Using "old" medications to fight new COVID-19: Re-purposing with a purpose.

When the COVID-19 pandemic first emerged at the end of 2019, there were many speculations about the potential impact and course of progression, but none would have imagined the speed and the scale of its spread and devastation to people's lives and livelihood across the global [1,2]. Despite the unprecedented efforts and rapid scientific progress in the discovery of the cellular and molecular details for the pathogenesis of COVID-19 as a result of SARS-COV2 infection, there are still no specific new therapies that have been approved to either prevent or treat COVID19 in clinics [1,2]. However, new insights towards the pathogenesis of COVID19 have led to many efforts to repurpose existing drugs for the disease. Among them, hydroxychloroquine [3], Remdesivir [4,5] and dexamethasone [6] have received a great deal of attention, albeit with mixed results.

While many of these repurposing attempts are aimed to interrupt the life-cycle of the SARS-COV2 virus infection or the ensuing systemic inflammatory injury, it is now clear that the adverse outcome of COVID19 can be strongly contributed by a number of pre-existing conditions, in particular hypertension and metabolic disorders. In recent retrospective studies led by a consortium of investigators based on a large clinical cohort of hospitalized COVID-19 patients in Hubei, China, one class of medicine originally used for blood pressure management (angiotensin-converting enzyme inhibitor or angiotensin-receptor blockers) [7], and another class of medication originally prescribed for hyperlipidemia (statins) [8], were analyzed for their association with COVID-19 related death and other secondary outcome. After extensive adjustment and matching for major clinical risk profiles, statistical analyses showed both ACEi/ARB and statins were found to be associated with a significant reduction in death and adverse outcome in hospitalized COVID-19 patients. For ACEi/ARB, several other studies have also reported either neutral or protective benefits [9,10]. For statin, this first report from Hubei cohort has not been confirmed by others. Nevertheless, it is emerging that several therapies originally approved to treat pre-existing conditions may bring clinical benefits to reduce death and severe complications in COVID-19 patients (Fig. 1 ). The putative SARS-CoV-2 entry receptor ACE2 is widely expressed in the cardiovascular system which has been suggested to play a key role in mediating the cardiovascular harm of the virus.

Fig. 1

Using standard medications to fight new COVID-19. As many comorbidities are contributing to the worse outcome of COVID-19 in selected patients, combining standard therapies such as statins and/or ACE inhibitors/angiotensin II receptor blockers with more specific anti-viral approaches may have beneficial effects in the long-term. ACEi, angiotensin converting enzyme inhibitor.

Angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) are designed to counter the hyperactivated renin/angiotensin system (RASS). While working in vasculature and myocardium to achieve blood pressure lowering and cardioprotective effects, this class of medication can also target immune system to tamper global inflammatory responses. Interestingly, although statins are mainly used to control serum cholesterol and lipid levels by inhibiting endogenous cholesterol/lipid synthesis pathways, extensive literature has also implicated their profound anti-inflammatory effects as well. Therefore, the underlying mechanisms for the observed benefits from ACEi/ARB or statins may go beyond the targeted amelioration for the hypertension or the hyperlipidemia conditions. If proven true, the application of these medications may be expanded to the COVID-19 patients without these pre-existing risk factors. While highly promising, the clinical application of these “old” medications as first-line treatment for COVID-19 will need to be carefully examined in randomized clinical trials. For researchers, these newly observed benefits of ACEi/ARB and Statins in COVID-19 patients also raise many questions about the viral-host interaction at molecular, cellular and organ levels. There is no doubt that some “old” knowledge from these repurposed medications may offer important clues to new and effective therapies for COVID-19 disease.

Declaration of Competing Interest

TT is founder and shareholder of Cardior Pharmaceuticals GmbH. YW is a founder and shareholder of Ramino Inc.