As new drugs are developed to treat Covid-19, it's important that combinational inhaled therapy is seen as a crucial part of the way forward, argues Tushar Saha, Professor Miguel Quiñones-Mateu and Associate Professor Shyamal Das.
It has been almost two years since the first Covid-19 cases were identified in China, and we are still finding effective treatments for the disease.
While several vaccines are helping people to develop immunity to the virus, their efficacy against newly emerging SARS-CoV-2 variants is being challenged. Now more than ever, we need other strategies to combat this pandemic.
SARS-CoV-2, the virus responsible for Covid-19, enters the body through the upper respiratory tract and makes its way to the lungs. In the latter phase, it may spread to the rest of the body from the lungs. So, the lungs are considered the primary replication site for this viral infection.
The scientific community started by testing a multitude of drugs and treatments, known to be effective against other diseases, including antiparasitics (hydroxychloroquine, ivermectin or niclosamide) and antivirals (favipiravir and remdesivir), just to name a few, against Covid-19. To date, only Veklury (remdesivir) has been approved for such ‘re-purposing’ by the U.S. FDA, for the treatment of Covid-19 requiring hospitalisation.
When we look at the current treatment approach for Covid-19, the key limitations that we observe are – the drugs are mostly given intravenously or orally, and drug concentrations in the lungs are usually suboptimal.
Orally given drugs, such as favipiravir and niclosamide, are used for Covid-19 but require high doses and have numerous side effects. Also, their poor absorption fails to ensure sufficient drug concentration in the lung. Besides these, many drugs are being researched in the clinical trials, and numerous shortcomings are identified, but these two problems are prominent.
It is clear, since SARS-CoV-2 predominantly targets the respiratory tract, inhaled drug delivery may be preferable as it may achieve higher drug concentrations in the lung, with low doses and limited side effects. Besides that, if we consider severe Covid-19 patients, immediate actions may be needed which can also be achieved by inhaled delivery of the drug.
There is available data that show promising outcomes of inhaled treatment for Covid-19. For example, using inhaled adenosine, the length of stay of Covid-19 patients in hospital was reduced by on average 6 days.
Although researchers are focusing on inhaled monotherapy treatment, we also need to consider the current trends of this virus and take lessons from the past. We believe that for Covid-19, combinational inhaled therapy may prove to be more effective than monotherapy treatment.
The main reason for combinational therapy is that drug resistance is one of the greatest concerns for viral and infectious diseases. SARS-CoV-2 is rapidly adapting to replicate in the human host, evidenced by the emergence of multiple variants such alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and the worrisome omicron (B.1.1.529).
To clarify this with one example: the “adamantanes” group of drugs, which were originally used for Influenza A virus as monotherapy, are no longer effective due to the selection of resistance viruses. As evidenced with HIV and HCV, it is hard to develop resistance against multiple drugs compared to a single drug. Until now, no reports are available for drug resistance against SARS-CoV-2, but we need to plan accordingly.
Inhaled combinational drugs are advantageous over monotherapy as the right combination of drugs can provide synergistic effects. A synergistic effect is desirable as the effect of two drugs are higher than the summation of the effect of them individually.
Comorbidity is another concern for Covid-19. Chronic obstructive pulmonary disease (COPD), asthma, arterial hypertension, diabetes, obesity, chronic kidney disease patients are more prone to Covid-19. It is quite complex to treat all these complications with a single agent. If we can choose the right combination of drugs that are effective against SARS-CoV-2 alongside different complications and can deliver directly to the lungs, this will be advantageous.
This novel coronavirus will be with us for a prolonged time. This is why policymakers need to strategise and focus on effective treatment alongside the vaccines. New drugs are being developed and there is hope that they will have a transformational effect on the pandemic. Combinational inhaled therapy may prove to be a crucial part of the way forward.
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*Tushar Saha is a PhD student in the School of Pharmacy at the University of Otago.
*Professor Miguel Quiñones-Mateu is a researcher in the Department of Microbiology and Immunology at the University of Otago. He is currently involved in multiple Covid-19 research projects, including anti-SARS-CoV-2 strategies and vaccine initiatives.
*Associate Professor Shyamal Das is a researcher in the School of Pharmacy at the University of Otago. He is an expert in inhaled drug delivery.
*The authors declare that they have no conflicts of interest.
