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.