Helsinn Healthcare SA, Research and Preclinical Department, 6915, Lugano, Switzerland,
J Cachexia Sarcopenia Muscle. 2014 Dec;5(4):329-37. doi: 10.1007/s13539-014-0159-5. Epub 2014 Sep 30.
Anamorelin HCl (ANAM) is a novel, orally active, ghrelin receptor agonist in clinical development for the treatment of cancer cachexia. We report in vitro and in vivo studies evaluating the preclinical pharmacologic profile of ANAM.
Fluorescent imaging plate reader and binding assays in HEK293 and baby hamster kidney cells determined the agonist and antagonist activity of ANAM, and its affinity for the ghrelin receptor. Rat pituitary cells were incubated with ANAM to evaluate its effect on growth hormone (GH) release. In vivo, rats were treated with ANAM 3, 10, or 30 mg/kg, or control orally, once daily for 6 days to evaluate the effect on food intake (FI) and body weight (BW), and once to assess GH response. In pigs, single (3.5 mg/kg) or continuous (1 mg/kg/day) ANAM doses were administered to assess GH and insulin-like growth factor (IGF-1) response.
ANAM showed significant agonist and binding activity on the ghrelin receptor, and stimulated GH release in vitro. In rats, ANAM significantly and dose-dependently increased FI and BW at all dose levels compared with control, and significantly increased GH levels at 10 or 30 mg/kg doses. Increases in GH and IGF-1 levels were observed following ANAM administration in pigs.
ANAM is a potent and highly specific ghrelin receptor agonist with significant appetite-enhancing activity, leading to increases in FI and BW, and a stimulatory effect on GH secretion. These results support the continued investigation of ANAM as a potential treatment of cancer anorexia-cachexia syndrome.
盐酸 anamorelin（ANAM）是一种新型的、口服活性的、胃饥饿素受体激动剂，正在开发用于治疗癌症恶病质。我们报告了评估 ANAM 的临床前药理学特征的体外和体内研究。
荧光成像板阅读器和 HEK293 和幼仓鼠肾细胞中的结合测定法测定了 ANAM 的激动剂和拮抗剂活性及其对胃饥饿素受体的亲和力。用 ANAM 孵育大鼠垂体细胞，以评估其对生长激素（GH）释放的影响。在体内，用 ANAM 以 3、10 或 30mg/kg 或对照口服的方式每天一次治疗大鼠 6 天，以评估对食物摄入量（FI）和体重（BW）的影响，并进行一次评估 GH 反应。在猪中，单次（3.5mg/kg）或连续（1mg/kg/天）给予 ANAM 剂量，以评估 GH 和胰岛素样生长因子（IGF-1）的反应。
ANAM 在胃饥饿素受体上显示出显著的激动剂和结合活性，并在体外刺激 GH 释放。在大鼠中，与对照组相比，ANAM 以剂量依赖性方式显著增加 FI 和 BW ，在 10 或 30mg/kg 剂量下显著增加 GH 水平。在猪中，给予 ANAM 后观察到 GH 和 IGF-1 水平升高。
ANAM 是一种强效且高度特异性的胃饥饿素受体激动剂，具有显著的食欲增强活性，导致 FI 和 BW 增加，并刺激 GH 分泌。这些结果支持继续研究 ANAM 作为治疗癌症厌食恶病质综合征的潜在疗法。
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