Anti-emetic effects of thalidomide: Evidence, mechanism of action, and future directions.
Anti-emetic effects of thalidomide: Evidence, mechanism of action, and future directions.
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DOI：
10.1016/j.crphar.2022.100138
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发表时间：
2022
影响因子：
--
通讯作者：
Sanger, Gareth J
中科院分区：
文献类型：
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作者：
Andrews, Paul L R;Williams, Robin S B;Sanger, Gareth J
在20世纪50年代末，使用沙利度胺(THD)治疗妊娠期间的恶心和呕吐的理由似乎是基于其镇静或催眠特性。与同时期关于吩噻嗪止吐活性的研究相比，我们无法确定报告THD作为止吐药物的临床前或临床评估的出版物。我们对文献的调查显示，1965年的一项临床研究表明，THD可以减少癌症化疗中的呕吐，这一点在2000年的类似研究中得到了证实，特别是在化疗引起的恶心和呕吐的延迟期显示出疗效。为了确定沙利度胺的止吐作用可能涉及的机制(S)，我们从恶心和呕吐的机制以及它们的药理作用，特别是化疗和妊娠方面综述了沙利度胺的药理作用。这个过程确定了以下可能的机制：减少生长分化因子15的分泌，抑制炎症/前列腺素的产生，下调细胞毒性药物诱导的iNOS上调，以及调节BK(KCa1.1)通道和GABAA/谷氨酸在呕吐通路的关键点(孤束核、最后区)的传递。我们提出了一些方法来研究这些假设的机制，并讨论相关的挑战(例如，恶心的客观量化)，以及开发治疗恶心和呕吐的新药的一些更一般的方面。沙利度胺在妊娠和化疗中的止吐作用机制尚不清楚。本文综述了沙利度胺的止吐作用和药理作用，并对其可能的作用机制进行了探讨。沙利度胺降低GDF15、iNOS和促炎基因表达可能是其作用机制之一。潜在的神经靶点是呕吐通路中临界点的KCa1.1、GABAA/谷氨酸。讨论了测试所提出的机制和开发新的止吐药物的挑战。
The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (KCa1.1) channels and GABAA/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting. The mechanism of the anti-emetic effect of thalidomide in pregnancy and chemotherapy is not known. Thalidomide's anti-emetic use and pharmacology is reviewed and potential mechanisms discussed. Thalidomide-induced reduction of GDF15, iNOS and proinflammatory gene expression are possible mechanisms. Potential neural targets are KCa1.1, GABAA/glutamate at critical points in emetic pathways. The challenges of testing proposed mechanisms and developing novel anti-emetics are discussed.