Finding new tricks for old drugs


Off-patent drugs can be surprisingly useful, writes Norman Swan.


TEK IMAGE / SCIENCE PHOTO LIBRARY / getty images

It costs up to a billion dollars and 20 years to develop a new drug. When it arrives, it’s barely affordable. The latest Hepatitis C drug costs about $80,000 for a course. New cancer drugs are not far behind.

This problem has prompted researchers to take a second look at old drugs, many of them off-patent and cheap. Maybe some could be repurposed?

It may not sound like a winning idea. But drugs nearly always have “side effects”. And in some cases they have been promoted to the main game with great effect.

Take aspirin, the poster child for repurposed drugs. It was first used to relieve pain and fever, as was the extract of willow bark that provided the original source of a similar chemical. Its tendency to cause bleeds – once viewed as a troublesome side effect – is now the mainstay of aspirin’s use to reduce clotting and prevent heart attacks. Yet another of aspirin’s side effects seems to be to reduce the risk of bowel cancer.

Then there’s metformin, a safe and cheap diabetes medication – also based on a folk medicine found in French lilac. It lowers blood sugar levels by suppressing the liver’s glucose output and increasing glucose uptake by the rest of the body. But, as it turns out, it also delays ageing in worms and mice. It’s now being trialled as an anti-ageing drug in a US study which goes by the name of TAME (Targeting Ageing with Metformin).

Traditionally, finding a novel use for an old drug was a matter of serendipity. Now the search is being systematised, taking advantage of medicine’s windfall of big data and mining it. For instance, in 2011, Atul Butte and his colleagues based at Stanford University in California used a computer algorithm to compare two vast databases. One carried profiles of gene activity in healthy versus diseased tissues, say normal lung versus lung cancer. The other showed how drugs affect gene activity profiles.

ITS TENDENCY TO CAUSE BLEEDS – ONCE VIEWED AS A TROUBLESOME SIDE EFFECT – IS NOW THE MAINSTAY OF ASPIRIN’S USE TO REDUCE CLOTTING AND PREVENT HEART ATTACKS.

The algorithm looked for matches in the databases: did some drugs shift the gene profiles in a healthy direction? Bingo. It found matches for two off-patent drugs. An anti-ulcer drug called cimetidine was a good match for lung cancer; topiramate, a drug for epilepsy, was a good match for Crohn’s disease – a nasty bowel disease. Both showed promise when tested in animal models.

Meanwhile last year, researchers at the Weizmann Institute in Rehovot, Israel, found evidence that an anti-asthma drug might be repurposed for dementia. Their lead came from an unexpected discovery. As part of their metabolism, our cells produce a dangerous by-product – oxygen free radicals. We have enzymes to clear them away but as we age the clean-up operation fails to keep up and our cells suffer so-called oxidative stress. Chemotherapy drugs, and globs of brain proteins associated with dementia, increase that oxidative stress.

The surprise finding was that in order to produce oxygen free radicals, the cells required a signal from another home-made chemical called a leukotriene. Leukotrienes are mostly associated with the immune system. Notably, in asthma they are the major culprits behind an overactive immune response. And that is what excited the researchers.

Asthma drugs, like montelukast, block the action of leukotrienes. Using similar drugs, the scientists found they could block oxidative stress in animals treated with chemotherapy. Another study showed these drugs also slowed dementia in ageing rats.

The hope is that this class of medications might be repurposed for treating human dementia.

There is, however, a major stumbling block. While it’s great that many promising drugs are off-patent and cheap, using them in a new way still requires a clinical trial to test their efficacy.

With no patent protection, companies are not interested. One answer to this market failure is known as “evergreening” – tweaking the chemical structure of the old drug so something new can be patented. The other solution is for governments to fund trials of old drugs for new indications. It’s certainly in their interests to do so, not to mention yours and mine.

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