By Hannah Johnson

When you have a headache, a fever, or inflammation, the usual response to obtain relief would be taking an NSAID (non-steroidal anti-inflammatory drug), such as aspirin or ibuprofen. While these are common over the counter (OTC) drugs that are often found in a person’s medicine cabinet, not much is commonly known about the origins of these medications and the alternate uses they can have in the prevention or treatment of diseases. In the case of aspirin, it is moderately recognized as a medication given for the prevention of heart problems after a cardiovascular event like a heart attack. Though it has a long and colorful history behind its development into a medication, aspirin is still being researched today for treatment of other diseases.

Aspirin, having just celebrated its 125^th birthday, is known under the chemical name of acetylsalicylic acid (Figure 2). Aspirin has been used to treat inflammation for centuries as its origins arise from willow bark.^1,2 But, aspirin has been used for much longer as there is evidence that the Sumerians used extracts from willow bark to treat inflammatory diseases and even the ancient Egyptians documented a recommendation for using willow bark to treat joint pain in the Ebers Papyrus in 1523 B.C.^1-3 Throughout history there have been documented accounts that the use of willow bark was used to treat inflammation and pain. However, it wasn’t until 1758, when Reverend Edward Stone used dried willow bark to treat 50 patients suffering from fever, that the first documented trial was completed, exhibiting its effectiveness in fever reduction.^1,2 Over a period of five years (1824-1829), scientists from multiple countries were able to establish the stable extraction of salicin, the active ingredient from willow bark.  In 1838, Raffaele Pirìa was able to extract salicylic acid from salicin and determine its molecular structure; moreover, in 1853 Charles Gerhardt was the first person to synthetically create acetylsalicylic acid.^1,2,4 However, not much came from this discovery until a few years later, as the inconsistent synthetic process that Gerhardt used to create the compound resulted in an unstable and impure product. Nevertheless, in 1855 Cesare Bertagnini, Pirìa’s student, wanted to observe the effects of salicylic acid in humans and decided to take 25 centigrams of salicylic acid every hour. He ended up ingesting about 6 grams of salicylic acid over a period of 2 days, upon which he discovered that high doses of salicylic acid can cause tinnitus as a side effect.¹ Still, the medical properties of this compound have proven to be useful. So, in 1876 Thomas Maclagan undertook the first clinical trial of salicin as atreatment for rheumatic fever.

In camaraderie with Bertagnini, Maclagan also decided to test salicin on himself before starting the clinical trial and though the clinical trial showed evidence of anti-inflammatory and anti-pyretic (fever reducing) effects, there was strong evidence of gastric irritation occurring.² With the side effects evident in both salicin and salicylic acid, there needed to be further optimization of this compound to alleviate these side effects. As a result, Bayer, originally a German dye manufacturer, opened a pharmaceutical department in 1890 where they pursued a way to synthesize a stable form of acetylsalicylic acid that did not have the side effects of its precursor molecules while maintaining its effectiveness. As such, on August 10^th, 1897, Felix Hoffmann was able to successfully produce a stable, pure form of acetylsalicylic acid through a reliable and simple synthetic route.^1,2,4 Though the process to finally obtain a usable form of aspirin took over a century from its first documented use in patients, the next process of understanding the mechanism behind a stable form of aspirin was just as important. Interestingly, it was only ten days after discovering aspirin that Hoffman also discovered heroin in an attempt to find a better non-addictive alternative to morphine.²

Once the stable form of acetylsalicylic acid was obtained, it was headed for clinical trials. Despite initial concerns of cardiotoxicity, aspirin successfully underwent clinical trials with minimal side effects and was trademarked by Bayer in 1899 in Germany and patented in 1900 in the U.S.²Though the actual discovery of aspirin has officially been accredited to Hoffmann, there have been multiple debates as to role that Carl Duisberg, Arthur Eichengrün, and Heinrich Dreser, all employed by Bayer’s pharmaceutical department at that time, played in its discovery.^1,2,4 Nevertheless, aspirin, which became so widely-used over the next 70 years that it was attributed as the most widely sold painkiller in 1950 by the Guinness World Records, still had not had its mechanism of action discovered yet.² It was only in 1975 that aspirin was recognized to inhibit the synthesis of thromboxane 2A, which is a vasoconstrictor and involved with platelet aggregation. Later, when the discovery of cyclooxygenase (COX) was completed, the overall mechanism of aspirin was revealed by its irreversible inhibition of COX-2 and COX-1.^1,2 This irreversible inhibition of COX-1 and subsequent thromboxane synthesis inhibition contributes towards the ability of aspirin to function as an antiplatelet and antithrombotic medication when given at low doses (Figure 3).¹

Aspirin has a very long and challenging history, with over a century of time needed to elucidate the most ideal compound structure and the subsequent decades required for a mechanism of action to be discovered. Today, there are still aspects of its mechanism being determined, partially due to some alternate uses for aspirin. Some of these more recent alternate uses largely lie in cancer prevention and treatment, as aspirin has an indicated ability to reduce the risk of some cancers.¹ But more applications of aspirin are likely to come as its uses seem to continually be expanded upon.

TL:DR

• Aspirin, though mostly known as a pain medication and cardio preventative, has a centuries long history behind its development as a medication and it is still being researched today for its applications in other diseases.

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References

1. Montinari, Maria Rosa, Sergio Minelli, and Raffaele De Caterina. “The first 3500 years of aspirin history from its roots–A concise summary.” Vascular pharmacology 113 (2019): 1-8.
2. Desborough, Michael JR, and David M. Keeling. “The aspirin story–from willow to wonder drug.” British journal of haematology 177.5 (2017): 674-683.
3. Smith, G. Elliot. Ancient Egyptian medicine: the papyrus ebers. Chicago: Ares Publishers, 1930.
4. Jeffreys, Diarmuid. Aspirin: the remarkable story of a wonder drug. Bloomsbury Publishing USA, 2008.
5. Huzefakifayet. (2020, June 18). Aspirin synthesis, SAR, MCQ,structure,chemical properties and therapeutic uses – Gpatindia: Pharmacy Jobs, admissions, scholarships, conference,grants, exam alerts. Gpatindia. Retrieved November 3, 2022, from https://gpatindia.com/aspirin-synthesis-sarmcqstructurechemical-properties-and-therapeutic-uses/
6. “Bayer Company Trademarked Hoffman’s Discovery under the Name ‘Aspirin.’” World History Project, https://worldhistoryproject.org/1899/bayer-company-trademarked-hoffmans-discovery-under-the-name-aspirin.
7. Rima. “Aspirin.” BioPharma Notes, 4 May 2022, https://biopharmanotes.com/pharmacology-of-aspirin/.