ASAving The World

21. November 2017
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The arrival of large-scale production of acetylsalicylic acid 120 years ago paved a new path of conquest. ASA, according to studies, protects patients from coronary events, as well as from cancer, and is effective against depression. Can (almost) everything be cured with ASA?

There are no miracle pills. The desire to defeat many diseases with one tablet is nonetheless one that acetylsalicylic acid (ASA) comes pretty close to fulfilling. Researchers even see uses in the treatment of treatment-resistant depression due to its anti-inflammatory effects.

Fire and flame in the brain

It came about as such: Andrew Miller and colleagues at Emory University School of Medicine have long suspected that, among other factors, chronic inflammatory processes trigger major depression. In the blood of many patients they found inflammatory markers such as C-reactive protein (CRP), interleukins IL-6 and IL-1 beta as well as tumour necrosis factor TNF-α. Miller’s first trial employing the TNF antagonist infliximab was rather disappointing. Patients with depression got no significant added value from the therapy compared to placebo.

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Acetylsalicylic acid © 28Smiles / CC SA 4.0

The idea of employing ASS because of its anti-inflammatory effects was born. However some time came to pass before the first clinical study of the molecule took place, since basic background research preceded it for some time. Using magnetic resonance imaging Miller found evidence for inflammation being associated with defective communication between two brain regions. The focal points involved here are the ventral striatum (VS) and the ventromedial prefrontal cortex (vmPFC):

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© Felger et al, Molecular Psychiatry

Depressive mice with inflammation

In order to verify the inflammation hypothesis and to pave the way for possible pharmacotherapies, Harald Engler from University Hospital Essen gave volunteer subjects endotoxin or placebo. Endotoxin triggers inflammation. Levels of IL-6 (interleukin 6) increased as expected. The more IL-6 Engler found, the more depressed his study participants were.

In another study it was found that the effect of stress-induced IL-6 release was able to be neutralised by antibodies – or at least in mice. This was reported by Kenji Hashimoto. He works at the Chiba University Center for Forensic Mental Health, China. However the scientist qualifies the observation by saying that it is still unclear whether the results could be transferred to humans.

This potential transfer is exactly what researchers are investigating in several clinical studies. They are testing ASA versus placebo in cases of depression. Aside from ASA there are other agents that are anti-inflammatory, such as the antibiotic minocycline. Initial results are expected in the coming year.

ASA as a matter of the heart

ASA does not just function as an anti-inflammatory but as an antiplatelet agent as well. This characteristic is appreciated by doctors in the secondary prevention of heart and brain infarctions. Potential gastrointestinal bleeding however makes its use risky. ASA, like others nonsteroidal anti-inflammatory drugs (NSAIDs), damages the gastric mucosa. Ulceration occurs, as does bleeding. This is due to the decreased synthesis of prostaglandin E2 (PGE2), a molecule with protective properties. It reduces the secretion of stomach acid and stimulates the secretion of gastric mucus.

Physicians are left with the task of indicating which patients are especially at risk when taking ASA as a prophylactic. Linxin Li from the University of Oxford pursued this matter in more depth. She included 3,166 patients with various cardiovascular diseases and using ASA as a prophylaxis in her cohort study. Proton pump inhibitors (PPI) do not belong to standard medication used for gastric protection. She accompanied all participants for over ten years. Some subjects left the study, others died. Over 13,509 patient years, 405 bleeding events occurred. The risk of severe to fatal bleeding increased with age. Most often the gastrointestinal tract was affected.

“PPI can minimise the risk”, Li summarises. She provides the needed to treat number (NNT) on account of its statistical value for pharmacotherapy. This defines the number of people treated in order to prevent bleeding. With patients younger than 65 years of age, the NNT was 338. That is, physicians gave 338 people PPIs in order to prevent bleeding. With patients older than 84 years of age, the NNT was 25. “Therefore, especially with older patients, stomach protection is worth the effort”, the scientist writes.

At your own risk: many take break from pills

The problem of side effects is not without consequences. It is estimated that every fifth to tenth patient discontinues low-dose aspirin in the first three years after his or her heart attack. In addition, sufferers feel healthy and do not understand why prophylactic, long-term drug administration makes sense.

Johan Sundström from the University of Uppsala wanted to know the effects of non-compliance. His work was based on a cohort of 601,527 patients with various cardiovascular diseases. Cardiologists had in all cases prescribed low-dose ASA for the prevention of heart attacks or strokes. Some people took their medication earnestly, others discontinued taking the pills arbitrarily.

During the follow-up running three years, a total of 62,690 events occurred. Depending on the adherence to therapy, there were considerable differences. Patients who discontinued their medication within 36 months increased their cardiac risk by 37 percent. In order to avoid this, physicians and pharmacists should give better advice, the lead author states.

Putting brakes on cancer using aspirin?

ASA not only protects against cardiovascular events but also plays a role in the prevention of bowel cancer. Peter M. Rothwell from the University of Oxford showed that even low doses of 75 mg per day lowered the risk of colon carcinoma by 76 percent. His work was based on several cohorts involving 14,033 participants without a history of colon cancer and a follow-up of 18.3 years. Other NSAIDs, for example celecoxib and sulindac, protect more effectively than ASA, but also come with significantly stronger side effects.

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Molecular model of the KRAS protein © Thomas Splettstoesser / Wikipedia, CC BY SA 4.0

In addition, ASA is suitable for recurrence prevention. Polly Newcomb, researcher at Fred Hutchinson Cancer Research Center in Seattle, put data from 2,419 colorectal cancer patients under the microscope. Those who swallowed ASA or other NSAIDs reduced their overall mortality risk by 25 percent. The risk of dying from bowel cancer actually even decreased by 56 percent.

Surprisingly, Newcomb found out that the pharmaceutical prophylaxis only works where earlier tumours had expressed the unmutated form of KRAS. This section of the genome is linked to the proliferation of cancer cells. Proto-oncogenes Like KRAS only become active through mutations of negative character. Then they produce altered proteins that permit cells to proliferate and survive longer.

How it happens that only “wildtype” KRAS is suitable as a pharmacological target is something Newcomb cannot explain. Even 120 years after initial industrial synthesis of ASA, scientists are still trying to elicit further secrets from the molecule.

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