Proposed drugs
Drugs that can increase ACE2 activity include losartan (NCT04312009, NCT04311177, NCT04340557, NCT04343001; clinicaltrials.gov), diminazene diaceturate, resorcinolnaphthalein, and xantenone [Li et al. 2020]. Furthermore, recombinant ACE2 has been proposed in both pneumonia [Khan et al. 2017] and Covid-19 [Monteil et al. 2020].
Currently, remdesevir, used against ebola, chloroquine/hydroxylchloroquine, used against malaria [Yazdany and Kim 2020; Luo et al. 2020], are being used for Covid-19 patients. A “cytokine storm” has been proposed several times as responsible of Covid- 19 lethality [Moccia et al. 2019]; therefore the anti-IL-6 receptor antibody, tocilizumab (used for the treatment of rheumatoid arthritis and CRS after CAR-T therapies), has been proposed in many clinical studies, and it is now in Phase II and Phase III studies in Covid-19 patients [Alvi et al. 2019; Lu et al. 2020; Luo et al. 2020]. Monoclonal antibodies, anti-IL-1 and anti-IL-6 and plasma derived from Covid-19 recovered patients have been proposed (https://www.sciencenews.org/article/coronavirus-covid-19-can-plasma-recovered-patients-treat-sick). Other anti-inflammatory drugs, comprising JAK inhibitors, and glucocorticoids may also be useful [Zhang et al. 2019]. Coagulopathies are also a prominent aspect of severe Covi-19 patients. Thus, anticoagulant treatment may decrease mortality [Tang et al. 2020]. While waiting for vaccines and new therapeutic strategies to fight this terrible pandemic different old antiviral options are under clinical trial as combination therapies. These include hydroxychloroquine given alone or with azithromycin, and remdesivir, as well as lopinavir/ritonavir alone or with interferon (ClinicalTrials.gov identifier: NCT04332094; NCT04332107; NCT04322123; NCT04335552; NCT04336332; NCT04339816). To the best of our knowledge none of these studies considered different therapeutic approaches for men and women. Moreover, for many of these drugs the effects on ACE/ACE2 ratio is unknown.
A recent study [Fagone et al. 2020] investigated the transcriptomic profile of primary human lung cells upon infection with SARS-CoV-2. In this study the transcriptomic profile of lung tissue from healthy women and men were compared with the transcriptomic induced by Covid-19. It emerged that at ages 40-60 years, the transcriptomic feature of female lung tissue was more similar to those induced by Covid-19 than in male tissue. The authors suggest that a lower threshold of acute response to SARS-CoV-2 infection in men may at least partly explain the lower lethality in women. Nevertheless, the potential factors that might induce this” COVID-19-resistant lung phenotype” in middle-aged women is not clear. In this study targeting the mammalian target of rapamycin (mTOR) pathway using sirolimus, appeared to be a promising therapeutic approach to fight Covid-19. Also mitogen-activated protein kinase kinase (MEK), I kappa B Kinase (IKK) and serine-threonine kinase (AKT) inhibitors have been proposed as candidate drugs [Fagone et al. 2020]. Of note some of these enzymese are linked to ACE2 anti-inflamamtory action [Dhawale et al. 2016]. Nevertheless, this study does not envisage different therapeutic approaches for men and women.
In conclusion, all the above mentioned drugs would warrant clinical studies. In particular, drugs that can affect ACE/ACE2 ratio may be considered (Fig 1). Besides a plethora of factors that may influence the outcome, sex must be one of the criteria to consider in order to select the appropriate therapy for the appropriate patients. Indeed, given the striking differences in lethality between the two sexes, we believe that studying the sex differences may help to find the appropriate therapies for all. Only large unbiased studies considering all the factors and hypotheses mentioned here concerning sex differences may explain why women are less at risk of dying from COVID-19 and might help to find the patient tailored therapy.