A Pain in the Aspirin Trivia Quiz

Answer: Salicin

Salicin is named after the genus Salix, the Latin name for willow. Salicin is the key compound found in willow bark which gets chemically modified to salicylic acid and then ultimately to acetylsalicylic acid or ASA, which we know today as modern day aspirin. Salicin as a natural remedy has a long history of being used to treat medical ailments over many millennia due to its anti-inflammatory, antipyretic (fever reducing) and analgesic (pain relieving) properties.

How do I get to aspirin from willow you ask? Structurally, salicin is composed of a salicyl alcohol molecule with a glucose molecule (D-glucose) attached. Next subject salicin to hydrolysis, using water to break the chemical bond between the sugar and salicyl alcohol (our bodies can do this naturally!) forming saligenin. Saligenin is then oxidized yielding salicylic acid, finally we acetylate this compound, and we arrive at aspirin or ASA.

In summary: Salicin--> Saligenin-->Salicylic Acid--> Aspirin.

Shout out to fellow pharmacist, the Frenchman Henri Leroux who, in 1829, was the first to obtain salicin in its pure crystalline form which was used to treat rheumatism at the time.

Answer: Sumerian

Amazingly, clay tablets dating from over 4,000 years ago in the Mesopotamian region are believed to be the first prescriptions recorded in human history. These clay tablets are attributed to being of Sumerian origin and contain cuneiform writings that document known 'medical prescriptions' for pain at the time, including willow bark. Other Mesopotamian cultures in the area, chiefly the Babylonian and Assyrian civilizations, also used willow tree extracts to treat pain, fever and inflammation.

The Egyptians dabbled in willow leaves according to the Ebers Papyrus, an ancient text c.1500 BC that describes the analgesic effects of willow leaves as 'drawing the heat out' of inflamed wounds.

The Chinese were next to experiment with willow bark over 2000 years ago to alleviate fever and pain. Additionally, the Chinese used poplar tree barks and willow shoots for centuries to treat rheumatic fever, colds, hemorrhages and goiter, and as a general antiseptic for wounds and abscesses.

Representing the Greek civilization, Hippocrates (460-370 BC), the famed physician recommended, chewing willow bark to sufferers of pain and fever and prescribed a brew of willow leaves to ease the intense pain of laboring women in childbirth. Other prominent Greek physicians who continued the practice of using willow included Dioscorides (100 AD) & Celsius (1 AD).

The Romans were involved as well with exploiting the wonderful properties of willow. Pliny the Elder (AD 23-79) recorded the use of 'burned willow bark paste' in the application of treating corns. The Roman & Greek physician Galen (129-216 AD) treated bloody wounds and ulcers with willow leaves.

As you can see, medicinal use of willow has a deep-rooted history (pun intended) that spans thousands of years which ultimately led us to arriving at aspirin.

Answer: Meadowsweet

Meadowsweet, also known colloquially as 'meadow-wort', is a plant found in damp environments such as swamps, marshes, wetlands and on the shores of lakes and rivers. Meadowsweet is easily recognizable by its distinct long stems and white flowers and is endemic to Europe and Asia. It was historically used in the Middle Ages for its anti-inflammatory properties, which was later determined to be due to the presence of compounds in the flowers.

Johann Pagenstecher, a Swiss pharmacist, extracted one such compound, salicylic aldehyde, from the flowers of meadowsweet in 1835 and passed along this sample to German chemist Carl Lowig who further oxidized the compound to yield salicylic acid. Later on, chemists at the German pharmaceutical firm who introduced 'Aspirin' to the world in 1899 used salicylic acid derived from meadowsweet to synthesize ASA.

'Aspirin' was derived from the German word for "Acetylspirsäure" which translates to acetylsalicylic acid. Breaking it down further, the 'A' refers to the addition of an acetyl group to salicylic acid through the chemical process of acetylation, 'Spir' refers to Spirsäure (salicylic acid) which was named for the meadowsweet plant (Spirea ulmaria was the named species at the time - it now goes by Filipendula ulmaria) - from which it could be derived, and finally the suffix -'in' which is a common drug name ending used to name pharmaceuticals at the time and was easy to pronounce.

The listed incorrect options are all plants possessing anti-inflammatory compounds and properties, but none of them contain the precursor compound from which aspirin was derived.

Answer: Bayer AG

Originally founded in 1863 as a dyestuffs company and not as the pharmaceutical giant known today, Bayer was a joint venture started by dye salesman Friedrich Bayer and master dyer Johann Friedrich Weskott. Bayer did not become a multinational company or have a chemical manufacturing division until 1881.

In August 1897, salicylic acid was preferentially chemically acetylated by Felix Hoffmann (a chemist employed at Bayer) to produce ASA. The process of this synthesis was detailed in his notebook and is as follows: Hoffman heated a combination of salicylic acid and acetic anhydride (an acetylating agent) for two hours, which resulted in a clear liquid. Upon cooling, this liquid yielded a mass of acetylsalicylic acid crystals, which he separated out and recrystallized, using dry chloroform to remove any remaining impurities.

This process of acetylating salicylic acid however was not a novel concept and was actually first achieved by Charles Frederic Gerhardt, a French chemist in the 1850s. Gerhardt is credited with identifying the chemical structure of salicylic acid and being the first to synthesize ASA, albeit in an impure and unstable form not suitable for pharmaceutical standards.

The story of aspirin synthesis is not without its fair share of controversy. Felix Hoffmann is credited as the sole inventor of aspirin by Bayer and, although he was not the first to acetylate salicylic acid, his process yielded a pure and stable form of the substance. A colleague of Hoffman's, by the name of Arthur Eichengrun, 50 years later claimed to have conceived the idea of aspirin and that he had directed Hoffmann to perform the synthesis without the latter's knowledge of the compound.

Eichengrun, who was Jewish, argued that the Nazis had erased his contributions when they rose to power, as the regime suppressed Jewish achievements at that time. While Bayer still maintains Hoffmann was the aspirin architect, many historians now believe Eichengrun was the true architect of the discovery and credit should be shared. Whatever the correct narrative was, a successful product emerged for Bayer to introduce to the rest of the world.

Bayer registered ASA under the trade name Aspirin on 6 March 1899 and first distributed aspirin to clinics and hospitals for the treatment of patients. Aspirin was not available 'over the counter' to the public without a prescription until 1915.

Interestingly, after the conclusion of World War I, the Treaty of Versailles contained reparations that allowed for the seizure of Bayer assets including the 'Aspirin' trademark in Allied countries such as France, the US, and Great Britain. Bayer eventually, and many years later, regained the trademark for the capitalized form of 'Aspirin'.

Answer: False

This is simply not true. Commercial manufacture of aspirin is performed on an industrial scale starting with salicylic acid and acetic anhydride. Salicylic acid is synthesized from phenol in a process known as the Kolbe-Schmitt reaction, the same process utilized by Felix Hoffmann.

Bulk quantities of salicylic acid and acetic anhydride are then reacted together using the presence of sulfuric acid to catalyze this reaction. This mixture then gets heated for several hours and finally left to cool. As the solution cools, ASA crystallizes, then gets filtered and ultimately dried to yield the powdered form of pure aspirin.

You may recall conducting this experiment if you were ever required to take an organic chemistry course before!

Answer: It caused far less stomach irritation

Salicylic acid is a gastric irritant due to its mechanism of blocking mucin, a secreted substance that is a component of the protective mucus barrier in the stomach. This serves to protect the gastric lining from the damaging effects of stomach acid. Stomach irritation which can further develop into ulceration, was one of the most common complaints amongst many patients being treated with salicylic acid before aspirin was synthesized. This side effect is what necessitated and ultimately facilitated the formation of aspirin.

Acetylation is the process of addition of an acetyl group (denoted by the chemical formula -COCH3) to a compound. ASA is formed by acetylating salicylic acid. Stomach irritation is still possible with ASA, but with a lower chance than salicylic acid. Aspirin formulations are still being worked on to this day that look to eliminate this side effect completely.

Additionally, ASA is more chemically stable than salicylic acid allowing for a longer shelf life.

Answer: Edward Stone

Reverand Edward Stone (1702-1768), a sufferer of intermittent fevers, was seeking relief through herbal treatments. He stumbled upon willow in 1757 when he accidentally tasted willow bark. Here is his account in his own words: "About six years ago, I accidentally tasted it, and was surprised at its extraordinary bitterness; which immediately raised in me a suspicion of its having the properties of the Peruvian bark."

Stone was aware of accounts of the beneficial effects of Peruvian bark, or cinchona bark, from which later quinine, an antimalarial compound, was derived. Suspecting the beneficial effects of willow bark, Stone experimented by drying willow bark for three months then pulverizing it into a powdered form. He dosed himself starting with tiny amounts until he found a satisfactory clinical effect of which this dose was approximately 1.25 grams every four hours. Stone found a remedy for his fevers: "the ague was soon removed."

Stone wanted to confirm this effect in others. He gave the powder to an estimated 50 people who were complaining of "agues" or fevers over several years and noted success in many of them. If the fevers were resistant to treatment, he would then add quinine which he found more effective, suggesting that some of his patients may potentially have had malaria. Before the modernization and strict protocols of clinical trials of today, a priest, of all people, laid the foundation for the value and importance of conducting clinical trials for new and potential treatments.

He published his experience with willow bark in a letter titled "An Account of the Success of the Bark of the Willow in the Cure of Agues" which he addressed to the Royal Society of England. After this report was received, willow bark became mainstream in many of the herbal publications of that time and paved the groundwork that led to the discovery and synthesis of aspirin.

Answer: True

This sage advice was courtesy of Nicholas Culpeper (1616-1654). Nicholas Culpeper was an English botanist and physician who wrote an herbal compendium titled "The English Physician; or, An Astrologo-Physical Discourse of the Vulgar Herbs of this Nation" in 1652. In this text, Culpeper described the willow tree's application for slowing bleeding wounds, reducing indigestion, improving urine flow, treating warts, and temporarily reducing the lust of men and women.

If you ever have the chance to read a summary about Nicholas Culpeper, I highly encourage it! He was an interesting man who ran an astrological-medical practice, was once accused of witchcraft and fought a duel for unspecified reasons. He certainly warrants a quiz if there isn't one already!

Answer: 1970s

The mechanism of action for aspirin wasn't fully understood until 1971. An English pharmacologist, by the name of John Vane, discovered that aspirin's anti-inflammatory, analgesic and antipyretic effects were due to the inhibition of an enzyme called cyclooxygenase (COX) that is involved in the formation of prostaglandins. Prostaglandins are hormone-like substances produced by virtually every cell and are involved in the inflammatory process by functioning as chemical mediators. This discovery led to the development of other non-steroidal anti-inflammatory drugs (NSAIDs) used for the treatment of pain and arthritis.

Vane shared the Nobel Prize in Medicine in 1982 with Sune Bergstrom and Bengt Samuelsson (Bergstrom and Samuelsson identified COX, Vane fully explained its mechanism) "for their discoveries concerning prostaglandins and related biologically active substances".

Answer: Heart Attack & Stroke

Aspirin has an antiplatelet effect primarily due to its action of inhibiting thromboxane A2 synthesis, a prostaglandin that promotes platelet aggregation and vasoconstriction. When an injury occurs to a blood vessel, platelets stop the bleeding by plugging up the wound and eventually forming a clot. However, sometimes these clots can embolize or travel to small coronary vessels leading to the heart or to small vessels in the brain and can form a blockage leading to tissue damage due to reduced blood flow at that site.

A blockage in a blood vessel to the heart resulting in tissue damage is referred to as a myocardial infarction (MI) or heart attack. In the brain, the blockage of a blood vessel due to a clot can cause a thrombotic stroke. Aspirin works in both of these conditions to reduce platelet count which can be implicated in clot formation

Numerous RCTs or randomized controlled trials have shown benefit for aspirin therapy and these results have supported its use as part of the acute treatment for (MI) and secondary prevention of future heart attacks. You may also see aspirin being used as part of a treatment therapy called dual-antiplatelet platelet therapy or 'DAPT' to prevent the reoccurrence of stroke.

Today millions of patients globally take aspirin on a daily basis for the treatment and or prevention of cardiovascular disease, one of the most common causes of death in our current world. Aspirin is by far the most widely studied antiplatelet drug due to its long history and its aforementioned benefits seen in multiple clinical trials over the past 60 years.