Recent articles have reported elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased patients with Covid-19. Platelets are critical in the formation of thrombi, and their most potent trigger is platelet-activating factor (PAF).

A recent exploration identified MK among the top-scoring clinically oriented drugs likely to inhibit SARS-CoV-2 main protease

PAF is produced by cells involved in host defence, and it’s biological actions bear similarities with Covid-19 disease manifestations, including pulmonary microthromboses and inflammation, possibly via activation of mast cells.   

The histamine1 receptor antagonist rupatadine was developed to have anti-PAF activity and inhibits the activation of human mast cells in response to PAF. Rupatadine could be repurposed for Covid-19 prophylaxis.   

Similarly, with the lack of effective therapy, focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic. Interestingly, a recent exploration identified montelukast (MK), from the Leukasts family (LKs; ie cysteinyl leukotriene receptors antagonists), among the top-scoring clinically oriented drugs likely to inhibit SARS-CoV-2 main protease (Huynh et al 2020).  

One retrospective study consistently found that older asthmatic outpatients receiving MK had fewer episodes of confirmed Covid-19 than those not using MK (Bozek and Winterstein, 2020).   

Background  

Coronaviruses are a large family of single-stranded RNA viruses, which infect animals and humans.  

Covid-19 is primarily spread between people during close contact, most often via small droplets produced by coughing, sneezing, and talking. Covid-19 is characterised by:   

  • Fever 
  • Cough 
  • Severe pneumonia 
  • RNAaemia. 

These are combined with the incidence of ground-glass opacities, clot formation and endotheliitis, and a variety of clinical signs including fatigue, cardiac and neurological outcomes (Ahn et al 2020). While the majority of cases result in only mild symptoms, some progress to acute respiratory distress syndrome (ARDS) possibly precipitated by a significant increase in blood levels of cytokines and chemokines. This cytokine storm, reportedly due to angiotensin-converting enzyme-2 (ACE2) downregulation by SARS-CoV-2 (Bourgonje et al 2020), triggers a pro-inflammatory environment that is strongly associated with severe tissue damages, contributing to ARDS and fatal outcomes of Covid-19 patients (Kimura et al 2013).  

As of June 2020, the Covid-19 pandemic has affected millions of people in 196 countries and left thousands dead.   

Rupatadine’s role  

Ackermann et al recently reported the presence of severe endothelial injury and widespread pulmonary microthromboses accompanied by increased angiogenesis in lungs from deceased patients with coronavirus 2019 (Covid-19). These results support other recent publications from different centres reporting the presence of elevated coagulation markers and microthromboses in the lung and other organs of patients with Covid-19. Most recently, platelet activation and aggregation have been reported in patients with severe Covid-19, but the triggers of these processes were not discussed.  

The most potent trigger of platelet aggregation is a platelet-activating factor (PAF), first discovered by Benvesiste in 1971. Demopoulos et al elucidated its structure as a glyceryl-ether lipid (1-O-alkyl-2-acetyl-snglycero-3-phosphocholine) and described its semisynthetic preparation in 1979. PAF is produced by cells involved in host defence, and it’s biological actions bear similarities with Covid-19 disease manifestations. It was recently reported that platelets, via release of PAF, trigger perivascular mast cell activation, leading to inflammation. Moreover, mast cell degranulation associated with interstitial edema and immunothrombosis was recently reported in alveolar septa of deceased patients with Covid-19.  

Mast cells are a rich source of PAF and are plentiful in the lungs, where they may contribute to Covid-19.  

It was previously reported that levels of PAF were increased in allergic rhinitis and chronic urticaria, both of which involve activation of mast cells. Moreover, PAF appears to play a central role in inflammation. In this context, innate immunity to Covid-19 appears to involve activated T cells and specific antibodies. In addition, lung pathologic findings seen in severe acute respiratory syndrome (SARS) associated with Covid-19 are caused by a release of a storm of proinflammatory cytokines.  

Mast cells are one of the richest sources of such cytokines, especially interleukin 6which has been implicated in Covid-19. Because mast cells are involved in lung diseases, it makes sense that such patients would be even more susceptible to pulmonary complications of Covid-19.  

Given these findings, it would make sense to try to inhibit the action of PAF. A number of PAF inhibitors have been synthesised but are not available for clinical use, except for the histamine receptor antagonist rupatadine, which was developed to specifically exhibit anti-PAF activity.  The study authors reported that rupatadine also inhibits the activation of human mast cells in response to PAF.  Rupatadine could, therefore, be repurposed for at least Covid-19 prophylaxis. Interestingly, certain natural flavonoids also have anti-PAF activity, in addition to their having anti-inflammatory actions and the ability to block Covid binding to target cells.  

Montelukast 

Barre´et al published a review of evidence in 2020 advocating that montelukast should be further tested to prevent and treat Covid-19 outcomes.  

With the lack of effective therapy, focusing on the immediate repurposing of existing drugs gives hope of curbing the pandemic. Interestingly, montelukast, a drug usually used in asthma, may be proposed as a potential adjuvant therapy in Covid-19. The aim of Barre´et al (2020) was to review the properties of montelukast that could be beneficial in Covid-19  

Ten experimentally supported properties were retrieved, either related to SARS-CoV-2 (antiviral properties, prevention of endotheliitis and of neurological disorders linked to SARS-CoV-2), and/or related to the host (improvement of atherogenic vascular inflammation, limitation of the ischaemia/reperfusion phenomenon, improvement of respiratory symptoms), and/or related to serious Covid-19 outcomes (limitation of the cytokine storm, mitigation of acute respiratory distress syndrome), and/or related to tissue sequelae (antioxidant properties, anti-fibrosis effects). Based on gathered theoretical evidence, the study authors argued that montelukast should be further tested to prevent and treat Covid-19 outcomes.  

MK works as cysteinyl leukotriene (cysLT) receptor antagonist. Leukotrienes are inflammatory mediators produced by the immune system. They promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and chronic obstructive pulmonary disease. Consequently, the use of high-dose MK as an anti-inflammatory agent is effective in acute asthma (Wu et al 2003). MK is mainly used as a complementary therapy in adults in addition to inhaled corticosteroids. The use of MK is also known to decrease the frequency and severity of wheezing after an upper respiratory tract infection caused by adenovirus, influenza, metapneumovirus or coronavirus (Brodlie et al 2015). Common side effects include diarrhoea, nausea, vomiting, mild rashes, asymptomatic elevations in liver enzymes and fever. In 2019 and 2020, concerns for neuropsychiatric reactions were added to the label in the UK and US where the most frequently suspected symptoms were nightmares, depression, insomnia, aggression, anxiety and abnormal behaviour (Glockler-Lauf et al 2019).  

Apart from MK, LKs also include zafirlukast (ZK) and pranlukast (PK). These three compounds may have properties of potential interest to treat Covid-19.  

Properties of MK related to SARS-CoV-2  

Antiviral properties 

Several antiviral properties of MK, potentially useful in Covid-19, have been described in vitro and in vivo, based on distinct mechanisms depending on the virus under investigation. For Influenzae A virus, an inhibition of the expression of the viral genome was observed with MK (Landeras-Bueno et al 2016).  

For Flaviviridae, particularly in the Zika virus, irreversible and early inactivation of the virus was reported, probably due to some damage to the lipid membrane (Chen et al 2020). Three distinct mechanisms were proposed to support the beneficial impact of MK on Zika virus: 1) a direct antiviral action, 2) an antagonisation of the cytokine storm, and 3) inhibition of the vertical transmission by an MK-related neuroprotective effect on the brain of a foetus 

For the hepatitis C virus, MK induced a dose-dependent decrease in the levels of RNAs expressed, indicating inhibition of viral replication (Ruiz et al 2020). Morita et al (2017) have reported a decrease of almost 50% in the number of colds in younger boys aged one to five.  

Endotheliitis induced by SARS-CoV-2 infection  

SARS-CoV-2 interacts with the ACE2 receptors to infect the host (Bourgonje et al 2020). This process is thought to promote the development of endotheliitis (Varga et al 2020), a condition that may be responsible for the multiplicity of clinical signs observed in Covid-19MK antagonises the inflammatory cascade induced by angiotensin II in vascular smooth muscle cells (Mueller et al 2010) and could therefore constitute a specific treatment for the inflammation induced by this condition (Fidan and Aydoğdu, 2020).  

Neurological disorders induced by SARS CoV-2 infection  

Central nervous system disorders affect ca. 36% of patients with Covid-19 (Mao et al 2020), mainly involving anosmia, dysgeusia, and headache. More serious manifestations such as seizures, delirium, encephalitis, and stroke have also been reported (Mao et al 2020). LK limits the damage induced on the blood-brain barrier. It was also reported that MK improves fiber re-organisation and long-term functional recovery after brain ischaemia, enhancing recruitment and maturation of oligodendrocyte precursor cells (Gelosa et al 2019).   

Properties of MK related to the host  

Atherogenic vascular inflammation  

It has been proposed that some severe complications of Covid-19 are mainly related to the host (Zhang et al 2020). They are influenced by age, gender and comorbidities, notably linked to preexisting inflammatory vascular and respiratory conditions.  

The cysLT are precisely strongly involved in the inflammatory phase of the atheromatous process although they are not used in this indication thus far. Antagonisation of cysLT receptors greatly attenuates arterial spasm on human coronary arteries with atherosclerotic lesions, but it has no effect on healthy coronary arteries (Allen et al 1993). A systematic review of the anti-atheromatous properties of MK in two studies concluded that all studies supported the efficacy of LKs and MK on the atheromatous process (Hoxha et al 2018). LKs could therefore reduce Covid-19 mortality in atheromatous patients, conferring protection that would be (theoretically) proportional to the extent and severity of the atheromatous lesions (Almerie and Kerrigan, 2020).  

Ischemia/Reperfusion  

The ischemia/reperfusion phenomenon results in downstream vascular lesions following reperfusion. In patients with the severe atheromatous disease, tissue hypoxia and hypoperfusion increase the risk of developing new endothelial lesions and ruptured atheroma plaque, inducing thrombosis and emboli. This may explain in part why Covid-19 is associated with an increased risk of arterial and venous thromboembolism, which affects approximately 30% of SARS-CoV-2-infected patients hospitalised in intensive care units (Klok et al 2020).   

Asthma, hyper-reactivity bronchitis, and post-infectious cough  

Asthma, for which LKs are usually prescribed, is a frequent and serious condition affecting 7%8% of the population, though it is still under-diagnosed and under-treated (Deschildre, 2014). MK is effective against cough when it is an asthmatic equivalent, regardless of the functional respiratory parameters (Miwa et al 2018).   

In contrast, MK has not shown any efficacy in chronic post-infectious cough (Wang et al 2014), even though there was a high level of subjective improvement in the placebo group in this study (Wang et al 2014). It would be of interest to examine MK on the mild symptomatic forms of Covid-19 respiratory damage (bronchospasms, cough, and chest pain).  

Properties of MK related to Covid-19 serious outcomes  

Rupatadine’s role in the cytokine storm 

 The cytokine storm, corresponding to an unopposed generation of both pro-inflammatory and anti-inflammatory cytokines by the innate immune system, is responsible for most of the serious pulmonary complications of Covid-19 (Russell et al 2020). 

The antagonist action of ZK on CystLT1 receptor protects the endothelium from inflammatory lesions induced by TNF-a (Zhou X. et al 2019). By increasing IFN-g production and inhibiting the expression of cytokines such as IL-1b, IL-6, and IL-8, the inflammatory chain-reaction could be better controlled (Han et al 2010). Clinically, MK is used to reduce drug-related cytokine reactions induced by daratumumab (Chari et al 2018) and rituximab (Kotchetkov et al 2020). In this indication, MK is associated with a marked decrease in frequency and intensity of cytokine reactions and this action seems to be strengthened by the addition of an H1-antihistamine, namely rupatadine (Kotchetkov et al 2020). 

Acute respiratory distress syndrome 

SARS-CoV-2-infected patients classically show mild symptoms that may gradually progress to more severe manifestations such as lethal ARDS. The type 1 ARDS is secondary to a direct alveolar inflammatory reaction, whereas the type 2 ARDS is secondary to systemic damage and occurs in the context of multi-visceral failure. To date, there is no effective chemotherapeutic treatment for ARDS.   

The cornerstone of this condition remains mechanical ventilation (Fan et al 2018).  

Regarding the type 1 ARDS, LK showed significant benefit on models induced by inhalation of an irritant product like chlorine (Hamamoto et al., 2017) or pro-inflammatory lipids (Aquino- Junior et al 2019), with a decrease in the intensity of the induced cytokine cascade and a lesser activation of neutrophils in the bronchoalveolar fluid.   

Properties of MK related to tissue sequelae  

Anti-Fibrosis Properties  

Using MK may limit the residual extent of Covid-19 sequelae of pulmonary fibrosis, as for scar formation after lung surgery (Peng et al 2017). MK regulates the extracellular remodelling matrix and inhibits the formation of fibrosis (Debelleix et al 2018). A recent meta-analysis confirmed in women that MK decreases the risk of retractile fibrosis after the placement of a silicone implant in breast reconstruction surgery (Wang et al 2020).  

Conclusions 

Rupatadine inhibits the activation of human mast cells in response to PAF.  Rupatadine could, therefore, be repurposed for at least Covid-19 prophylaxis.   

Although quantity is not quality, the 10 effects of MK may constitute as many synergistic and potentiating therapeutic possibilities in Covid-19. MK is a commonly used drug that does not require any prior cardiological or biological examination; it can be prescribed for pregnant women and frail older adults, and it shows a comfortable therapeutic range. Moreover, it could be all the more effective for patients with comorbidities such as diabetes, sleep apnoea, smoking, obesity, or symptomatic atherosclerotic lesions. “We support the conduct of clinical trials testing the effect of MK in Covid-19 patients from a variety of populations while keeping in mind its adverse effects,” the study authors stated.  

They emphasised, however, that the potential massive use of MK in Covid-19 would risk depriving asthma patients of their treatment.  

REFERENCES:   

Barre´ J, Sabatier J-M and Annweiler C. Montelukast Drug May Improve COVID-19 Prognosis: A Review of Evidence. Front. Pharmacol. 2020:11:1344. doi: 10.3389/fphar.2020.01344.  

Theoharides TC, Antonopoulou S, Demopoulos CA. Coronavirus 2019, Microthromboses, and Platelet Activating Factor. Clin Ther. 2020;42(10):1850-1852. doi:10.1016/j.clinthera.2020.08.006