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Aspirin: Not Approvable
Why many familiar medicines might flunk FDA approval today

Derek Lowe
Medical Progress Today
November 17, 2005

With all the headlines in recent years about dangerous prescription drug side effects, many people must be wondering what happened to the days of safe, reliable medicines. Where are the new drugs that can get the job done safely? Where are the new aspirin, penicillin, acetaminophen?

As a drug discovery researcher, I can tell you something that might sound crazy: many of these older drugs would have a hard time getting approved today. Some of them would never even have made it to the FDA at all.

The best example is aspirin itself. It's one of the foundation stones of the drug industry, and it's hard to even guess how many billions of doses of it have been taken over the last hundred years. But if you were somehow able to change history so that aspirin had never been discovered until this year, I can guarantee you that it would have died in the lab. No modern drug development organization would touch it.

Thanks in part to advertisements for competing drugs, people know that there are some stomach problems associated with aspirin. Actually, its use more or less doubles the risk of a severe gastrointestinal event, which in most cases means bleeding seriously enough to require hospitalization. Lower doses such as those prescribed for cardiovascular patients and various formulation improvements (coatings and the like) only seem to improve these numbers by a small amount. Such incidents, along with others brought on by other oral anti-inflammatory drugs, are the most common severe drug side effects seen in medical practice.

It doesn't take too long to see these effects in a research program. Aspirin causes gastric lesions in rats and dogs, which are the standard small and large animal models for drug toxicity. This side effect occurs at levels which would raise red flags for any new compound. What would a present-day research organization do about it? If we stipulate that they could determine that aspirin worked by inhibiting cyclooxegenase enzymes, they would surely try to break the vascular effects of the drug apart from its anti-inflammatory effects. They would try to find new compounds that selectively inhibited only one of the enzyme subtypes. They would, in other words, produce Vioxx, and Celebrex, and the other COX-2 inhibitors, and this is just why these drugs were developed.

What about acetaminophen, then, known to much of the world under its brand name of Tylenol? This is another pain reliever that's been taken by untold millions of patients. But it has a chemical backbone (known as a para-amino phenol) that most medicinal chemists now shy away from. I've personally crossed compounds off lists of potential drug leads because they share too much of acetominophen's structure.

Here's the problem: the drug is usually cleared harmlessly by the body, but one pathway produces a compound that is potentially toxic. Even then, a defensive compound in the body known as glutathione reacts with it, and no harm is done. But if the body's stocks of glutathione are depleted, or if more of the acetaminophen is shunted through the minor pathway, serious liver injury occurs when the toxic metabolite is given a free hand.

An overdose of acetominophen can overwhelm the usual safeguards, as can the use of alcohol or other drugs that saturate the safe clearance routes. This effect would be impossible to miss as well. It's easily seen with high doses in rats and dogs, and was in fact noted in the 1950s when acetaminophen first came into clinical use. But the standards for such things are much higher today, and I seriously doubt that most drug companies would now take on the risk.

That brings us up to penicillin, a drug with a clean reputation if ever there was one. But at the same time, everyone has heard of the occasional bad allergic reaction to it and related antibiotics. Even with the availability of skin tests for sensitivity, these antibiotics cause about one fatality per 50 to 100,000 patient courses of treatment. Other severe reactions are twenty times as common. Those are interesting figures to put into today's legal context: over 9 million prescriptions were written for Vioxx, for example. Any modern drug that directly caused that number of patient deaths and injuries would bury its company in a hailstorm of lawsuits, because (unlike the Vioxx cases) there would be little room to argue about other risk factors. Anaphylactic shock is hard to mistake for anything else.

I could go on. Just recently, another classic antibiotic (erythromycin) was found on close examination to roughly double the risk of sudden cardiac death in patients who used it in combination with other medications. No doubt there are other effects of this kind waiting to be found.

What are we to make of all this? Itís possible to be both glad and worried. We can be relieved that we've learned so much more about pharmacology, ensuring that the drugs that manage to gain approval today are the safer than ever. Or we can think about how people seem to use aspirin and the other legacy drugs anyway, safety problems and all, and wonder how many more useful medicines we're losing by insisting on a higher bar.

I definitely see the point of the former, but I lean a bit toward the latter. Drugs have side effects, after all. Imagining that the older ones didn't, or pretending that the newer ones mustn't, is a recipe for disappointment. We're better served by reality, as it was and as it is.

Derek Lowe received his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. He is also the author of a blog on developments in the biopharmaceutical industry called In the Pipeline.

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