After Sushant Singh Rajput’s demise, Koffee with Karan was criticized at many levels. Being called the ‘flag-bearer of nepotism’, Karan Johar might ban his own show. As my fellow netizens might refrain from watching the show again, I would like to take the opportunity and entertain you with ‘Doughnuts with drugs’. Unlike KWK, this is a one-day affair. It will not be aired for decades and does not support any form of discrimination in the name of ‘hot brewing gossip’. So, feel free to read on.
For months now, it has been known that the drugs- Dexamethasone and Remedesvir have shown potential in the treatment of Covid-19 patients. Dexamethasone is the first drug to show a reduction in the number of deaths. With a new case just a few houses from mine, I would like to dive deeper and understand these drugs better. Would you like to join me in this quest and develop a better understanding?
Firstly, what is dexamethasone?
It is a synthetic glucocorticoid belonging to the steroid class of drugs. It has anti-inflammatory and immunosuppressive properties and has been shown to reduce deaths by one-third in Covid-19 patients on ventilators. Its potential was discovered in the RECOVERY trial that had been launched in March to test various potential therapies. Its effect on critically ill patients was note-worthy and thus, has been claimed to be a ‘breakthrough’.
“It is a major breakthrough,” says Peter Horby, an infectious-disease specialist at the University of Oxford, UK, and a chief investigator on the trial.
What are glucocorticoids?
These are hormones produced in the adrenal cortex (present in the periphery of the adrenal gland) and secreted into the blood. Glucocorticoids inhibit many molecules that are associated with inflammation like cytokines, chemokines, etc. Often, anti-inflammatory mediators are upregulated by glucocorticoids.
What is its mechanism of action?
Our body is made of cells which are like little houses having rooms for various actions. The rooms or organelles float on an aqueous medium called the cytoplasm. Glucorticoids bind to glucocorticoid receptors(GR) present in the cytoplasm. GR stays in a complex with hsp90,hsp70 and hsp56. These are heat shock proteins and hsp 90 and hsp 56 leave the complex when glucocorticoid passively diffuses into the cell and binds with GR. The activated GR complex moves into the nucleus where hsp 70 leaves the complex.
Glucocorticoids have the following actions:
- They prevent the transcription (refer to the first blog) of cytokines and chemokines.
- They reduce the neurokinin receptor expression. This prevents its action as mediators of the effects of Substance P.
- Glucocorticoids inhibit the synthesis of inducible nitric oxide synthase. They also inhibit gene expression of Phospholipase A2 and cyclooxygenase-2 which results in the reduction of prostaglandins and thromboxanes production.
- They also reduce the surface expression of adhesion molecules.
- They inhibit the overactivation of macrophages.
All the aforementioned effects play a role in reducing inflammatory responses.
As I had mentioned about the cytokine storm in my previous posts, Dexamethasone’s anti-inflammatory role helps reduce death caused by it. It has been shown that the drug reduces death from 40% to around 28% in critically ill patients. It is cheap and can be administered orally and intravenously. Like most drugs, this drug also has side effects but its clinical benefits are more overpowering.
What is Remedesvir?
It is a broad-spectrum antiviral prodrug (present in an inactive form but gets activated inside the host cell). It was developed by Gilead Sciences and is a nucleotide analog (specifically, adenosine analog). It was designed primarily for treating Ebola virus.
How does it work?
Remedesvir resembles adenosine and its active form gets incorporated into the RNA of the virus. This terminates genome replication. It has also been observed that this drug plays a role in the evasion of proofreading activity of the viral exoribonuclease. This promotes mutation in the viral RNA. It has been shown to reduce SARS-Cov-2 replication in Rhesus monkey and thus, shows promise. However, being a broad-spectrum drug, scientists are worried about its harmful side effects like antiviral resistance.
"Therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques."-Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2,Nature,2020
With this, we come to the end of Doughnuts with drugs. A shout out to all the frontline workers including Debdutta Ray (our college alumnus) who has recently lost her life while tending migrant workers. The fight against the pandemic is getting worse day-by-day. I urge all the readers to not take this virus lightly. Please wash your hands before eating doughnuts, wear your PPEs, and try to stay indoors.