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The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: A phase II, randomized, double-blind, placebo-controlled, multicenter study

机译:醛固酮合酶抑制对高血压患者醛固酮和皮质醇的影响:II期,随机,双盲,安慰剂对照的多中心研究

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摘要

Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30mg once daily with a 90% prediction interval of 0.88mg once daily to 1.81mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.
机译:阻断肾素-血管紧张素-醛固酮系统(RAAS)是降低高血压患者血压的一种既定方法。 RAAS级联的最终产物醛固酮通过增加肾脏中的盐分重吸收和儿茶酚胺从肾上腺髓质中释放而发挥作用。当前可用的醛固酮抑制剂具有增加循环醛固酮的缺点,因此可能导致醛固酮突破。醛固酮合酶抑制(ASI)是一种抑制RAAS的新方法。由于负责醛固酮合成(CYP11B2)和皮质醇合成(CYP11B1)的酶之间的同源性,醛固酮合成的阻断作用也可能抑制皮质醇的释放。作者评估了新型ASI LCI699对高血压患者对促肾上腺皮质激素(ACTH)刺激的皮质醇反应的作用,以寻找该患者群体的最大耐受剂量(MTD)。在评估的63位患者中,LCI699对醛固酮和ACTH刺激的皮质醇都有剂量和时间依赖性。根据暴露-反应分析,MTD估计为每日一次1.30mg,90%的预测间隔为每天0.88mg至每天1.81mg。没有患者需要对肾上腺功能不全进行干预。 LCI699具有良好的耐受性,无严重不良事件。

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