Little John was elated. Christmas Day had finally arrived in Birmingham, England. He scurried out of bed to the living room where his family’s evergreen tree stood, shimmering with shiny ornaments. Beneath its branches, he spotted what he was looking for; an oblong shaped box. As he tore through the plain brown paper wrapping, he couldn’t contain his excitement.
“Wow, a chemistry set!” What 12-year-old kid wouldn’t be thrilled?
John’s parents, a Russian immigrant married to an English Midlands farmer’s daughter, had carefully considered what gift to purchase for their son. After all, they had struggled hard to achieve middle class status, and they hoped their talented son would one day far surpass their social standing.
John took to chemistry in a flash. In fact, one of his earliest experiments, which involved the creation of hydrogen sulfide gas, caused a minor explosion, turning the newly painted decor of his “laboratory” (better known as the family kitchen) from a pale shade of blue to a slimy green. Rather than being angry, his father, who ran a small business building small portable sheds, erected a shed next to their house and equipped it with a laboratory bench and real gas and water lines. The Bunsen burner could finally be disconnected from the kitchen stove.
John loved to dabble with his chemistry set, and when it came time to apply to college, he chose to study chemistry at the University of Birmingham. Much to his chagrin, he discovered that experimentation in chemistry was nonexistent at the university.1 Unhappily, he persisted in his studies. As graduation neared, the chair of the chemistry department questioned John about his future career plans. “Anything but chemistry” was his acerbic reply. Recognizing his true talent, the chair suggested that John pursue training in the emerging field of pharmacology.
John recalled, “Without hesitation, I grasped the opportunity and immediately went to the library to find out what pharmacology was all about.” The library. Yes, this is where people went looking for information before there was Google.
Attention all parents: That Christmas gift chemistry set paid handsome dividends. Thirty-three years after its purchase, John Vane was awarded the 1972 Nobel Prize in Physiology and knighted for his groundbreaking work in deciphering how aspirin works. In his Nobel lecture, Vane fondly recalled his aha moment:1
It was this experiment that led me to the idea (over the weekend) that aspirin might be interfering with prostaglandin biosynthesis. On the Monday morning I said … “I think I know how aspirin works” and set about doing an experiment. I homogenized some guinea pig lungs, spun off the cell debris, divided the supernatant into test tubes, added arachidonic acid and measured by bioassay the amounts of (prostaglandin) PGE2 and PGF2alpha formed. By the end of that day, I was convinced that aspirin and indomethacin (but not morphine) strongly inhibited the formation of prostaglandins from arachidonic acid.
The importance of this finding cannot be overstated. In addition to clarifying the mechanism of action of a drug widely used as an analgesic and antiinflammatory agent for almost a hundred years, it pointed the way to treatments for various diseases and opened avenues of research and drug discovery that are still being explored.2
Vane did not rest on his laurels. He subsequently identified the ephemeral substance released from the lungs during anaphylactic shock, previously referred to as rabbit aorta contracting substance, as thromboxane A2 (TxA2). He demonstrated that TxA2 was derived from the same precursors as prostaglandins, but instead of mounting a similar antiinflammatory response, it seemed to have the opposite effect, unleashing a series of powerful platelet-aggregating activities.
A few decades later, rheumatologists learned just how potent these actions could be.
As we were doling out the newest NSAIDs, we focused on our patients’ bellies & bowels. Perhaps we should have looked elsewhere: to their hearts & blood vessels.
Chewing on Bark
The ancient Greeks were well aware of the health benefits of willow bark. Hippocrates touted its benefits as an analgesic during childbirth, and Galen described its antipyretic properties. Over the course of the next millennium, it was used to treat the agues and other shivering maladies. However, by the time of the Middle Ages, its popularity had waned. Willow was eclipsed by another tree, the cinchona. This tree, indigenous to South America, was a coveted import to the Old World, where efforts to cultivate it failed. Armed with an entrepreneurial spirit, a British clergyman, the Reverend Edward Stone, set out in search of a cinchona substitute. He was guided by the prevailing view at the time, which held that many cures could be found right where illnesses most commonly occurred.3 Wasn’t this Nature’s way of creating some form of balance?
Because fevers and agues were often described in marshy areas, this became the prime area for Stone’s arboreal search. Willow trees thrived in the marshes of England. He observed that the bitter taste of their bark resembled that of the cinchona tree. An ancient remedy was reborn. The abundant supply and popularity of willow trees across Europe and parts of North America led to an explosion of activity in trying to purify its primary medicinal ingredient, salicylic acid.
A French chemist, Charles Gerhardt, was the first person to synthesize aspirin in a simple form in 1853; however, he is rarely cited for this milestone. Instead, the honor is bestowed on a 29-year-old chemist, Felix Hoffman, who was working for a small German aniline dye turned pharmaceutical outfit, the Bayer Co.
According to legend, Hoffman’s father suffered from a severe form of arthritis and could not tolerate the crude form of salicylic acid that was being sold at the time. Pleading with his son to find a remedy, the younger Hoffman devoted the next four years of his life to this task. He succeeded in tweaking the chemistry of the reaction and produced a purer compound, acetylsalicylsaure, a tongue twister in any language. The drug was highly successful in alleviating his father’s pain.
Bayer’s chief pharmacologist, Dr. Heinrich Dreser, rejected this new formulation, erroneously believing it to be cardiotoxic. Perhaps Dr. Dreser was preoccupied with his own recent discovery of a novel and, at the time, commercially successful cough suppressant, heroin.3 Eventually, the pharmacologists at Bayer recognized the true value of their new product. Because its cumbersome name described the generic version of the drug, a new trade name had to be invented so that it could be patented. Dr. Dreser created aspirin, an acrostic that combined the letter a, for acetyl, spir for Spiraea (the genus of the willow bark tree) and—in, a popular suffix for drugs at the time.
The potent antiinflammatory, analgesic and antipyretic properties of aspirin made it one of the best-selling drugs around the world. Rheumatologists embraced it, and aspirin became the mainstay of therapy for virtually all of the arthritic disorders for decades. Many of us may recall being taught how to titrate a patient’s aspirin dose based on the presence or absence of tinnitus, a hallmark sign of salicylate toxicity.
The Dawning of a New Era
In those simpler therapeutic times, aspirin ruled. But we recognized that aspirin was far from perfect. Its short half-life required frequent dosing, which resulted in a heightened frequency of gastrointestinal side effects. Following Vane’s elucidation of prostaglandin synthesis and the role of the cyclooxygenase enzyme pathways, a dizzying array of new nonsteroidal antiinflammatory drugs (NSAIDs) came to market.
Each successive product touted its purported superior clinical efficacy and reduced risk for gastrointestinal adverse events, particularly peptic ulcer disease, gastric perforation and bleeding. In the U.S., it was estimated that these events were responsible for about 8,000 deaths annually. Not surprisingly, as we were doling out the newest NSAIDs, we focused on our patients’ bellies and bowels. Perhaps we should have looked elsewhere: to their hearts and blood vessels.
For rheumatologists, the advent of the more selective cyclooxygenase (COX) inhibitor drugs was a game changer. Their development was based on the premise that these enzymes, critical to prostaglandin formation, could be sorted into either good or bad forms. By selectively blocking the bad form (COX-2), an ideal antiinflammatory benefit could be provided to our patients while sparing them the deleterious consequences of blocking the good form (COX-1), considered essential to maintaining several critical body functions. For example, we could now eliminate the adverse gastrointestinal side effects associated with the older, less selective NSAIDs that populated the market.
The selective theory of COX inhibition took hold of us. We were smitten. Because COX enzymes were found in just about every human tissue, these drugs were studied in myriad diseases. Although they failed to slow the progression of Alzheimer’s disease, they showed efficacy in preventing the development of certain forms of inherited adenomatous polyps that required COX-2 to grow. Every major pharmaceutical company had similar drugs in their development pipelines. This was supposed to be the dawning of a new era.
Dawn Fades to Dusk
Perhaps we should not have been astonished to see how quickly dawn faded to dusk. After all, it was long known that aspirin use provided significant antithrombotic effects. For example, one of the first anticoagulants, dicumarol, was found to spontaneously metabolize to salicylic acid. More than 60 years ago, Dr. L.L. Craven, an astute otolaryngologist practicing in Glendale, Calif., observed that his tonsillectomy patients who chewed an aspirin-containing gum excessively tended to bleed more profusely after their surgery. He reasoned that aspirin might be useful in preventing myocardial infarction (MI) and began treating all his older male patients with it.
In two astonishingly prescient papers, both published in the Mississippi Valley Medical Journal, Dr. Craven claimed that none of the 8,000 men he had treated during his years in practice had succumbed to either an MI or a stroke.4 Who needs randomized, controlled studies when the data is so good? Ironically, Dr. Craven himself died of an MI a year following the study’s publication. Yes, he was an aspirin user.
For many years, it remained unclear whether NSAIDs or selective COX inhibitors provided a similar benefit. Nearly a decade ago, the answer came crashing down. A major study of the selective COX-2 inhibitor, rofecoxib, in preventing adenomatous polyps found the drug highly effective.5 The really bad news was that there appeared to be a spike in the incidence of cardiovascular adverse events in the treated patients. Actually, this spike turned into a flood. It has been estimated that rofecoxib may have accounted for an excess of 88,000 to 140,000 cases of serious heart disease over the course of its few years on the U.S. market.6
It soon became apparent that all NSAIDs and COX-2 inhibitors lacked the highly beneficial and sometimes lifesaving effect of aspirin on the production of TxA2. Playing with TxA2 levels, the rabbit aorta contracting substance, was clearly life contracting for some patients.
Before long, rofecoxib and its sister drug, valdecoxib, were withdrawn from the market at the request of the U.S. Food and Drug Administration. As major purveyors of NSAID therapy, I think we have all become skittish about their use in many of our patients.
When a kid tinkers with a chemistry set, there may be a flash and a charred kitchen wall. When doctors tinker with nature, the damage may be much harder to repair.
Simon M. Helfgott, MD, is associate professor of medicine in the division of rheumatology, immunology and allergy at Harvard Medical School in Boston.
References
- Edelson AM. John Robert Vane: 1927–2004. J Cardiovasc Pharmacol. 2005;45(3):280–282.
- Moncada S. Obituary: John R. Vane (1927–2004). Nature. 2005;433(7021):28.
- Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development and directions for the future. Circulation. 1994;89(1):432–449.
- Craven LL. Experiences with aspirin (acetylsalicylic acid) in the nonspecific prophylaxis of coronary thrombosis. Miss Valley Med J. 1953;75(1):38–44.
- Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092–1102.
- Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: Nested case-control study. Lancet. 2005;365(9458):475–481.
