Centre for Human Drug Repurposing and Medicines Research, University of Newcastle, NSW, 2305, Australia.
University of South Australia, South Australia, Australia.
Br J Clin Pharmacol. 2021 Mar;87(3):875-885. doi: 10.1111/bcp.14551. Epub 2020 Nov 18.
With any new disease a framework for the development of preventative or treatment therapeutics is key; the absence of such in COVID-19 has enabled ineffective and potentially unsafe treatments to be taken up by governments and clinicians desperate to have options for patients. As we still have few therapies and nil vaccines yet available, the void of a clear framework for research and practice is increasingly clear. We describe a framework that has been used to prioritise therapeutic research in previous pandemics which could be used to progress clinical pharmacology and therapeutics research in COVID-19. This is particularly relevant as discussion has already moved on from antiviral therapeutics to delineating the treatment of the host from treatment and elimination of the infective agent. Focussing on the host brings together three concepts: host treatment, the damage response framework and therapeutic repurposing. The integration of these three areas plays to the traditional strength of pharmaceuticals in providing a period of stabilization to permit time for the development of novel antiviral drugs and vaccines. In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must possess by way of a framework. There must be homology, i.e., the same or similar relation with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the viral attack; there must be a defined locus within the spectrum to prevention to severe disease and the framework must draw upon the historical dose and safety experience of the repurposed drug. To illustrate, we have mapped therapeutics that impact upon a key dysregulated pathway in COVID-19 - the renin angiotensin system - using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the importance of the details of the known pathophysiological response to viruses in approaches to treating the host.
对于任何新疾病，制定预防或治疗疗法的框架都是关键；在 COVID-19 中缺乏这种框架，使得政府和临床医生急于为患者提供选择，从而采用了无效且可能不安全的治疗方法。由于我们仍然几乎没有治疗方法和疫苗，因此研究和实践的明确框架的缺失变得越来越明显。我们描述了一个以前在大流行中用于优先考虑治疗研究的框架，该框架可用于推进 COVID-19 的临床药理学和治疗学研究。这一点尤为重要，因为讨论已经从抗病毒疗法转移到了从治疗和消除感染因子的角度来描述宿主的治疗方法。关注宿主将三个概念结合在一起：宿主治疗、损伤反应框架和治疗重新定位。这三个领域的整合发挥了制药行业的传统优势，为开发新型抗病毒药物和疫苗提供了稳定期。在整合重新定位、宿主治疗和损伤反应的方法时，我们确定了一个潜在有效重新定位药物必须具备的三个关键特性，即框架。必须具有同源性，即与疾病的发病机制相同或相似，理想情况下针对病毒攻击的保守病理生理结果进行靶向治疗；必须在预防严重疾病的范围内具有明确的位置，并且该框架必须利用重新定位药物的历史剂量和安全性经验。例如，我们使用这种方法来映射影响 COVID-19 中关键失调途径的治疗药物 - 肾素血管紧张素系统。总的来说，这种类型的分析揭示了现有数据（重新定位信息和行政观察数据）的重要性，以及在治疗宿主时了解病毒引起的已知病理生理反应的细节的重要性。
