Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV) are
single-stranded positive-sense RNA viruses that cause severe respiratory
diseases to the affected individuals
(Cheng et al. 2007). In December 2019, a
cluster of pneumonia cases emerged in Wuhan, China
(Huang et al. 2020). This disease is now
known as coronavirus disease 2019 (COVID-19) caused by the novel
coronavirus now known as SARS-CoV-2 (severe acute respiratory syndrome
coronavirus 2) that has spread globally, affecting a large portion of
the human population across the world
(Cohen and Normile 2020;
Zhu et al. 2020).
The full range of symptoms for COVID-19 includes self-limiting
respiratory tract illness to severe pneumonia, acute respiratory
distress syndrome (ARDS), multi-organ failure, and death
(Huang et al. 2020;
Ruan et al. 2020a;
Wang et al. 2020a). However, with time
as the number of COVID-19 positive patients increase across the world,
few neurological symptoms such as headache, paresthesia, and
consciousness disorders were reported as well
(Wu et al. 2020b). More recently,
unusual manifestations of COVID-19, including encephalitis,
(Ye et al. 2020), acute necrotizing
hemorrhagic encephalopathy (Poyiadji et
al. 2020), and myocarditis (Doyen et al.
2020) have been documented. Besides, it has been noted that thrombotic
complications in COVID-19 ICU patients increased remarkably
(Klok et al. 2020). Lastly, skin
manifestations like erythematous rash, urticaria, or chickenpox-like
vesicles mainly in the body trunk in COVID-19 patients were reported in
multiple studies (Joob and Wiwanitkit
2020; Recalcati 2020).
Therapeutic options to contain the COVID-19 pandemic is urgently needed.
Favipiravir (T-705) (Wang et al. 2020b)
and ribavirin have been evaluated on COVID-19 patients
(ChiCTR2000029387
), but ribavirin reported side effects
(Zumla et al. 2016). Remdesivir
(GS-5734) has been suggested (Al-Tawfiq et
al. 2020; Cao et al. 2020b) and a
compassionate-use remdesivir study showed 68% clinical improvement in
COVID-19 patients (Grein et al. 2020).
However, very recently, WHO reported controversy to the aforementioned
data, and a full COVID-19 clinical trial of remdesivir was terminated
due to the adverse side effects (unpublished report from WHO
website). In addition, lopinavir–ritonavir treatment on COVID-19
patients did not show any improvement (Cao
et al. 2020a). However, chloroquine, hydroxychloroquine
(Gao et al. 2020;
Gautret et al. 2020) and azithromycin
with hydroxychloroquine showed potential clinical benefits but only in a
limited number of COVID-19 patients
(Gautret et al. 2020). Tocilizumab
(Xu et al. 2020), as well as
convalescent plasma therapy (Duan et al.
2020) in severely ill COVID-19 patients, also improved clinical
outcomes, but inadequate clinical data to justify the observed effect.
Although a range of the aforementioned therapies can be a near-term
strategy to tackle COVID-19, there is still an evident lack of specific
treatment for COVID-19 (Huang et al.
2020).
Methylxanthines are heterocyclic compounds that are methylated
derivatives of xanthine comprising of coupled pyrimidinedione and
imidazole rings (Talik et al. 2012).
Methylxanthines have been widely used for therapeutic purposes for
decades, with proven therapeutic benefits in different medical scopes.
For example, the naturally occurring methylxanthines like caffeine,
theophylline, and theobromine have been used in the treatment of
respiratory diseases (Lam and Newhouse
1990), cardiovascular diseases (Batterman
et al. 1959), cancer (HAYASHI et al.
2005; Kimura et al. 2009) and the
commercially produced xanthine derivative drug like pentoxifylline has
been widely documented to have immunomodulatory properties including the
downregulation of Tumour Necrosis Factor (TNF) α to treat the injurious
effects due to immune activation in the syndrome of chronic heart
failure (CHF) (Shaw et al. 2009).
Pentoxifylline and its active metabolites enhance blood flow by
decreasing blood viscosity and ameliorating erythrocyte flexibility.
Administration of pentoxifylline produced hemorheological activity in a
dose-dependent manner. Based on the aforementioned mode of action,
pentoxifylline has been approved to treat intermittent claudication due
to chronic occlusive arterial disease of the limbs
(Dettelbach and Aviado 1985). In these
patients, pentoxifylline improves microcirculation and tissue
oxygenation (Hsu et al. 1988;
Harris et al. 2017). Pentoxifylline is
also used for the management of alcoholic hepatitis (severe)
(Whitfield et al. 2009) and venous leg
ulcer off-label (Coccheri and Bignamini
2016; Zito and Murgia III 2018).
Moreover, the effect of pentoxifylline has been demonstrated to treat
fibrotic lesions by immunomodulation and by reducing inflammation
(Wen et al. 2017).
Previous research has extensively established the effects of caffeine in
the treatment of respiratory disease, its bronchodilatory effect via
phosphodiesterase (PDE) inhibition, and adenosine receptor antagonism
(Sullivan et al. 1994;
Tilley 2011). Furthermore, caffeine is
widely used to treat apnea of prematurity (AOP) in preterm infants by
improving minute ventilation, CO2 sensitivity, respiratory muscle
function, and neural respiratory drive. Caffeine administration also
improved microcirculation in humans (Okuno
et al. 2002), and moderate caffeine consumption was related to reduced
coronary heart disease and stroke (Bøhn et
al. 2012). Therapeutic indications of caffeine also include its role as
the CNS stimulant to maintain seizure control during epilepsy
(van Koert et al. 2018) as well as its
role in treating headaches. As an adjuvant to analgesics, it enhances
the efficacy of analgesics to treat headache
(Lipton et al. 2017). Besides, the OTC
labeling of caffeine is to restore mental alertness or wakefulness
during fatigue (Childs and de Wit 2008).
Despite the numerous benefits of caffeine, high doses of caffeine may
lead to anxiety disorder (Lara 2010), and
patients with an anxiety disorder are more sensitive to caffeine
(Bruce et al. 1992).
Herein, we review with extensive evidence that widely used
methylxanthines like caffeine and pentoxifylline may be used as an
adjuvant therapy to treat COVID-19 induced respiratory symptoms by
exploiting their reported immunomodulatory and anti-inflammatory
potentials. Tissue oxygen levels have also been shown to be
significantly increased by therapeutic doses of pentoxifylline in
patients with peripheral arterial disease.