A drug used in WW II to treat inflammation may hold the key to saving lives in the fight against flu deaths.
Over the last decade we have seen a rise in hospitalisations and deaths due to seasonal outbreaks of severe influenza. Currently in Australia the flu causes around 3500 deaths and 18 000 hospitalisations annually.
While vaccination can help prevent the flu, when patients with severe flu are admitted to hospital several days after the onset of symptoms there are no drugs available to help.
A pre-clinical study at Hudson Institute has shown that two existing anti-inflammatory drugs could be used to fight the flu at any stage of the infection.
The first drug, Probenecid was developed in the 1940s as an anti-diuretic that would prolong the life of penicillin – an exceptional property for the drug at a point in history when penicillin was very rare. Today the drug is still used but it has been re-purposed for treating gout.
The second drug, known as AZ11645373, has been clinically trialled for treating inflammatory diseases such as arthritis.
Both drugs target ATP receptor P2X7 – a molecule in humans that plays a key role in inducing inflammation.
The findings of the study, led by Dr Michelle Tate and Associate Professor Ashley Mansell, have been published in the prestigious medical journal, British Journal of Pharmacology.
The team believes the way these two drugs interact with the immune system to dampen the immune response may save lives in cases of severe influenza.
How do the drugs work?
They key to understanding why these drugs are effective against severe influenza is understanding why it’s possible to die from the flu.
Dr Tate said “While our immune system is important for fighting off infections, it is possible for our immune system to overreact when fighting off severe influenza.
“It is this overreaction of the immune system, rather than the direct effects of the virus itself, that causes symptoms such as fever, and can lead to tissue and organ damage.
“People often wait until they have severe flu symptoms before going to a hospital – this is usually around five days after the onset of symptoms. Clinical data shows that by this point anti-viral drugs, such as Tamiflu, are largely ineffective,” she said.
These drugs reduce the inflammation just enough to leave the good inflammation that may be protective rather than damaging
Turning down the volume on inflammation
A/Prof Mansell said, “The solution to preventing multi-organ failure or respiratory failure therefore could lie in controlling the body’s inflammation response.
“The NLRP3 inflammasome, part of the body’s own immune response, is critical to fighting against influenza. It is also the part of the immune system that can become overstimulated and work against us.
“The drugs we have been studying turn down the volume on the inflammation that causes the damage.
“It is important to remember that during infection we need inflammation; it is necessary to fight off the infection, but too much is detrimental and causes damage that can lead to death.
“These drugs reduce the inflammation just enough to leave the good inflammation that may be protective rather than damaging,” he said.
Dr Tate said, “With Probenecid, it’s a classic case of ‘old drug, new tricks’. It’s a very promising solution because it is cheap to buy and make and stable at room temperature. It’s also very safe in large amounts.
“The second drug also has a very good safety profile,” she said.
Where to from here?
The results of this study may have extraordinary implications for preventing severe flu deaths, and lead the development of new strategies to treat the flu.
The Tate and Mansell laboratories at Hudson Institute are now seeking to collaborate with the relevant health authorities and clinicians to propose clinical trials to treat Avian flu or severe influenza infections.
“Given these drugs are already in clinical use for other diseases and have excellent safety profiles, we are hoping the process of getting from clinical trials for flu and to having the end product in the hands of patients will be a faster process than usual.
“We will also need to look at how the drug will be administered to patients – for example, whether it can be taken nasally or via drip.
“Taking into account these factors, we anticipate it could be several years before we see this drug available on the market,” Dr Tate said.
Collaborators: La Trobe University
Funders: National Health and Medical Research Council, Victoria State Government Operational Infrastructure Scheme