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Collateral medicine

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Collateral damage is one of those weasely words of our times that masks human tragedy and loss in war zones. Clenching a cigar between his teeth, the US general told assembled reporters: “It was a successful mission; we took out the intended target, although there was inadvertent loss of life at a nearby school.” It’s a militaristic take on the adage that you can’t make an omelette without breaking eggs.

Medicine has been working with collateral damage for years. Doctors call it a side-effect or adverse reaction when they need to explain the unexpected consequences when a drug, for arthritis, say, also happens to cause migraine. Every drug comes with side-effects, and a weighty tome called the Physicians’ Desk Reference (PDR) documented every known side-effect and required around 2,000 pages of tiny type to do so.

Even then, it listed only those side-effects that had been recorded in medical trials or from reports sent in by doctors as they started prescribing the drug. A French study once estimated that just one in 20,000 side-effects are ever recorded, usually because of time pressure and the reluctance of the doctor to fill out yet another piece of paper – which is just as well for the publishers of the PDR and those doctors who have to lift it onto their bookcases.

For many years, the public was not allowed to read the PDR or its UK equivalent. Unlike the military’s collateral damage, medicine’s is secret and invisible, and we don’t want to frighten women, children or anyone, actually. And, anyhow, the neck and arm strains that would result from lifting the PDR would be a further burden on an already overstretched health system.
To illustrate the point, researchers at Brigham and Women’s Hospital in Boston did some computer modeling to see how 700 drugs approved by the US Food and Drug Administration (FDA) interacted with different proteins.

Drugs are designed to lock onto a diseased protein target – but it’s always been known that they can interfere with unintended targets and other biological processes, which causes the side-effects and adverse reactions that have been so amply recorded.

But nobody knows the extent to which this happens or what some of the other biological impacts may be – especially those that may not be immediately apparent or witnessed by researchers and doctors.

For instance, they discovered that Tegretol (carbamazepine) – a drug designed to treat epilepsy and neuropathic pain – can also cause coronary artery disease. Since diabetics may be prescribed carbamazepine, they could be inadvertently increasing their risk of heart disease, which is already high.1

This is a new side-effect that nobody had recorded before, because who could have guessed that an anti-epilepsy drug would cause heart disease? It was only when the researchers looked at the biological processes at play that they could see this was an unintentional, and unsuspected, reaction.

And that’s true for most of the 700 drugs tested. Almost all have an effect that nobody had been aware of before. As the lead researcher Joseph Loscalzo put it: “The great majority of drugs are not unique to the single target for which they’ve been developed.”

All the drugs tested had been approved as safe and effective – but this also explains the many thousands more that work in the laboratory on single-cell tests but fail when they’re tested on humans. It’s because we are complex beings with a multitude of inter-related biological parts and processes.

And that’s why there’s no such thing as a safe drug. But it’s not all doom and gloom, at least not according to Dr Loscalzo – there’s an upside too. If a drug can have an unintentional side-effect that increases the risk of a completely different disease, perhaps it could have a positive knock-on effect, too, so a drug for cold sores might happen to cure cancer as well (now, that really is a bonus).

Now Big Pharma has the tools, courtesy of this new modeling, to “facilitate drug repurposing,” Dr Loscalzo said. What a boon this would be. No more expensive and laborious testing in the lab, just figure out all the other great ways that the current generation of drugs could be treating different and diverse conditions.

It’s rather like a general who, having inadvertently blown up a neighboring school (and killing those inside), points out the great redevelopment opportunity this presents.

The military would never be so crass; medicine just might be.

1 Nat Commun, 2018; 9: 2691

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