Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Am J Obstet Gynecol. 2022 Feb;226(2S):S1157-S1170. doi: 10.1016/j.ajog.2020.09.014. Epub 2020 Sep 16.
There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.
针对子痫前期的预防或治疗，人们一直在寻找新的治疗药物，这些药物可以影响潜在的疾病病理生理学。候选治疗方法的分子靶点包括氧化应激、抗血管生成因子以及血管紧张素、一氧化氮和促炎途径。正在进行临床前和临床试验评估的拟议治疗方法被认为作用于胎盘或内皮疾病或两者兼有。大多数治疗方法都采用了重新利用药物的实用策略。在所提出的所有治疗药物中，普伐他汀受到了最多的关注。有临床前研究表明，它具有多种作用，可以对多个分子靶点产生有利影响，并可以解决许多动物模型中的子痫前期表型。一项早期临床试验表明它可能具有治疗活性。几项大型预防试验正在计划或进行中，完成后可以明确确定普伐他汀是否可以预防子痫前期。质子泵抑制剂、二甲双胍和柳氮磺胺吡啶是其他具有多种分子作用的临床前证据的药物，可以解决子痫前期的病理生理学。这些药物也正在临床试验中进行评估。最近有许多临床前研究确定了许多天然化合物治疗子痫前期的潜力，例如具有强大抗炎或抗氧化活性的植物提取物和微量营养素。最近的临床前研究还提出了新的分子靶向策略，例如针对肿瘤坏死因子-α、胎盘生长因子和小干扰 RNA 技术的单克隆抗体，以沉默可溶性 fms 样酪氨酸激酶-1 或血管紧张素原的基因表达。其他已过渡到人体试验的治疗方法（从单臂到已完成或正在进行的 III 期试验）包括叶酸、一氧化氮供体（如 L-精氨酸）、重组抗凝血酶 III、地高辛免疫抗原结合片段和褪黑素。有病例系列表明，清除循环中的可溶性 fms 样酪氨酸激酶-1 可能有助于稳定病情并延长妊娠时间。有趣的是，有病例报告表明，单克隆抗体依库珠单抗（补体抑制剂）可能具有治疗潜力。如果发现新的药物被证明可以有效预防或治疗子痫前期，那么改善全球母婴和围产期健康的潜力将是巨大的。
