PDF(Pubmed)
Abstract：
Drug repurposing has gained significant interest in recent years due to the high costs associated with de novo drug development; however, comprehensive pharmacological information is needed for the translation of pre-existing drugs across clinical applications. In the present study, we explore the current pharmacological understanding of the orphan drug, hemin, and identify remaining knowledge gaps with regard to hemin repurposing for the treatment of cardiovascular disease. Originally approved by the United States Food and Drug Administration in 1983 for the treatment of porphyria, hemin has attracted significant interest for therapeutic repurposing across a variety of pathophysiological conditions. Yet, the clinical translation of hemin remains limited to porphyria. Understanding hemin\'s pharmacological profile in health and disease strengthens our ability to treat patients effectively, identify therapeutic opportunities or limitations, and predict and prevent adverse side effects. However, requirements for the pre-clinical and clinical characterization of biologics approved under the U.S. FDA\'s Orphan Drug Act in 1983 (such as hemin) differed significantly from current standards, presenting fundamental gaps in our collective understanding of hemin pharmacology as well as knowledge barriers to clinical translation for future applications. Using information extracted from the primary and regulatory literature (including documents submitted to Health Canada in support of hemin\'s approval for the Canadian market in 2018), we present a comprehensive case study of current knowledge related to hemin\'s biopharmaceutical properties, pre-clinical/clinical pharmacokinetics, pharmacodynamics, dosing, and safety, focusing specifically on the drug\'s effects on heme regulation and in the context of acute myocardial infarction.
摘要：
近年来，由于与从头药物开发相关的高成本，药物再利用获得了极大的兴趣；然而，在临床应用中翻译现有药物需要全面的药理学信息。在本研究中,我们探索目前对孤儿药的药理学理解，血红素,并确定剩余的知识差距方面的血红素再利用心血管疾病的治疗。最初由美国食品和药物管理局于1983年批准用于治疗卟啉症，血红素在各种病理生理条件下对治疗性再利用引起了极大的兴趣。然而，血红素的临床翻译仍然限于卟啉症。了解血红素在健康和疾病中的药理作用增强了我们有效治疗患者的能力，确定治疗机会或局限性，并预测和预防不良副作用。然而,1983年美国FDA孤儿药法批准的生物制剂（如血红素）的临床前和临床特征要求与现行标准明显不同，在我们对hemin药理学的集体理解以及对未来应用的临床翻译的知识障碍方面提出了根本的差距。使用从主要和监管文献中提取的信息（包括提交给加拿大卫生部的文件，以支持hemin在2018年获得加拿大市场的批准），我们提出了一个全面的案例研究，目前与血红素的生物制药特性有关的知识，临床前/临床药代动力学，药效学,给药,和安全,特别关注药物对血红素调节和急性心肌梗死的影响。
