26/02/2026
From Willow Bark to the Pharmacy Shelf.
Aspirin is the most widely used drug in the world. Except that it nearly wasn't. Its parent chemical business, 'Bayer AG', almost abandoned researching aspirin in favour of another new medicine, one you've undoubtedly heard of. Aspirin swept the medical world by storm at the start of the twentieth century; international politics upended the aspirin market, and aspirin's anti-blood clotting properties solidified its place as the medication we all keep in our medicine cabinets. You've undoubtedly heard that aspirin originated from the willow tree. And this is somewhat accurate, but not entirely. It is a member of the lineage, but not a direct descendant of willow. Willow has been employed in therapies by ancient Assyrians and Egyptians, as well as traditional Chinese, African, and indigenous American healers. And it is true that they recorded how it may lower fevers and inflammation, with the proviso that 'fevers' and 'inflammation' had different meanings back then than they do now.
So, by the time the study of pharmacology began, scientists were eager to explore whether they could utilise chemistry to discover the therapeutic chemical in willow. However, these 17th and 18th-century scientists were initially more interested in a different medicinal plant, cinchona, which led to quinine, the first antimalarial medicine. Now, if you've ever had a gin and tonic, you know how bitter quinine is. So these early drug searchers hypothesised that additional bitter plants could also have therapeutic effects. Sure enough, in 1758, Reverend Edmund Stone, an English priest, chewed on some willow bark and discovered that it tasted bitter as well. And, because cinchona was not native to England, he pondered whether willow might be used as a cheap, local alternative for Peruvian bark, another name for cinchona. There was little scientific study on the subject, so he decided to run his own experiment. He would ground some willow bark and mix it with water. Then, when he saw a patient with agues, another term for malaria fever, he'd give them ever larger amounts until their fevers subsided. He performed this for five years, treating fifty individuals in all. So he thought, "Great!" I discovered a new quinine! However, in actuality, the plants function somewhat differently. Quinine destroys the parasite that causes malaria, while the active substance in willow just alleviates symptoms such as fever.
Stone submitted his report to the Royal Society in 1763, but he died before it gained momentum. Nevertheless, willow was so firmly ingrained in pharmacy, pun intended, that chemists continued returning to it. In 1824, two Italian chemists identified willow's active element, which is a component of a medication that has a physiological effect; in this instance, it decreases fevers. They gave it the name salicin, which is derived from the Latin meaning willow. A few years later, other scientists developed ways for producing higher quantities of pure, separated salicin crystals, making experimentation more accessible. And by the 1830s, scientists had developed salicylic acid. Some began with salicin produced from willow, while others began with salicylaldehyde taken from meadowsweet, a salicylate-producing rose. And it seemed that salicylic acid would be much more effective than salicin. So in 1859, a chemical professor called Herman Colby discovered a technique to synthesise salicylic acid. No additional willow trees are necessary. One of Colby's students even created a chemical plant to generate salicylic acid, and other chemical businesses quickly followed suit. As a consequence, salicylic acid became immensely popular as a pain and fever reliever since it was not only one of the few medications on the market that worked, but it could also be mass-produced at a low cost. Throughout the 1870s and 1880s, physicians conducted clinical studies on the medicine, confirming that it was particularly successful at decreasing fevers and alleviating pain.
Unfortunately, there was one adverse effect of aspirin that they could not ignore. It harmed the sufferers' stomachs. And it turned out that someone already had a solution; they simply didn't realise it yet. In 1853, Charles Gerhardt developed acetylsalicylic acid, the active element in aspirin. Unfortunately, Gerhardt's procedure for producing the molecule was complex and time-consuming, so acetylsalicylic acid did not take off straight immediately. Until a few chemical corporations began dabbling in the pharmaceutical sector, one of which was Friedrich Bayer and Company, or just Bayer. In 1888, Bayer directed one of their chemists, Carl Duisburg, to begin hunting for viable medications to produce. By the mid-nineteenth century, chemistry had advanced to the point that existing molecules could be tweaked into new substances with varied qualities, as Duisburg intended to accomplish with medications. He would start with well-known medicinal molecules and chemically change them to create new and better compounds. To that objective, salicylic acid served as an excellent target. It has a proven track record as an antipyretic and was readily available. And Duisburg knew that if he could preserve salicylic acid's anti-inflammatory effects while modifying it into a more palatable version, they'd have a winner on their hands. So he recruited a chemist called Arthur Eichengren and a pharmacologist named Heinrich Dreser, and the two didn't get along. In August 1897, Eichengren instructed one of his chemists, Felix Hoffmann, to explore whether he could add acetyl groups to two existing medications, morphine and salicylic acid. This salicylic acid came from Meadowsweet, not Willow. He succeeded in both, producing diacetylmorphine and acetylsalicylic acid. So he submitted both substances to the pharmacology team, and both passed animal testing. As a result, a problem arose. With a restricted research budget, which new chemical would you pursue? Given the history of adverse effects with salicylic acid, Dreser and the pharmacology team were more interested in diacetylmorphine, while Eichengren's chemical team saw greater potential in acetylsalicylic acid. For example, anything that reduces temperature, discomfort, and inflammation might be utilised to treat a variety of illnesses. Both medications showed potential for economic success.
Ultimately, Duisburg agreed with the pharmacological team. Bayer sought diacetylmorphine, which he later released as he**in. But Eichengren opted to explore acetylsalicylic acid nevertheless. As the proverb goes, asking for forgiveness is simpler than asking for permission. He contacted a Bayer representative, Felix Goldman, and began planning a human experiment in Berlin. Goldman sent a number of samples to physicians and dentists, who provided them to their patients and reported back to Goldman. Obviously, failing to get informed permission from these individuals was unethical, but I assure you that it was hardly the worst thing Bayer ever done. Check watch my film about sulfa medications to learn about some messed-up things that happened during WWII. Regardless, they saw excellent results immediately away. It provided remarkable pain relief for toothaches, healed fevers, and produced a variety of other findings that pointed to a miracle medication. So Eichengren takes his findings and presents them to Dracer. And he is still not impressed. He is cited as stating, "The product has no value." However, after seeing the findings, their supervisor, Duisburg, determined that acetylsalicylic acid was a commercially viable product. It passed clinical testing without incident, and by 1899, Dracer, the original hater, had written an article on his findings that made no mention of anybody else on the team. Now it was time to begin promoting the medicine. But Bayer would need a memorable name. They substituted A for acetyl, Spear for Speria almeria, the scientific name for the salicin-producing meadowsweet plant, and in to make it simpler to say. Aspirin was born. If we were to conclude the narrative here, aspirin would already be considered legendary in medical history.
For years, people have discovered pharmaceuticals in nature. We obtained morphine from o***m, digitalis from foxglove, and quinine from cinchona. But now that we had this new chemistry, we switched from plants to chemicals that could be isolated, synthesised, and studied. Aspirin constituted a turning point in contemporary pharmacology. We'll get to the marketing narrative shortly, but first, there is some dispute about the story I just told you. According to Bayer's website, Hoffman was experimenting with salicylic acid not because Eichengren urged him to, but because his father wanted a medication to treat his rheumatism and was weary of the negative effects of normal salicylic acid. None of the scientists engaged in aspirin's development published formal descriptions of the discovery immediately away, and Bayer did not produce an official history until the 1940s. But at the time, the N***s were in charge. So, rather of thanking the Jewish Eichengren, they gave credit to Hoffman. Eichengren was imprisoned in a concentration camp in 1944 and survived to relate his side of the tale. So in 1949, he said, 'I had a part in this too,' which he hadn't been comfortable stating previously. Despite the fact that he provided paperwork demonstrating his leadership, most current accounts make no mention of him. However, the original US patent from 1900 simply mentions Hoffman as the discoverer, and you're unlikely to get that one through without supervisor permission.
Now that Bayer has ownership of aspirin, they must promote it. However, they understand that in order to execute it correctly, they must avoid a mistake committed ten years before. See, a few years before aspirin, Bayer introduced another pain-relieving fever reducer called phenacetin. They patented it in the United States in 1888 and first sold it for a dollar per ounce, which was the same amount they charged in Germany. However, because to German patent legislation, they were unable to patent it locally, so rivals began producing their own copies, lowering the price. However, since they possessed an American patent and could defend their monopoly, Bayer maintained the dollar-per-ounce pricing in the United States. As a consequence, American pharmacies began importing the medicine from other nations, such as Canada, where it cost only 35 cents per ounce. So Bayer sued American chemists, dealers, and importers, claiming that it had exclusive rights to sell phenacetin in the United States. Here is the thing. Phenacetin is a registered brand name. The generic name was acetophenetidine. However, the American patent identifies phenacetin as the innovation, implying that it was the generic name. Bayer attempted to behave ethically while developing this medicine. So they did not market phenacetin to patients and did not vigorously protect its trademark. In practice, the brand term 'phenacetin' has become the de facto generic name. It's pretty similar to Kleenex and face tissues.
When it came time to commercialise aspirin, Bayer was resolved not to make the same mistake again. Acetylsalicylic acid has previously been recorded in Germany by Gerhardt, hence it was ineligible for a German patent. However, Bayer may get patents in Great Britain and the United States, as they did in 1900. And, as with phenacetin, American chemists imported aspirin from other nations, and Bayer threatened to suit. They would absolutely defend their intellectual property this time around. Bayer also trademarked the word 'aspirin' prior to obtaining patents. They wanted consumers to identify the term aspirin with the brand Bayer. And thus was the second prong of their aspirin strategy: branding. This included branding the bottles, which first held aspirin powder before transitioning to branded tablets. This was accompanied by a massive marketing push—allegedly the single largest campaign for any single medicine in history up to that date. According to early twentieth-century standards, aspirin was the first blockbuster medicine. Technically, a blockbuster is a medication that generates a billion dollars in yearly sales, but because it was released before billionaires existed, we'll adjust our criterion. But the good times couldn't continue forever, and Bayer saw some ups and downs during the following several decades. In 1905, a British court found that Bayer's patent on aspirin was invalid. The court determined that Hoffman's procedure was not significantly different from one created before him, and therefore Bayer lost its patent in Britain, as well as its market supremacy.
A similar action was filed in the United States, but the court found in favour of Bayer. This was wonderful news for them, since it was 1910 and aspirin accounted for 25% of Bayer's American sales. And then World War I began. The UK ceased purchasing German products, but physicians continued to prescribe aspirin. As a result, their board of trade cancelled Bayer's trademark in the United Kingdom, allowing English drugmakers to produce and sell aspirin. Bayer's US patent on acetylsalicylic acid expired in 1917, and rivals began making their own. After the war, the US confiscated some German intellectual property under the Trading with the Enemy Act, which included Bayer's other IP, including the trademark for the word 'aspirin'. The office sold the aspirin brand and Bayer emblem to Sterling Drug, an American patent pharmaceutical firm, for $3.5 million. This is also when 'aspirin' begins to replace 'acetylsalicylic acid' as a generic name. Okay, so World War I is finished, aspirin's patent has expired, and each pharmaceutical business is releasing their own versions. This is why you may get these little aspirin tins on eBay. They were so prevalent that they were available in plenty. Throughout the 1920s, aspirin's popularity grew worldwide. While aspirin controlled the pain management market for decades, other medications emerged and ate into its share. The earliest of these rivals, paracetamol, or paracetamol, was introduced in the early 1950s. Then, in the late 1950s, a scientist called Stuart Adams began working on another new one. He worked for Boots Pure Drug Company in the United Kingdom and was tasked with developing a non-steroid treatment for rheumatoid arthritis. So Adams wondered, what about aspirin? It's an effective anti-inflammatory, and I'm sure we could find a way to manufacture something that doesn't bother stomachs. Adams and his colleagues spent the next ten years brute-force screening hundreds of chemicals one after the other. Propionic acid seemed to be a promising choice, however it did not perform well in clinical testing.
Adams' team understood they were on the correct track. So they developed a propionic acid derivative called 2P-isobutylphenylpropionic acid, which became known as ibuprofen. In 1969, a US-based business named Upjohn licensed it from Boots and later commercialised it under the brand name Motrin. A few years later, another business made a lesser dosage of ibuprofen accessible over the counter, which they marketed as Advil. Aspirin and ibuprofen were among the first of a new class of medications known as NSAIDs, or nonsteroidal anti-inflammatory drugs. Of course, new medications entered the market, such as naproxen, often known as Aleve, which was licensed in the United States in 1976, and diclofenac, also known as Voltaren, in 1988. However, physicians were beginning to discover certain unusualities among aspirin users. They bled a much. In 1945, an American doctor examined a group of tonsillectomy patients and discovered that those who used aspirin for pain tended to bleed more a few days following surgery. By 1948, a British doctor called Paul Gibson thought whether it may be because aspirin had an anticoagulant effect, preventing blood cells from sticking together. So the following year, he published case studies in the Lancet explaining how aspirin helped alleviate chest discomfort. These were not scientific research; rather, they are well-documented stories. However, it piqued physicians' interest in the use of aspirin to treat cardiovascular disease. By the middle of the century, some physicians started prescribing anticoagulants such as dicoumarol to treat heart attacks. However, it was still contentious. The notion was that if someone already had atherosclerosis, aspirin would prevent blood clots from forming in the restricted arteries. In any case, by 1950, aspirin had firmly established itself as the best-selling pain reliever. There was just one item. Nobody understood how it operated. At the time, scientists were discovering that molecules known as kinins had a role in the inflammatory response. And a scientist named Henry Collier was particularly interested in a form of kinin known as bradykinin, which causes loosened blood vessels and greater discomfort. However, it may cause bronchoconstriction, or tightness of the airway, especially in patients with asthma.
Collier conducted trials in which he induced bronchoconstriction in asthmatic guinea pigs by administering bradykinin. However, he discovered that if he gave them aspirin before bradykinin, their airways remained open. Initially, he believed that aspirin was a bradykinin antagonist, preventing bradykinin from binding to its target receptors. That would explain the analgesic characteristics, but not how it may decrease inflammation or fevers. So he enlisted the help of Priscilla Piper, who worked with another researcher called John Vane, who had created a potentially valuable test. This is how it worked. They placed guinea pig lungs at one end of an experiment, followed by little fragments of tissue at the other. This might include chicken rectums or the stomach lining of a rat. Then they'd cause shock in the lungs, which would leak an undetermined cocktail of chemicals across the medium, mixing with the tissues on the opposite side. So one day, Vane and Piper performed their experiment using an aorta from a rabbit on the other end, and they got it to twitch. So they named this mysterious chemical Rabbit Aorta Contracting chemical. Kind of a placeholder name. However, they were able to prevent the rabbit aorta from twitching by injecting aspirin into the guinea pig lungs prior to causing shock. Whatever the aorta contracting drug was, it was not an antagonist. Aspirin prevented the lungs from secreting anything. Piper and Vane reported their findings in the journal Nature in 1969. Two years later, they identified the mysterious contracting chemical as a prostaglandin and proved that aspirin was not a prostaglandin antagonist. Aspirin really hindered the cell's capacity to produce new prostaglandins. In 1975, a Swedish researcher named Bent Samuelsson discovered that aspirin blocked a chemical known as thromboxane A2. Its major function is to cause platelets in the blood to clot together. The term thrombo in thromboxane refers to coagulation. However, it may cause blood arteries to tighten, which is likely why Vane and Piper's rabbit aorta was twitching.
The following year, a study team at the University of Michigan discovered the missing piece of the puzzle. They discovered an enzyme required to produce prostaglandins, which is what aspirin truly targets. It's called the cyclooxygenase enzyme, or COX for short. It's acceptable to laugh. Here's our current understanding of how it works. When you are harmed, your body produces prostaglandin, which triggers an inflammatory reaction. This is where things like redness, discomfort, and swelling originate. When your body sends the signal to produce prostaglandins, your cell membranes release arachidonic acid. subsequently a few enzymes attach to arachidonic acid, producing prostaglandin precursors, which are subsequently converted into further prostaglandins. We are interested in two of these enzymes: COX-1 and COX-2. This is what aspirin prevents. Think of COX-1 as your everyday driving enzyme. It accomplishes a variety of things, including catalysing the production of prostaglandins, which help preserve our stomach linings. This is where the stomach side effects originate. poorer COX-1 activity equals poorer protection against stomach acid. It is also involved in the manufacture of thromboxane A2 in platelets, which are the components of blood that cause it to clot. That's why all those tonsillectomy victims bled so profusely. COX-2, on the other hand, is often produced during the inflammatory response. However, it is not a complete binary, since both may be produced during inflammation. Acetylsalicylic acid binds to each COX enzyme in the same location as arachidonic acid would bind. So the enzymes can no longer convert it into prostaglandin or thromboxane A2. More crucially, aspirin is non-selective, which means it binds to both COX enzymes rather than just one. However, it is more effective in inhibiting COX-1 than COX-2. It is also irreversible, which means that once aspirin binds to an enzyme, it will not let go. Ibuprofen and most other NSAIDs function similarly. They inhibit both COX enzymes.
So, back to the narrative. Before scientists found both COX enzymes, they conducted extensive pharmacological study. They ultimately discovered COX-2 about 1990, at which time medicinal developers pondered whether they might create a medication that exclusively inhibited COX2. After example, if COX-1 inhibition was causing the majority of the adverse effects, preferentially targeting COX-2 would target inflammation and eliminate the stomach issues. And this would be particularly beneficial for chronic inflammatory illnesses. Fortunately, since so many businesses had been investigating NSAIDs for decades, there were a large number of viable medications to choose from. By that moment, DuPont had discovered an anti-inflammatory chemical called DUP-697. This one did not burn holes in people's stomachs, indicating that it was not a conventional NSAID. So when the COX-2 enzyme was identified, scientists thought, "Oh, this might be a selective COX-2 inhibitor." The first to be developed was Celecoxib, often known as Celebrex. It was introduced on the American market in December 1988, followed by Rofocoxib a few months later. You may be familiar with Vioxx. And, as you can undoubtedly see, Coxib is a COX-2 inhibitor. These novel COX-2 inhibitors sold quite well at initially. Rofecoxib, celecoxib, and Pfizer's valdecoxib all became blockbusters. However, after a few years, allegations and lawsuits began to pile up alleging that Vioxx caused heart attacks.
Merck discontinued Rofocoxib in September 2004, marking the largest medication withdrawal to date. Pfizer followed suit, removing Valdecoxib (brand name Bextra) off the market in 2005. As far as aspirin was concerned, all of the mechanism of action studies from the 1970s ultimately revealed how it functioned. But there was still one major issue. Does this medication genuinely lower the risk of heart attack? Yes, it suppresses thromboxane A, but this does not guarantee that it will be therapeutically helpful. In 1974, a group of researchers headed by Peter Elwood released a study in the British Medical Journal that attempted to address that issue. They had enrolled almost 1,200 males under the age of 65 who had all been released from the hospital after their first myocardial infarction, or heart attack. Then they were randomly assigned to receive either a single dosage of 300 mg aspirin per day or a placebo each day. The researchers followed up one week, one month, and then every three months after that, noting if the subjects had another heart attack or died. While there was no statistically significant difference in second heart attacks, there was a decrease in overall mortality after a year of follow-up, and a greater difference after two years in the aspirin group. In the same edition of the British Medical Journal - literally the next article - a Boston-based research group released their own aspirin study. Beginning in 1966, they conducted basic surveys of hospitalised patients, asking them what medications they consumed on a daily basis. Then they attempted to uncover links between drugs and whatever they had been diagnosed with. The Boston group felt more confidence in their findings. They believed they had data to show that aspirin reduced the risk of heart attacks. However, none of these investigations were very strong on their own. This is where meta-analyses come in. These are research that compare comparable studies in order to extract patterns from aggregated data.
In 1980, a scientist called Richard Pito, whom I mentioned in the smoking video, produced a meta-analysis of research examining the impact of aspirin on heart attacks. He collected six studies with a total of over 10,000 people who had previously experienced heart attacks and were randomly assigned to receive either a placebo or aspirin. Pito found from the pooled data that taking aspirin reduced the likelihood of a second heart attack by 21% and decreased the risk of stroke. A few years later, a VA research found that aspirin may be able to prevent initial heart attacks in persons with unstable angina, or chest discomfort caused by the heart muscle not receiving enough oxygen, often due to clogged veins surrounding the heart. Aspirin's potential to reduce the risk of cardiovascular disease was becoming more clear. However, it took many years and numerous hearings, one of which became rather heated, to persuade the FDA to allow aspirin manufacturers to include new claims on their labels. Finally, in 1985, the FDA authorised aspirin as a therapy for acute heart attacks and to help prevent future heart attacks. In 1988, the second international research on infarct survival, mistakenly shortened to ISIS-2, gave more data. They observed participants who had heart attack symptoms and then randomly assigned them to either 162 mg of aspirin or a placebo for 30 days. At 5 weeks, the aspirin group had a lower chance of dying from heart attacks and stroke, as well as a lower risk of non-fatal heart attacks and strokes. And it seemed to be a safe therapy. For example, the aspirin group saw a little increase in mild bleeding, but there was no increased risk of anything life-threatening. So, in 1997, the American Heart Association issued a policy statement claiming that aspirin was a safe and effective treatment for acute myocardial infarction.
More data has come out since then, prompting the AHA to revise their stance statement. The 2019 suggestions are somewhat more nuanced. They still advocate using aspirin to prevent subsequent heart attacks, but note that it is not as widely recommended for primary prevention or preventing cardiovascular disease in otherwise healthy individuals. For example, there were dangers and benefits, which varied depending on the individual. This also seems like a good time to remind you that this is not medical advise, and please do not base your medical choices on what some idiot on the internet says about history. So, returning to the video's concept and the series as a whole, why did NSAIDs become the world's most regularly used medicines? The first reason is that aspirin has been targeting the largest markets for a long time. For example, when it was first released in 1900, there were no antibiotics and just a few vaccinations available, therefore fevers from infectious diseases were highly frequent. Even when we had antibiotics, aspirin remained the most available treatment for aches and pains. When acetaminophen and ibuprofen were introduced, it wasn't long before aspirin was being studied for cardiovascular disease, which was becoming more frequent by the end of the twentieth century. So, for starters, blockbusters are produced in large markets. Number two: branding. When Bayer introduced aspirin, it made a strong push for its brand. This was due in part to the lessons learnt during the Phenacetam fiasco, but it was also worthwhile. It was so worthwhile that Bayer paid a billion dollars in 1994 to repurchase its North American subsidiary. Again, aspirin was an inexpensive generic at the time. Bayer was spending a billion dollars on its name. Finally, aspirin provided more value than its rivals. Aspirin was not the first antipyretic, but it was considerably easier on the stomach than normal salicylic acid. Furthermore, the production procedure reduced the cost compared to willow tree products, which consumers typically like. Of fact, competition does not always result in lower prices for drugs with a large market.
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