First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension.
First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension.
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DOI：
10.1161/hypertensionaha.121.17159
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Burnett JC Jr
中科院分区：
文献类型：
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作者：
Chen HH;Wan SH;Iyer SR;Cannone V;Sangaralingham SJ;Nuetel J;Burnett JC Jr
MANP是一种新的心钠素(ANP)类似物，被设计为一种创新的颗粒鸟苷酸环化酶A受体(GC-A)激活剂。其设计的基本原理是开发一种同类最好的GC-A激动剂，与内源性ANP相比，具有增强cGMP激活、利钠、抑制醛固酮和降低血压(BP)的作用，用于治疗高血压。在这里，我们报道了第一项关于MANP在高血压患者中的安全性、耐受性、神经体液、肾脏和血压降低特性的研究。这是一项开放标签的序贯单一递增剂量(SAD)设计，所有受试者在接受单次MANP皮下注射(SQ)之前停用所有抗高血压药物14天。MANP是安全的，耐受性良好，激活cGMP，诱导钠尿，降低醛固酮，降低血压，达到或低于最大耐受量。因此，MANP具有良好的安全性，并对人类高血压产生预期的药理作用。我们的结果支持进一步研究MANP作为一种潜在的降压、利钠和抑制醛固酮的药物来治疗高血压，特别是难治性高血压。MANP作用机制：MANP是一种40个氨基酸的设计利钠肽，它激活GC-A受体，刺激其第二信使cGMP的产生。在与肾、血管和肾上腺的GC-A结合后，MANP介导利钠、血管扩张和醛固酮抑制。
MANP is a novel atrial natriuretic peptide (ANP) analogue engineered to be an innovative particulate guanylyl cyclase A receptor (GC-A) activator. The rationale for its design was to develop a best-in-class GC-A activator with enhanced cGMP activating, natriuretic, aldosterone suppressing and blood pressure (BP) lowering actions, compared to endogenous ANP, for the treatment of hypertension. Here we report the first-in-human study on the safety, tolerability, neurohumoral, renal and BP lowering properties of MANP in hypertension subjects. This was an open label sequential single ascending dose (SAD) design in which all subjects stopped all anti-hypertensive agents for 14 days prior to receiving a single subcutaneous (SQ) injection of MANP. MANP was safe, well-tolerated and activated cGMP, induced natriuresis, reduced aldosterone, and decreased BP at or below the maximal tolerated dose. Thus, MANP has a favorable safety profile and produced expected pharmacological effects in human hypertension. Our results support further investigations of MANP as a potential future BP lowering, natriuretic and aldosterone-suppressing drug for hypertension especially resistant hypertension. MANP Mechanism of Action: MANP, a 40 amino acid designer natriuretic peptide, activates the GC-A receptor stimulating the generation of its second messenger cGMP. After binding to GC-A in the kidney, the vasculature and the adrenal gland, MANP mediates natriuresis, vasodilatation and aldosterone inhibition.