The Doctor Weighs In

By Dov Michaeli MD, Ph.D

The aspirin story

The discovery of aspirin is a fascinating story (to me, at least). In 1853 the French chemist Charles Frederic Gerhardt (yes, I’m sure he was French) studied a group of organic chemicals called anhydrides (an=without, hydride=water). Among many molecules of this group he synthesized one called acetyl salicylic acid, or ASA. He then put the vial containing the white powder on a shelf, and forgot about it. And there it sat for over 40 years until 1897, when a German chemist named Felix Hoffmann, working for Bayer, the German chemical and pharmaceutical company, rediscovered the compound using a different synthetic procedure, tested it for analgesia, and voila! It was used as an analgesic and antipyretic (fever-lowering) since then.

But the story doesn’t end there. Nobody knew how aspirin worked. It was only in 1971 that it was discovered that aspirin works by inhibiting the enzyme cyclooxygenase (COX). For that discovery John Robert Vane, working for the Royal College of Surgeons (no, he was not a surgeon; he was a real scientist), received the Nobel Prize. What’s the big deal about this enzyme? It is a critical enzyme in the synthesis of a group of substances called prostaglandins, which are mediators of inflammation and pain. So aspirin very quickly became the mainstay of treatment for arthritis and other inflammatory diseases. In its soluble form, sodium salicylate, it was used in the treatment of Crohn’s disease, or colitis, a devastating inflammatory disease of the colon. And within a few short years a new group of COX inhibitors, called NSAID (non-steroidal anti inflammatory drugs), was synthesized. Famous members of this group are ibuprofen (Advil), naproxen (Naprocyn), and others.

But wait, wait, there is more. In the late 70s, it was discovered that low dose aspirin or NSAID inhibit platelet aggregation, which was the basis for using them as a preventative for myocardial infarction.

This is quite a remarkable demonstration how learning the molecular details of biology and pharmacology can lead in totally unexpected directions, and to undreamed of new therapies.

New respect for the humble DEET

Who doesn’t know DEET? Certainly nobody who has ever gone on a hiking or camping trip. I personally experienced the wrath of a cloud of mosquitoes when I forgot “to DEET”. We were on our way to watch the chimps in Africa , and my memory of that particular outing is total body itch. If there are species that I wouldn’t shed tears if they became extinct it is the mosquitoes.

Like aspirin, DEET was synthesized a long time ago (over 50 years ago), and notwithstanding the long-held reasonable assumption that it is a mosquito repellent, nobody really investigated its mode of action. That is surprising, given the medical importance of mosquito-borne diseases, such as malaria, dengue fever, yellow fever, and more.

In the latest Science magazine a group of molecular neurobiologists from Rockefeller University published a report on DEET’s mode action. And surprise, surprise: it is not a repellent. It doesn’t smell bad to the mosquito. In fact, it doesn’t smell at all.

Female mosquitoes (and fruit flies) smell lactic acid in our sweat, and carbon dioxide and a certain alcohol (1-octen-3-ol) in our breath. Those three odorants evoke in the little pests the equivalent of a Pavlovian response—but instead of drooling they home in like heat-seeking missiles.

How do they smell it? For each of the 3 odorants there is a specific receptor on mosquitoe’s antennas. Once a molecule of say, lactic acid lands on its receptor, it triggers an electrical discharge in the olfactory nerve leading to the brain. And there, a behavioral pattern is unleashed that sends the blood sucker hurtling toward the source of the odor.

DEET works by occupying the receptors, so that the odorants cannot bind. Result: the insect is unaware of them, no chemical attraction, no bite.

Could the aspirin story be repeated?

I think so. DEET was discovered the old fashioned way; chemists synthesized thousands of compounds which were then tested for any activity imaginable. This approach gave us most of the drugs being used to date. But it also has a weakness: because the drug was discovered by the hit or miss approach and not by designing it to bind to a specific target, its binding to the target molecule was essentially accidental and almost never was at a maximum. It was good enough, and was rushed to market. Now that we know the molecular details of the mode of action of DEET, chemists can synthesize new classes of molecules that will bind more specifically and more tightly to the receptors. In other words, they can create less toxic and vastly more effective compounds that will protect us from insect bites. This is important, because DEET is toxic to infants. But even more important, blood-feeding insects transmit many of the world's deadliest diseases. Malaria alone infects an estimated 500 million people annually, leading to the deaths of about 1 million people per year! These are mind-boggling numbers. Spraying or dabbing on a new and improved version of DEET, could turn out to be a powerful means of malaria control. Bill and Melinda, are you listening?

Let’s not forget the repulsive ticks; they are attracted to humans by exactly the same odorants. Lyme disease, tick-borne relapsing fever, Rocky Mountain spotted fever, tick typhus—these are all diseases transmitted by ticks. In the new world of global warming insect-borne diseases are going to become significant public health problems; Ebola and chikungunya are harbingers of what’s coming.

And who knows what else is waiting around the corner once DEET-like drugs are made? After all, did Hoffmann, toiling in the Bayer laboratory, ever dream of what aspirin would turn out to be?

By Dov Michaeli MD, Ph.D

Clinical researchers at the University of Glasgow published in the September issue of the Annals of the Rhumatic Diseases an unassuming, almost self-effacing study on the effect of diet on rheumatoid arthritis. Here is the stated objective of the study: “To overcome obstacles to healthy eating by a community-based intervention promoting a Mediterranean-type diet in patients with rheumatoid arthritis or RA living in socially deprived areas of Glasgow.” What was this modest paper doing amongst all the high-powered papers on the molecular mechanisms of rheumatic diseases and the latest potent therapies based on insights into those mechanisms?

The study

Methods: 130 female patients with RA aged 30–70 years (median 55), disease duration 8 years were recruited from three hospital sites. The intervention group (75 patients) was taught how to switch to the Mediterranean diet, which is rich in fruits, vegetables, fish and olive oil. They attended weekly 2-hour sessions for 6 weeks in the local community, including hands-on cooking classes backed up with written information. The control group (55 patients) were given dietary written information only. Both groups completed food frequency questionnaires (FFQs), and clinical and laboratory measures were assessed at baseline, 3 and 6 months.

Results: By way of introduction: Statistical significance requires that a “p value” will be < 0.05. That means that the result has less than 5% probability of being due to chance rather than due to the treatment. If the p value is < 0.01, the result has less than 1% probability of being due to chance, and is considered “highly significant”.

Significant benefit was shown in the intervention group compared with controls. For patient global assessment at 6 months (p = 0.002), pain score at 3 and 6 months (p = 0.011 and 0.049), early morning stiffness at 6 months (p = 0.041) and Health Assessment Questionnaire score at 3 months (p = 0.03). Analysis of the FFQs showed significant increases in weekly total fruit, vegetable and legume consumption and improvement in the ratio of monounsaturated:saturated fat intake and systolic BP in the intervention group only. The cooking classes were positively received by patients and tutors; cost/patient for the 6 week course was £84 ( EUR124 or $168).

So what’s the big deal?

I think that the study is important for three main reasons:

1. Once again simple measures, in this instance a good diet, proved to be the most effective means of warding off disease. Diet rich in fruits and vegetables, fish and olive oil has been shown to improve cardiac health (note the reduced systolic blood pressure in the intervention group), weight control and diabetes, and certain cancers (notably colon cancer).
2. The Mediterranean diet can also be dubbed “the anti-inflammatory diet”. Among many factors that mediate inflammation there is a class of small molecules called prostaglandins. Not all prostaglandins are born equal; some are pro-inflammatory (they cause inflammation) and others are anti-inflammatory. RA is caused, in part, by the pro-inflammatory prostaglandins. Steroids, by the way, inhibit the synthesis of prostaglandins, hence their anti-inflammatory action. There are other drugs that inhibit the synthesis of prostaglandins that are not steroids. These are called non-steroidal anti inflammatory drugs or NSAID, like aspirin and ibuprofen (Advil). Indeed, these drugs are the first line of defense in newly diagnosed RA. But the drugs are not risk-free. Steroids taken on a chronic basis have many serious adverse effects: suppression of the immune response, bone loss, fluid retention, mood disturbances. NSAID  cause stomach irritation, ulcer and bleeding. On the other hand, olive oil and fish (part of the Mediterranean diet), are rich in monounsaturated fatty acids. Rather than the sledge hammer effect of the drugs, these fatty acids very subtly divert the synthesis of prostaglandins from the pro- inflammatory to the anti-inflammatory ones. No immunosuppression, no bone loss, no ulcer. Once again, nature provided a clean and simple solution that has eluded the best minds in drug development.
3. The inflammatory response is gradually assuming a central role in many diseases that have not been on the usual suspects list: diabetes, atherosclerosis, coronary heart disease, all the autoimmune diseases (such as rheumatoid arthritis, lupus, systemic sclerosis or scleroderma), and even certain cancers. The effect on our health and our national health budget of an anti-inflammatory diet, such as the Mediterranean diet, could therefore be enormous. I can foresee a time when insurance companies would reduce the premiums of people who stick to a regimen of regular exercise and an anti-inflammatory diet, just as they do now for non-smokers.

So, hooray to the modest clinicians who published this unassuming work. Their conclusion: “Results demonstrate that a 6 week intervention can improve consumption of healthier foods. If implemented more widely it may prove a popular, inexpensive and useful adjunct to other RA treatment.” To this I would add: "this study provided a scientific basis for a wider adoption of a diet that could revolutionize our eating habits, our health and our health care." I guess those Scots are not given to such overt enthusiasm; is it the climate?

A recent study from the Mayo Clinic, published in the Journal of the National Cancer Institute (JNCI, vol. 99, p. 825, 2007), looks at the relationship between the use of aspirin and non-aspirin NSAID (non steroidal anti inflammatory drugs) in postmenopausal women and the incidence of death from cancer, heart disease, and death from any cause.

How the study was done

The investigators studied data on about 22,500 women who were enrolled in the Iowa Women's Health Study, a long-term health study of women living in Iowa. Starting in 1986, the women completed surveys periodically about their medical history, diet, physical activity, smoking, and other factors every year until 1992. In that year, the women also reported their use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. They were then followed, without filling out additional questionnaires, until 2002.

And the results were…

· Women who took aspirin were 13% less likely to die of cancer.

· They were 25% less likely to die of heart disease.

· They were 18% less likely to die of any cause during the study.

· Non-aspirin NSAID had no effect on mortality.

What’s wrong with this picture?

Plenty. Let me count:

1. The study was observational; such studies are fraught with problems, and are not very reliable. For instance, the investigators did not study the effect of aspirin by giving the drug, and following them for the study period (known as a prospective study). They got their data from a questionnaire filled out by the participants.

2. The study started in 1986 and ended in 2002—16 years in duration. And only at one point in time (1992) were the participants asked to recall their aspirin use. The quality of such recall has been shown in several studies as flawed.

3. The questionnaire did not ask about the frequency and dose of the aspirin. And even if they did, such data would have been of questionable utility. Would you trust your own recollection of your aspirin intake several years back? Or even the prior 6 months?

4. The study was restricted to postmenopausal women, mostly white. Does this finding extend to other population groups?

5. Only aspirin had an effect on mortality. Non-aspirin NSAID, such as Advil, Motrin and Aleve, had no effect. This finding is conflict with other studied showing non-aspirin NSAID having a survival benefit similar to aspirin. Both types of drugs have a similar mode of action; they are anti-inflammatory drugs, targeting the same metabolic pathway ( prostaglandin synthesis). If however, this observation stands up to repeat studies, it would be a great contribution, which may uncover some subtle differences of clinical importance between aspirin and other NSAID.

Should you start taking aspirin?

Obviously, this is at best an incomplete study. On this basis alone, it would be inadvisable to start taking aspirin on a daily basis. Admittedly, other studies suggest that daily aspirin is beneficial, to a small degree, in the prevention of breast cancer and colon cancer, as well as heart disease.

But consider these two facts:

· Aspirin is not harmless. It can cause all kinds of stomach problems, like gastritis (inflammation of the lining of the stomach) and ulcer. It can also cause bleeding problems, including hemorrhagic (bleeding) stroke.

· Why take medicine for a 13% reduction in cancer mortality when you can eat well (five helpings of fruits and vegetables a day) and exercise (30 minutes walk, six times a week) and cut your risk of death from breast cancer by 50%! See my earlier post, "Women with breast cancer can lower their risk of dying by 50%." The same type of protection has been shown for colon cancer, and for heart disease.

As far as I am concrned, the choice is obvious.

Dov Michaeli MD, Ph.D