Université Paris Descartes, Faculté de Médecine, Paris, France.
Hypertension. 2010 Nov;56(5):831-8. doi: 10.1161/HYPERTENSIONAHA.110.157271. Epub 2010 Sep 13.
We report the first administration of an orally active aldosterone synthase inhibitor, LCI699, to 14 patients with primary aldosteronism. After a 2-week placebo run-in, patients received oral LCI699 (0.5 mg BID) for 2 weeks, LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in hormone concentrations, plasma potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of LCI699 (-68%; P<0.0001) and to 133 pmol/L (95% CI: 100 to 177 pmol/L) after 1.0 mg of LCI699 (-75%; P<0.0001). Plasma 11-deoxycorticosterone concentrations increased by 710% after 0.5 mg of LCI699 (P<0.0001) and by 1427% after 1.0 mg of LCI699 (P<0.0001). The plasma potassium concentration increased from 3.27±0.31 to 4.03±0.33 mmol/L (P<0.0001) after only 1 week on 0.5 mg of LCI699. Twenty-four-hour ambulatory systolic blood pressure decreased by -4.1 mm Hg (95% CI: -8.1 to -0.1 mm Hg) after 4 weeks of treatment (P=0.046). Basal plasma cortisol concentrations remained unchanged, whereas plasma adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of LCI699 (P=0.08) and by 113% after 1.0 mg of LCI699 (P<0.0001), and the plasma cortisol response to an adrenocorticotropic hormone test was blunted. All of the variables except plasma 11-deoxycorticosterone concentration returned to initial levels after the placebo. LCI699 was well tolerated. In conclusion, the administration of LCI699, up to 1.0 mg BID, effectively and safely inhibits aldosterone synthase in patients with primary aldosteronism. This 4-week treatment corrected the hypokalemia and mildly decreased blood pressure. The effects on the glucocorticoid axis were consistent with a latent inhibition of cortisol synthesis.
我们报告了首例原发性醛固酮增多症患者口服醛固酮合酶抑制剂 LCI699 的治疗。在为期 2 周的安慰剂导入期后，患者接受 LCI699（0.5mg，bid）治疗 2 周，LCI699（1.0mg，bid）治疗 2 周，随后安慰剂治疗 1 周。我们评估了激素浓度、血浆钾水平、24 小时动态收缩压的变化以及安全性。LCI699 0.5mg 治疗后，卧位血浆醛固酮浓度从 540pmol/L（95%CI：394-739pmol/L）降至 171pmol/L（95%CI：128-230pmol/L）（-68%；P<0.0001），LCI699 1.0mg 治疗后降至 133pmol/L（95%CI：100-177pmol/L）（-75%；P<0.0001）。LCI699 0.5mg 治疗后，11-脱氧皮质醇浓度增加了 710%（P<0.0001），LCI699 1.0mg 治疗后增加了 1427%（P<0.0001）。仅在 LCI699 0.5mg 治疗 1 周后，血浆钾浓度从 3.27±0.31mmol/L 增加至 4.03±0.33mmol/L（P<0.0001）。治疗 4 周后，24 小时动态收缩压下降-4.1mmHg（95%CI：-8.1 至-0.1mmHg）（P=0.046）。基础血浆皮质醇浓度保持不变，而 LCI699 0.5mg 治疗后，促肾上腺皮质激素浓度增加 35%（P=0.08），LCI699 1.0mg 治疗后增加 113%（P<0.0001），且促肾上腺皮质激素试验的皮质醇反应受到抑制。除血浆 11-脱氧皮质醇浓度外，所有变量均在安慰剂后恢复至初始水平。LCI699 耐受性良好。总之，LCI699 的给药剂量高达 1.0mg，bid，可有效、安全地抑制原发性醛固酮增多症患者的醛固酮合酶。这种 4 周的治疗纠正了低钾血症并轻度降低了血压。对糖皮质激素轴的影响与皮质醇合成的潜在抑制一致。
