Macro shot of white asprin on white. 1500x996 px

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 acetylsalicylic 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 NSAIDs (non-steroidal anti-inflammatory drugs), was synthesized. Famous members of this group are ibuprofen (Advil), naproxen (Naprosyn), 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 a story in 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 the mosquito’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 bloodsucker 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?

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

2 COMMENTS

  1. The Bark Of A Willow TreeAlmost on a daily basis, one may read about a new medication being developed or approved for the benefit of patients with a particular medical condition or disease state that they exist at the time. At times, these announcements may praise the innovation and novelty of such new drugs that are available to all in need of it, and rightfully so, in many situations.But it’s possible the one particular drug is not new and really may be a super drug. In fact, it’s one of the oldest medications available, and that would be aspirin- the first non-steroidal anti-inflammatory drug (NSAID) initially for those patients experiencing pain.Noted as ASA by doctors typically, aspirin effects have been noted for thousands of years, as the active ingredient comes from the bark of a White Willow tree, and long ago, patients with pain or a fever would chew on this bark for relief. Yet due to the harshness of the natural chemical of this bark, Bayer decided to synthesize it to make it more tolerable for the user.Fast forward to over a hundred years ago and Bayer pharmaceuticals (pronounced ‘Beier’), which is the same company that brought us heroin (named so due to its perceived ‘heroic’ qualities as a believed non-addictive substitute for morphine addicts) and mustard gas, as well as methadone. The company originated in Germany, but presently has its U.S. headquarters in New York. Felix Hoffman, seeking to develop an agent for his father’s rheumatism, was involved in the development of what is known now as aspirin. And it was a difficult task to develop this drug, as it was toxic to the stomach due to the nature of the active ingredient again obtained from the bark of the white willow tree. Dr. Hoffman and others at Bayer developed a drug that proved to be tolerable to patients while keeping the active ingredient in tact through a method of delivery developed by Dr. Hoffman’s team at Bayer. After launching the medication, aspirin was priced at about 50 cents an ounce, as at the time it was only available in power form. Soon before 1920, aspirin developed the tablet form of the drug and was then available by prescription. Regardless, aspirin was responsible for one third of sales for Bayer during this time, due to its popularity due to the effects of this medication in need of relief.While all drugs have side effects, aspirin is one of very few drugs that offers suitable efficacy with perhaps mild side effects associated with the drug, comparatively speaking. Aspirin has been found to be beneficial for a wide variety of disease states. In fact, some of aspirin’s additional uses have been only recently discovered. This may be why the New York Times called aspirin a wonder drug in the 1960s, according to others. In the 1970s, the mechanism of aspirin was isolated, which is the blockage of prostaglandins. Prostaglandins are inside the human body and are a contributor for physiological inflammation.Aspirin has been associated with decreased risk of asthma and prostate cancer in the elderly. Also, aspirin has been linked with lowering the risk of breast cancer and colon cancer as well. Yet these conclusions are based on limited research with aspirin.Aspirin is a blood thinner, and has been associated with decreasing the risk of heart attacks and strokes in certain patient populations, as the drug prevents clots. However, aspirin has not been shown to prevent heart attacks in diabetic patients. The cardiovascular benefits of aspirin were first suggested in the 1940s, and the FDA suggested that it be the drug of choice for those who experienced a heart attack over a decade ago. Aspirin intake is also beneficial for those after coronary bypass procedure. In addition, aspirin has been shown to reduced blood pressure with those who have mild hypertension, if aspirin is taken at night with such patients. A topical formulation of aspirin was developed recently for those experiencing Herpes pain. The drug has been proven beneficial for those experiencing migraine pains. Aspirin at low doses is taken by many as a preventive drug to decrease cardiovascular incidents that may occur.Aspirin has been the best selling painkiller absent of the past addictive qualities of opiate meds since the 1950s. It is also the most studied drug- with over 3000 scientific papers published worldwide. Also, over 15 billion tablets of aspirin are sold annually, which amounts to about 80 million aspirin tablets consumed daily by others. This amounts to over 16,000 tons of aspirin consumed during this time, or about 70,000 metric tons of aspirin a year. Over a decade ago, a study was performed and concluded that twice as many people would choose aspirin over a computer, given the two choices, because of the benefits of the drug. Side effects would include GI bleeding if taken in large amounts, along with an association of Reye’s syndrome in children, yet both are relatively rare. Yet all things considered, clearly the benefits of aspirin outweigh any risks of the drug.Lately, there have been issues with other NSAIDs, such as Cox II inhibitors, without full recollection or knowledge that aspirin is in fact the world’s most widely used drug, and for good reasons. At times, something newer is not always better.“There is no genius without a touch of madness.” — Vaslav NijinskyDan Abshear

  2. Interesting.. Recent studies also have demonstrated that secular drugs like digitalis and ouabain (cardiac glycosides), at low doses, show antiviral, anticancer, anti-stroke. anti-inflammatory and anti-infarction effects.Regarding anti-viral effects see the study Anti-HSV activity of digitoxin and its possible mechanisms., published in Antiviral Res. 2008 Feb 21Regarding cancer see the article Digitalis: The Insulin for Cancer? at http://www.infarctcombat.org/media/042006.html Regarding stroke see the article Cardiac Glycosides in Prevention of Stroke at http://www.infarctcombat.org/media/071006.html Regarding anti-atherosclerotic and anti-infarction effects of cardiac glycosides please see at our acidity theory of atherosclerosis with E-print at http://www.infarctcombat.org/AcidityTheory.html

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