。






作者:Emel Aygören-Pürsün, M.D., Anette Bygum, M.D., D.M.Sci., Vesna Grivcheva-Panovska, M.D., Markus Magerl, M.D., Jochen Graff, M.D., Urs C. Steiner, M.D., Olivier Fain, M.D., Aarnoud Huissoon, M.B., Ph.D., Tamar Kinaciyan, M.D., Henriette Farkas, M.D., Ph.D., D.Sc., Ramon Lleonart, M.D., Hilary J. Longhurst, F.R.C.P., Ph.D., F.R.C.Path., William Rae, M.R.C.P., Massimo Triggiani, M.D., Werner Aberer, M.D., Mauro Cancian, M.D., Ph.D., Andrea Zanichelli, M.D., William B. Smith, M.B., B.S., Ph.D., Maria L. Baeza, M.D., Ph.D., Aurelie Du-Thanh, M.D., Mark Gompels, M.B., B.S., Teresa Gonzalez-Quevedo, M.D., Ph.D., Jens Greve, M.D., Mar Guilarte, M.D., Ph.D., Constance Katelaris, M.D., Ph.D., Sylvia Dobo, M.D., Melanie Cornpropst, Ph.D., Desiree Clemons, M.S., Lei Fang, M.S., Phil Collis, Ph.D., William Sheridan, M.B, B.S., Marcus Maurer, M.D., and Marco Cicardi, M.D.
期刊名称:The New England Journal of Medicine
发表时间:2018-07-26
N Engl J Med 2018; 379:352-362 | DOI: 10.1056/NEJMoa1716995


2015级英语翻译  卢君帅  3151201059
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