{"title":"内皮素靶向疗法终于准备好进入黄金时代了吗?","authors":"Francesca Schinzari, Manfredi Tesauro, Carmine Cardillo","doi":"10.1042/CS20240607","DOIUrl":null,"url":null,"abstract":"<p><p>The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Is endothelin targeting finally ready for prime time?\",\"authors\":\"Francesca Schinzari, Manfredi Tesauro, Carmine Cardillo\",\"doi\":\"10.1042/CS20240607\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.</p>\",\"PeriodicalId\":10475,\"journal\":{\"name\":\"Clinical science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-06-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1042/CS20240607\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1042/CS20240607","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
内皮素肽家族长期以来一直被认为是多种生物功能的生理调节剂,并从机理上参与多种疾病状态,包括心血管系统、肾脏和神经系统等。然而,内皮素系统的药理阻断在进入临床主流领域时遇到了巨大障碍,直到最近才获得了少数几个经证实的适应症。这种转化上的差距主要归因于内皮素受体拮抗剂(ERA)的相关副作用,尤其是体液潴留。然而最近,随着人们对内皮素相关病理生理过程的了解不断加深,以及新的内皮素受体拮抗剂的开发或剂量的调整,推动了新临床试验的蓬勃发展。其中一些试验的良好结果将 ET 靶向治疗的适应症扩展到多种临床病症,包括抵抗性动脉高血压和肾小球疾病。此外,基于强有力的临床前证据,其他研究也在进行中,以测试ERA与其他治疗方法联合使用的潜在益处,如体液潴留状态下的钠-葡萄糖协同转运体2抑制剂或实体瘤的抗癌疗法。此外,目前正在测试可长期阻断内皮素受体的抗体,以克服大多数小分子内皮素拮抗剂半衰期短的问题。这些努力可能会为内皮素靶向策略在临床实践中的应用带来新的生机。
Is endothelin targeting finally ready for prime time?
The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.
期刊介绍:
Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health.
Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively:
Cardiovascular system
Cerebrovascular system
Gastrointestinal tract and liver
Genomic medicine
Infection and immunity
Inflammation
Oncology
Metabolism
Endocrinology and nutrition
Nephrology
Circulation
Respiratory system
Vascular biology
Molecular pathology.