Aspirin: From Tree Bark to Bayer A Drug for the Ages

James Sur, M.D. History of Medicine The University of Chicago

How Much Do You Know?

What is the chemical name of Aspirin? Who is responsible for discovering Aspirin? What are the current medicinal uses of Aspirin? Its not just for pain anymore.
We will attempt to answer all of these.

A Case, of course
Mr. Cinchona is a 67 year old guy who comes to your clinic for primary care. He is proud that he is on no medications and feels great. Hes never been sick, oh except for the little stroke he had 4 years ago but aside from a little weakness in his fingers, he is back to feeling strong like bull. He says his cholesterol was 160 two years ago. His wife agrees but is also concerned about a polyp he had removed on a colonoscopy he had when he was followed up with screening around the time of his stroke.

The Case
You examine Mr. Cinchona and you find:
Afebrile, 137/92, 88, 14, 98% RA, he is bull like as he almost knocks you over with his arm strength. You also notice he smells like a pack of Marlboros and he admits to having a smokey treat every once in a while.

What can you offer Mr. Cinchona aside from the usual screening that might help keep him healthy? What about aspirin?

What is ASPIRIN?

Ahhh, Molecular Sructures and for those that loved playing with the models in orgo

Visual Daily Double

Visual Daily Double Worth: One Bag of Swedish Fish

Who Dat?

That is Correct!

Hippocrates 460 BC - 377 BC

The History of Aspirin

400 B.C. None other than the father of medicine himself, the Greek formerly known as Hippocrates, was said to recommend a brew made with leaves from the willow tree (Cortex salicis) to ease pain of certain eye diseases and of childbirth.

Aspirin makes the Bible!

The Old Testament Book of Leviticus reads in one passage in reference to the medicinal benefits from the fruits of the willows:
'boughs of goodly trees, ... willows of the brook'

Rolling into A.D. times

100 AD Dioscorides, a Greek surgeon suggests:
The leaves [of the willow] being beaten small and dranck with a little pepper and wine doe help such as are troubled with the Iliaca Passio [colic]... The decoction of ye leaves and barck is an excellent formentation for ye Gout ...

And for Ye Gout and More

Caius Plinius Secundus (AD23-79) records in his Natural History recordings many uses of ash for the willow, one of which was for sciatica.

Like the sands through the hour glass

Not much was written or modified on Hippocrates initial remedy from the willow tree until the 17th century when the fruits of the fever tree were cultivated in South America. In 1633, an Augustinian Monk named Calantha living in Peru described how bark from this fever tree, made into powder and given as a beverage cured high fevers.

History has it
In 1638, Calantha used this product to treat the Countess of Chinchon, wife of the viceroy to Peru who fell ill to a wicked case of malaria. The Jesuits began importing this tree bark back to Europe where it became known as Peruvian or Jesuit bark. Call it what you want Cinchona, Jesuit, Peruvian, whatever it worked and was used for over a century to treat fevers when the active principle was finally isolated it was QUININE.

History rolls on
What does Quinine have to do with aspirin? Good Question. The bitterness of the quinine was the basis for the next chapter in the history of Aspirin. After a few Gin and TONICS (quinine) an English clergyman named Rev. Edward Stone, decided to walk through a marsh and start tasting bark from trees some one needed to be cut off!

History tells the story

1758 Rev Stone recognized a similarity in the bitterness of the cinchona bark and its quinine and that of the taste of the bark from the white willow tree (Salix alba).

Paracelsus's Doctrine of Signatures

So many believed that the best place to find cures for disease was in the same place it was caused. In that, many people with rheumatic diseases used to complain in damp environments of worsening pain and even fevers. Rev. Stone, using this doctrine, with the bitter flavor of the willow bark, a tree that grew in damp marshy environments, might be a link to treating fevers and rheumatism.

To the Lab good Reverand

1763 - Rev. Stone made an extraction from the willow bark and administered it to 50 people. His extraction was effective in reducing fevers and he presented this to the president of the Royal Society in 1763 (The New England Journal of the 1700s in Europe.)

Willow Bark Takes off!

Cinchona Bark remained as the staple for treating fevers until it gradually became scarce and was then replaced with the willow bark preparation.

A few years later

1828 Johann Buchner, professor of pharmacy at the University of Munich, isolated a tiny amount of bitter tasting yellow, needle-like crystals, which he called salicin. Two Italians, Brugnatelli and Fontana, had in fact already obtained salicin in 1826, but in a highly impure form. By 1829 Henri Leroux had improved the extraction procedure to obtain about 30g from 1.5kg of bark.

Meadowsweet
1831 Johann Pagenstecher, a pharmacist from Berne, had obtained salicylaldehyde by distilling the flowers of meadowsweet, and sent it to a German chemist, Karl Lowig. 1835 Lowig oxidized it to an acid that he called spirsaure later proved to be identical to salicylic acid.

Were Getting there

In 1838 Raffaele Piria, around the same time, then working at the Sorbonne in Paris, split salicin into a sugar and an aromatic component (salicylaldehyde). He soon converted the latter, by hydrolysis and oxidation, to an acid of crystallised colourless needles, which he named salicylic acid.

By Chance
Two sources of salicylic acid (meadowsweet and willow bark) were cultivated to keep up with the demand from those patients seeking relief of their fever and pain. Unfortunately though, no pain no gain .

SO Much More is Right!

The current preparations came with distressing side effects Severe irritation of the mouth, esophagus, and stomach as well as tinnitus.

Sodium, the Great Neutralizer!

Not so much attempts to neutralize the salicylic acid as a neutral sodium salt were done without much improvement. This formulation however was endorsed globally because it was felt to be a step in the right direction.

Finally, a new kindler gentler ASA!

1853 French Chemist, Charles Frederich Gerhardt combined sodium salicylate and acetyl chloride to get an entirely new compound acetylsalicylic acid (ASA).

Any credit for Gerhardt?

No. He found this acetyl group addition did buffer the compound however was a very tedious and complex procedure so he unfortunately abandoned his research on the topic. He also died at age 40 never to have a chance to revisit his work.

HoffMAN is the MAN!

At least the story books say so Felix Hoffman, a young chemist working for the pioneering pharmaceutical firm of BAYER, had an interest in this acetylsalicylic acid as an alternative to still being used sodium salicylate.

More on the Hoffmeister

Hoffman was Born in Ludwigsburg, Germany in 1868, started his career as a dispensing chemist after leaving school, fascinated, he decided to study pharmacy and chemistry in Munich.
In 1891 he achieved the first great success of his life - he completed his pharmaceutical studies at Munich University with honors. He continued to study chemistry and successfully completed his doctorate in 1903. When Felix Hoffmann retired in 1928, "his" Aspirin was known throughout the world. He, however, lived unrecognized until his death on February 8, 1946 in Switzerland. There he devoted himself to a passion which had nothing to do with pharmacy and chemistry, namely the history of art.

ASPIRIN IS BORN!
1897 August 10th first sample prepared by Hoffman - tries it out on his pops, he loves the stuff for his rheumatism couldnt handle the sodium salicylate. A- Acetylation, SPIR Spiraea ulmaria (meadowsweet), IN thats what they were ending drug names with in those days. 1899 Bayer releases acetyl-salicylic acid in a powder form for medicinal purposes, credits Hoffman with the discovery, patent approved!

Patent Submission Get out your glasses!

Hoffman gets it done in the US too!

History is written by the WINNERS?

Whats a good history talk without a little conspiracy Remember:
1853 French Chemist, Charles Frederich Gerhardt discovered the new compound acetyl-salicylic acid (ASA). Hoffman - "his" Aspirin was known throughout the world. He, however, lived unrecognized until his death on February 8, 1946 Aspirin supposedly produced in Hoffmans lab in August, 1897 and patented in 1899.

Who is Arthur Eichengrn?

Jewish Scientist - Hoffmans boss at Bayer. Credited with many other acetylation discoveries including acetylcellulose. Held in Theresienstadt concentration camp for 14 months starting in 1944 after being banned from civil service and independent positions in the professions. Not in the position in Nazi Era to report what he says is the truth about aspirin

Eichengrn Ignored!
He actually narrows the spectrum of salicylic derivatives to find acetylsalicylic the superior form for efficacy and minimal side effects. Hoffman simply follows his instructions in the lab. 1946 - when Hoffman dies and is celebrated for his Aspirin, Eichengrn is forced silent by the Nazi regime. His discoveries of acetylcellulose in the Hall of Honour (chemical section) at the German Museum in Munich, remain uncredited to this day. 1949, the year he died, his letter is released reporting all this it remained largely ignored until the 1990s when many of his claims were verified.

So Back to Bayer
Mass production of ASA! Finally pill form in 1900 as 500mg tablets. Its uses spread like wildfire throughout US and Europe.

The First RCT? Ok, so not Randomized or controlled

April 1899 - First clinical trials of ASA as an antipyretic carried out by an internist, Dr. Kurt Wittauer, at Deaconess hospital in Halle. The findings are published the same year in a journal entitled "Die Heilkunde" ("Medical Science").

And the Hits just keep on Comin!

1900 - Bayer releases water soluble tablets first drug sold in this form, cuts cost in . 1911 Bayer refutes imposter aspirins, advertises its ASA as the true aspirin Ironically also states DOES NOT AFFECT THE HEART>>>>>>>>>> 1912 Kafka mentions aspirin in his letters to Bauer. 1915 Aspirin available without a prescription.

DOH, Patent is up!

1917 - Bayer loses its patent in many major marketed countries. 1919 WWI US ceizes Bayer operations. 1919 - The Bayer company name and trademarks, including Aspirin, are auctioned off in the USA to highest bidder, Sterling Products Company, later - Sterling Winthrop. The pharmaceutical company wins the auction w/ offer = $5.3 Mil.

The Wonder Drug

1953 Dr. Lawrence Craven reports in the "Mississippi Valley Medical Journal" about 400 of his patients on ASA without MI! 1968 Aspirin to the Moon! Accompanies Armstrong and Apollo 11 in its medicine cabinet.

The Era of Aspirin Its not just for pain anymore!

1971 - Smith and Willis, from the United Kingdom, first to prove that the blood-thinning properties of ASA are based on its inhibition of prostaglandin synthesis in platelets. June 23, 1971 - Sir John Vane, Pharmacologist at the London Royal College for Surgeons, publishes his studies on mode of action of ASA titled "Inhibition of Prostaglandin Synthesis as a Mechanism of Action of Aspirin-like Drugs" in the journal "Nature."

The Story continues to unfold Aspirins Second Career

1980 FDA approves use to reduce risk of stroke after TIA in men. (Stroke, 1977), (NEJM 1978) 1982 Sir John Vane awarded nobel prize for his work. 1985 FDA approves use of ASA to prevent MI in pts with previous MI (NEJM 1983) or UA history (NEJM 1985). 1996 FDA proposes change of label to include its use in acute management of MI. 1997 FDA broadens its recommendations in prevention of stroke to include women w/ TIA history, Men and women with minor stroke or MI history - and in lower doses (NEJM 1991) . 1998 FDA officially endorses:
Reduces risk of death in AMI Prevents recurrent CVA/TIA Low Dose ASA reduces risk MI or CVA

Aspirin Round Three

1988 Australian Surgeon G. Kune shows may reduce risk of colon cancer. 1991 NEJM validates Dr. Kunes claim with 600,000 patient megastudy, reduces colon cancer by 40%. 1995 Another study in NEJM by Harvard group shows colon cancer reduction of 44%. 2003 Findings revalidated in NEJM in those with polyps or previous colon cancer less incidence or recurrence.

Others
1994 Metanalysis shows less DVT/PE. 1997 Aspirin endorsed for preventing migraines. 1999 HAPPY 100th BIRTHDAY ASPIRIN! 2002 Annals of IM metanalysis endorses aspirin use for the primary prevention of ischemic stroke, MI, and cardiovascular death if your Framingham risk is above 5% for 5years.

Were almost done

So what about our patient from the beginning, Mr. Cinchona should we give him an aspirin? What is his Framingham risk? Age 67, Smoker, Chol 160, SBP 137 = 20% Hx of CVA Hx of colon polyps

And about those questions? For some more Swedish fish

1. What is the chemical name of Aspirin? 2. Who is credited for discovering Aspirin? 3. What are two current medicinal uses of Aspirin?

Thanks to those who stayed awake!

References:
1. Elwood PC. Aspirin: past, present and future. [Historical Article. Journal Article] Clinical Medicine. 1(2):132-7, 2001 Mar-Apr. 2. Sneader W. The discovery of aspirin: a reappraisal. [Biography. Historical Article. Journal Article] BMJ. 321(7276):1591-4, 2000 Dec 23-30. 3. Manley L. A look back: the wonder drug. [Historical Article. Journal Article] Journal of Emergency Nursing. 26(1):75, 2000 Feb. 4. Anonymous. The discovery of aspirin. [Biography. Historical Article. Journal Article] Nursing Standard. 13(21):33-4, 1999 Feb 1016. 5. http://www.aspirin.com/world_of_aspirin_en.html 6. http://www.bayeraspirin.com/press/factsheets/aspirin_history.pdf