Pros And Cons.
Researchers at Warwick Medical School have published the most comprehensive review of the benefits and risks of a daily dose of prophylactic aspirin and warn that greater understanding of side effects is needed.
The possible benefits of a daily dose have been promoted as a primary prevention for people who are currently free of, but at risk of developing, cardiovascular disease or colorectal cancer.
However, any such benefit needs to be balanced alongside a fuller understanding of the potentially harmful side effects such as bleeding and gastrointestinal problems.
The paper, published by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme, reviews the wealth of available randomised controlled trials (RCTs), systematic reviews and meta-analyses, allowing the team from Warwick Evidence to quantify those relative benefits and risks.
The reported benefits of taking aspirin each day ranged from 10% reduction in major cardiovascular events to a 15% drop in total coronary heart disease. In real terms, that would ultimately mean 33-46 fewer deaths per 100,000 patients taking the treatment.
There was also evidence of a reported reduction in incidents of colorectal cancer, which showed from approximately five years after the start of treatment. This would equate to 34 fewer deaths from colorectal cancer per 100,000 patients.
The adverse effects of aspirin were also noted with a 37% increase in gastrointestinal bleeding (an extra 68-117 occurrences per 100,000 patients) and between a 32%-38% increase in the likelihood of a haemorrhagic stroke (an extra 8-10 occurrences per 100,000 patients).
Aileen Clarke, Professor of Public Health Research and Director of Warwick Evidence at Warwick Medical School, said, “This study looks deeper into the range of research on regular aspirin use than anything before, using more innovative methods, and it makes it clear that there is an incredibly fine balance between the possible benefits and risks of the intervention. We need to be extremely careful about over-promoting aspirin intervention without having first fully understood these negative side effects.
“There are a number of ongoing trials that will be completed in the coming six years which may help to clarify this further, including the impact of different dose regimens.”
Aspirin And HMGB1.
Researchers have found that salicylic acid targets the activities of HMGB1, an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful aspirin-like drugs may be developed.
Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. A recent study conducted by researchers at the Boyce Thompson Institute (BTI), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, shows that aspirin’s main breakdown product, salicylic acid, blocks HMGB1, which may explain many of the drug’s therapeutic properties. The findings appear Sept. 23, 2015 in the journal Molecular Medicine.
“We’ve identified what we believe is a key target of aspirin’s active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma,” said senior author Daniel Klessig, a professor at BTI and Cornell University.
Aspirin’s pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins, hormone-like compounds that cause inflammation and pain, a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.
“Some scientists have suggested that salicylic acid should be called ‘vitamin S’, due to its tremendous beneficial effects on human health, and I concur,” said lead author Hyong Woo Choi, a research associate at BTI.
In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neuro-degenerative diseases such as Alzheimer’s and Parkinson’s diseases, plus approximately two dozen additional candidates that have yet to be characterized.
In the body, HMGB1 is normally found inside the nucleus, but can enter the blood stream when released from injured tissues or secreted by certain immune or cancer cells. The protein in the blood stream triggers inflammation by recruiting immune cells involved in preventing infections and repairing damaged tissues. HMGB1 also activates these recruited immune cells to express genes that code for pro-inflammatory cell-signaling proteins called cytokines.
To further investigate the interactions between salicylic acid and HMGB1’s role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.
“We’ve found that HMGB1 is involved in countless situations where the body confronts damage to its own cells, which occur in many disease conditions. In retrospect, it’s almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger,” said Bianchi.
Klessig also teamed up with biophysicist Gaetano Montelione at Rutgers, The State University of New Jersey, to not only confirm that salicylic acid can bind to HMGB1, but also to identify the salicylic acid binding sites.
The Klessig group identified two derivatives of salicylic acid, which are far more effective than salicylic acid in blocking HMBG1’s pro-inflammatory activities. They synthesized one compound in the lab, while a second was isolated from a licorice plant used as a Chinese medicinal herb.
“We’ve identified both synthetic and natural derivatives of salicylic acid which are 50 to 1000 times more potent than salicylic acid or aspirin in suppressing the pro-inflammatory activity of extracellular HMGB1,” said Klessig, “thereby providing proof of concept that more effective salicylic acid-based drugs are attainable.”
“Our analyses of these derivatives revealed that appropriate modifications of salicylic acid can enhance the strength of its interaction with HMGB1, providing the basis for rational design of new aspirin-like molecules,” said Montelione.
(P.S. See also Aspirin.)