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- Canadian immunologist and geneticist
A drug cocktail could help fight the new variant after results show it is four times better at keeping people out of intensive care than the current treatment.
Sir Christopher Edwards, the former vice-chancellor of Newcastle University, has recently conducted trials showing that a combination of spironolactone, a heart failure drug, and the steroid dexamethasone work far better than dexamethasone alone.
Dexamethasone became the first drug to be licensed for the treatment of Covid-19 after Sir Christopher recommended the treatment to Sir John Bell, regius professor of medicine at Oxford University, who was tasked with finding drugs which could be repurposed for coronavirus.
But he believes more lives could be saved if spironolactone was included, and is calling for wider trials of the “SpiDex” regime after early trials showed extremely promising results.
In a randomised controlled trial in Delhi, just 5.4 per cent of hospitilised patients taking “SpiDex” needed to be admitted to intensive care compared to 19.6 per cent of those taking dexamethasone alone.
A study published last week in Frontiers in Endocrinology also showed that 40 Covid-19 patients taking the “SpiDex” cocktail did better on every clinical, biochemical and radiological measure than 40 patients on a high dose of dexamethasone.
No patients died while taking “SpiDex” but there was one death in the dexamethasone-only group.
In 20 out-patients treated with “SpiDex” there were no adverse events, and 95 per cent were asymptomatic at 10 days including full recovery of taste and smell.
Rather than targeting the virus itself, the treatments work by turning off the devastating impact on the body, so it means the drug combination should work against the extremely mutated “Nu” variant which is alarming scientists.
Sir Christopher, an eminent endocrinologist, said: “All the variants of the coronavirus use the same taxi to get into the cell, namely the ACE2 receptor.
“The destruction of the taxi results in a specific series of biochemical consequences which produce the symptoms and complications.
“‘SpiDex’ treatment blocks the consequences and does not depend on how the virus gets into the taxi. It is thus likely to be effective regardless of mutations in the spike protein of the virus such as those found in the recently discovered Nu variant.”
How the drugs work
The drugs work by shutting down the reaction which allows the virus to escape from cells and infect other cells. It also stops the deadly clotting and fluid retention in the lungs which often leads to death in Covid-19.
The success of the drugs also give clues about why young and healthy people are largely immune from the devastating impact of Covid-19.
Younger people have fewer receptors in the lining of the blood vessels meaning the virus cannot cause problems in the more dangerous parts of the body.
Sir Christopher was so convinced the treatment would work that he recommended it to his daughter-in-law when she became seriously ill with Covid-19 and was struggling to breathe. She made a full recovery.
Large trials of dexamethasone were shown to reduce deaths by a third for people on ventilators, but the combination could stop large numbers needing intensive care in the first place.
Sir John Bell told The Telegraph: “Dexamethasone is great. There are good theoretical arguments for adding spironolactone. It would be great if there was some good trial data to support it.”
Combination of the two drugs now starting to show impressive results in trials
In mid-June 2020, the eminent medic Sir Christopher Edwards received a text message from the equally eminent Oxford immunologist Sir John Bell, writes Sarah Knapton.
It contained just three words: “You were right!”
Months earlier, when Sir John was first tasked with finding treatments for the new virus that was sweeping the globe, Sir Christopher urged him to consider the steroid dexamethasone.
Within months, large trials of dexamethasone were shown to reduce deaths by a third for people on ventilators, providing the first known treatment for Covid-19 and a ray of light amid the gloom.
What is less well known, is that Sir Christopher had wanted to combine the steroid with a second drug - spironolactone - which he believes could have made a far greater impact on the pandemic. The combination of the two drugs is now starting to show impressive results in trials.
“I would have been a lot more right if both drugs had been used,” he told The Telegraph.
“I have had a rather large number of sleepless nights thinking about how many people have died that actually didn’t need to die. That’s upsetting.”
From early on in the pandemic, it was clear that Covid-19 was a very different disease to other respiratory infections. Patients were experiencing loss of taste and smell, while post-mortems revealed severe blood clotting and fluid in the lungs of the dead.
Sir Christopher, a renowned endocrinologist and former vice-chancellor of Newcastle University, realised that the mechanisms behind the strange symptoms and pathologies were the key to understanding how to stop the disease.
“The problem is we spent too much time trying to stop the virus, with antivirals and the like,” he said. “If a thief pinches and crashes your car, you don’t get the car going again by chasing after the thief.
“I’m afraid we spent a vast amount of time chasing the thief - the virus. We have spent very, very little time actually working out what’s wrong with the car.”
Coronavirus has small grappling rods called spike proteins on its shell which it uses to latch on to a claw-like receptor on human cells called ACE2. The virus uses this as a taxi to get into the cell.
Once inside, it must multiply and find a way out so it can spread further.
Studies have shown that the coronavirus hitches a ride in lysosomes - tiny enzyme-holding sacs which recycle cellular waste. These sacs move to the cell surface and allow the virus to escape from the cell, in a process called exocytosis.
This cycle is speeded up in Covid-19 because the virus causes cells to lose their “moat”, which keeps out the hormone cortisol. Cortisol triggers the release of the hijacked lysosomes which carry out the virus as well as the energy molecule ATP.
It was this ATP release that proved the crucial clue in understanding this process. When too much is produced in certain locations the body shuts off its sensory receptors as a protective mechanism and also activates specific nerves.
So as coronavirus infects cells in the nose and mouth it sparks a loss of taste and smell, and when released in the lungs, activates the cough reflex - all classic symptoms of Covid-19.
Sir Christopher realised that using a combination of the drug dexamethasone to suppress cortisol secretion together with spironolactone to block the ACE2 receptor could restore the “moat” around cells and keep cortisol out.
“If you can block this process then you are going to inhibit the basic problem,” he added.
His work has also suggested an explanation for why some groups of patients are at much higher risk of getting the lethal complications of Covid-19. This relates to the virus entering the cells lining blood vessels.
Sir Christopher suggested that when the virus enters these cells it triggers the release of a substance called the Von Willebrand factor which spreads out like a spider’s web, forming a mesh that collects key cells in the blood called platelets, causing local clotting.
It also triggers the production of a factor called angiopoietin-2 which prevents fluid being cleared from the lungs.
“If you look at people dying from Covid-19 and compare them to the lungs of people dying from influenza, there are 10 times as many micro-clots,” he said.
“The body normally has in the alveoli (air sacs) a very clever system where key cells actually produce a substance that acts like a very clever plumber and his job is to seal leaks.
“But when the blood vessels are infected, the plumber stops working because of damage to these cells and angiopoietin-2 released from the infected blood vessel cells produces an incredible series of leaks, and so basically you drown.
“So, when you look at people in intensive care, the higher the levels of the Von Willebrand Factor and angiopoietin-2 the more likely you are to be getting clotting and an immense amount of fluid.”
The mechanism also explains why older and sicker people are more vulnerable to the disease.
Younger people carry ACE2 receptors – the taxi used for cell entry – on key cells that line the nose, tongue and specific cells in the respiratory tract, which is why they suffer largely mild infections.
However, the receptor is virtually absent from cells lining their blood vessels, meaning Covid-19 rarely becomes serious in younger age groups.
In contrast, older people and those suffering from conditions such as heart disease and diabetes, carry many ACE2 receptors, giving coronavirus an easy ride into far more dangerous parts of the body.
This is where spironolactone becomes a second crucial backstop because it is synergistic with dexamethasone and together they produce a much greater benefit.
Not only could this dual approach prevent deaths and serious illness, but it could possibly be repurposed as a nasal spray, which might stop cells pumping out new viruses and help stop transmission.
“If we can reproduce on a larger scale what these early trials suggest, the benefits could be extraordinary,” added Sir Christopher.
“We all hope Covid-19 is going to go away, but it’s not going away. Spironolactone and dexamethasone are cheap off-patent drugs that could be immediately available, especially for parts of the world that cannot afford expensive anti-viral drugs or antibodies.
“If you look at the number of cases we’ve got and what’s going on, I think we’ve all got to wake up. You’ve only got to have a variant, or vaccine resistance, and you’re back to square one. We have to act now.”
Happily, the scientific world may be finally starting to come around to his point of view.