From the Departments of Surgery and Obstetrics and Gynecology, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center.
Plast Reconstr Surg. 2021 Apr 1;147(4):875-885. doi: 10.1097/PRS.0000000000007699.
Propranolol, a nonselective β-adrenergic receptor antagonist, is approved by the U.S. Food and Drug Administration to treat problematic infantile hemangiomas, but a subset of patients experience treatment complications. Parents wary of long-term use and side effects consult plastic surgeons on surgical options or as a second opinion. Understanding the mechanism(s) of action of propranolol will allow plastic surgeons to better inform parents.
A systemic literature search was performed to query published translational and basic science studies on propranolol effects on infantile hemangiomas and cells derived from these lesions.
In experimental studies, propranolol was antiproliferative and cytotoxic against hemangioma endothelial and stem cells and affected infantile hemangioma perivascular cell contractility. Propranolol inhibited migration, network formation, vascular endothelial growth factor A production, and vascular endothelial growth factor receptor 2 activation and down-regulated PI3K/AKT and mitogen-activated protein kinase signaling in hemangioma endothelial cells, but it increased ERK1/2 activity in hemangioma stem cells. At effective clinical doses, measured propranolol plasma concentration is 100 times higher than necessary for complete β-adrenergic receptor blockade, yet was 10 to 100 times less than required to induce hemangioma stem cell death.
Propranolol targets multiple cell types in infantile hemangiomas by means of β-adrenergic receptor-dependent and -independent mechanisms. Plasma concentration played a significant role. At clinically relevant doses, incomplete infantile hemangioma suppression may explain the rebound phenomenon and worsening ulceration, and propranolol off target effects may lead to commonly reported adverse effects, such as sleep and gastrointestinal disturbances. Propranolol limitations and complications underscore the importance of surgical treatment options in cases of rebound and severe adverse effects. Surgical intervention remains an important treatment choice when parents are hesitant to use propranolol.
普萘洛尔是一种非选择性β肾上腺素能受体拮抗剂，已被美国食品和药物管理局批准用于治疗有问题的婴儿血管瘤，但有一部分患者会出现治疗并发症。对长期使用和副作用持谨慎态度的父母会咨询整形外科医生，了解手术选择或作为第二意见。了解普萘洛尔的作用机制可以使整形外科医生更好地告知家长。
进行了系统的文献检索，查询了已发表的关于普萘洛尔对婴儿血管瘤及其衍生细胞影响的转化和基础科学研究。
在实验研究中，普萘洛尔对血管瘤内皮细胞和干细胞具有抗增殖和细胞毒性作用，并影响婴儿血管瘤周围细胞的收缩性。普萘洛尔抑制了血管瘤内皮细胞的迁移、网络形成、血管内皮生长因子 A 的产生和血管内皮生长因子受体 2 的激活，并下调了血管内皮生长因子受体 2 的磷酸肌醇 3-激酶/蛋白激酶 B 和丝裂原活化蛋白激酶信号通路，但增加了血管瘤干细胞中的细胞外信号调节激酶 1/2 活性。在有效的临床剂量下，测量的普萘洛尔血浆浓度是完全阻断β肾上腺素能受体所需浓度的 100 倍，但诱导血管瘤干细胞死亡所需的浓度则低 10 至 100 倍。
普萘洛尔通过β肾上腺素能受体依赖性和非依赖性机制作用于婴儿血管瘤的多种细胞类型。血浆浓度起了重要作用。在临床相关剂量下，不完全抑制婴儿血管瘤可能解释了反弹现象和溃疡恶化，普萘洛尔的非靶点作用可能导致常见的不良反应，如睡眠和胃肠道紊乱。普萘洛尔的局限性和并发症突出了在出现反弹和严重不良反应时手术治疗选择的重要性。对于犹豫不决是否使用普萘洛尔的家长来说，手术干预仍然是一个重要的治疗选择。
