history of aspirin

8/13/2019 History of Aspirin

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Aspirin: From Tree Bark to

BayerA Drug for the Ages

James Sur, M.D.

History of MedicineThe University of Chicago


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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 ison no medications and feels great. Hes never

been sick, oh except for the little stroke he had 4years ago but aside from a little weakness in hisfingers, 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 apolyp he had removed on a colonoscopy he hadwhen he was followed up with screening aroundthe time of his stroke.


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What is ASPIRIN?


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Ahhh, Molecular Sructures

and for those that loved playing

with the models in orgo
http://www.bris.ac.uk/Depts/Chemistry/MOTM/aspirin/aspirin.pdbhttp://www.bris.ac.uk/Depts/Chemistry/MOTM/aspirin/aspirin.pdb


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Visual Daily Double


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That is Correct!

Hippocrates

460 BC - 377 BC


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The History of Aspirin

400 B.C.None other than the father of

medicine himself, the Greek formerly

known as Hippocrates, was said torecommend a brew made with leaves from

the willow tree (Cortex salicis) to ease pain

of certain eye diseases and of childbirth.


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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'


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Rolling into A.D. times

100 ADDioscorides, a Greek surgeon

suggests:

The leaves [of the willow] being beatensmall 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 ...


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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 forsciatica.


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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 fevertree 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 abeverage cured high fevers.


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History has it

In 1638, Calantha used this product to treat theCountess of Chinchon, wife of the viceroy to Peruwho fell ill to a wicked case of malaria.

The Jesuits began importing this tree bark back toEurope where it became known as Peruvian orJesuit bark.

Call it what you wantCinchona, Jesuit,Peruvian, whateverit worked and was used forover a century to treat fevers when the active

principle was finally isolatedit was QUININE.


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History rolls on

What does Quinine have to dowith aspirin?

Good Question.

The bitterness of the quininewas the basis for the nextchapter in the history ofAspirin. After a few Gin andTONICS (quinine) an Englishclergyman named Rev. Edward

Stone, decided to walk througha marsh and start tasting barkfrom trees some one neededto be cut off!


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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 usedto 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.


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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 NewEngland Journal of the 1700s in Europe.)


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Willow Bark Takes off!

Cinchona Bark remained as the staple for

treating fevers until it gradually became

scarce and was then replaced with thewillow bark preparation.


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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 extractionprocedure to obtain about 30g from 1.5kg of bark.


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Meadowsweet

1831 Johann Pagenstecher, a

pharmacist from Berne, had

obtained salicylaldehyde by

distilling the flowers of

meadowsweet, and sent it to aGerman chemist, Karl Lowig.

1835 Lowig oxidized it to an

acid that he called spirsaure -

later proved to be identical to

salicylic acid.


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SO Much More is Right!

The current

preparations came

with distressing sideeffectsSevere

irritation of the mouth,

esophagus, and

stomach as well astinnitus.


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Finally, a new kindler gentler ASA!

1853French

Chemist, Charles

Frederich Gerhardtcombined sodium

salicylate and acetyl

chloride to get an

entirely newcompound acetyl-

salicylic acid (ASA).


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Any credit for Gerhardt?

No.

He found this acetyl group addition did

buffer the compound however was a verytedious and complex procedure so heunfortunately abandoned his research on thetopic.

He also died at age 40 never to have achance to revisit his work.


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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 acetyl-

salicylic acid as analternative to still being

used sodium salicylate.


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More on the Hoffmeister

Hoffman was Born in Ludwigsburg, Germany in 1868,started hiscareer as a dispensing chemist after leaving school, fascinated, hedecided to study pharmacy and chemistry in Munich.

In 1891 he achieved the first great success of his life - he completedhis pharmaceutical studies at Munich University with honors. Hecontinued to study chemistry and successfully completed his doctoratein 1903.

When Felix Hoffmann retired in 1928, "his"Aspirin was knownthroughout the world. He, however, lived unrecognized until his deathon February 8, 1946in Switzerland. There he devoted himself to a

passion which had nothing to do with pharmacy and chemistry, namelythe history of art.


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ASPIRIN IS BORN!

1897August 10thfirst sample prepared byHoffman - tries it out on his pops, he loves thestuff for his rheumatismcouldnt handle the

sodium salicylate.

A- Acetylation, SPIRSpiraea ulmaria(meadowsweet), INthats what they wereending drug names with in those days.

1899Bayer releases acetyl-salicylic acid in apowder form for medicinal purposes, creditsHoffman with the discovery, patent approved!


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Patent SubmissionGet out your

glasses!


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Hoffman gets it done in the US too!


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History is written by the

WINNERS? Whats a good history talk without a little

conspiracy

Remember:

1853French Chemist, Charles Frederich Gerhardtdiscovered the new compound acetyl-salicylic acid(ASA).

Hoffman - "his"Aspirin was known throughout theworld. He, however, lived unrecognized until his death

on February 8, 1946 Aspirin supposedly produced in Hoffmans lab in

August, 1897 and patented in 1899.


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Who is Arthur Eichengrn?

Jewish Scientist - Hoffmans boss at Bayer.

Credited with many other acetylation discoveriesincluding acetylcellulose.

Held in Theresienstadt concentration camp for 14months starting in 1944 after being banned fromcivil service and independent positions in the

professions.

Not in the position in Nazi Era to report what hesays is the truth about aspirin


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Eichengrn Ignored! He actually narrows the spectrum of salicylic derivatives to

find acetylsalicylic the superior form for efficacy andminimal side effects.

Hoffman simply follows his instructions in the lab.

1946 - when Hoffman dies and is celebrated for hisAspirin, 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 allthisit remained largely ignored until the 1990s whenmany of his claims were verified.


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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. KurtWittauer, at Deaconess

hospital in Halle. The

findings are published the

same year in a journalentitled "Die Heilkunde"

("Medical Science").


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And the Hits just keep on Comin!

1900 - Bayer releases watersoluble tabletsfirst drug soldin this form, cuts cost in .

1911 Bayer refutes imposter

aspirins, advertises its ASA asthe true aspirinIronically alsostatesDOES NOT AFFECTTHE HEART>>>>>>>>>>

1912Kafka mentions aspirinin his letters to Bauer.

1915Aspirin availablewithout a prescription.


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DOH, Patent is up!

1917 - Bayer loses its patent inmany major marketed countries.

1919 WWIUS ceizes Bayeroperations.

1919 - The Bayercompanyname and trademarks, includingAspirin, are auctioned off inthe USA to highest bidder,Sterling Products Company,later - Sterling Winthrop. The

pharmaceutical company winsthe auction w/ offer = $5.3 Mil.


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The Wonder Drug

1953Dr. Lawrence

Craven reports in the

"Mississippi Valley

Medical Journal" about400 of his patients on

ASA without MI!

1968Aspirin to the

Moon!AccompaniesArmstrong and Apollo 11

in its medicine cabinet.


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The Era of AspirinIts not just for

pain anymore! 1971 - Smith and Willis, from

the United Kingdom, first toprove that the blood-thinningproperties of ASA are based onits inhibition of prostaglandinsynthesis in platelets.

June 23, 1971 - Sir John Vane,Pharmacologist at the LondonRoyal College for Surgeons,

publishes his studies on modeof action of ASA titled

"Inhibition of ProstaglandinSynthesis as a Mechanism ofAction of Aspirin-like Drugs"in the journal "Nature."


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Others

1994Metanalysis shows less DVT/PE.

1997Aspirin endorsed for preventing migraines.

1999HAPPY 100thBIRTHDAY ASPIRIN! 2002Annals 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.


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Were almost done

So what about our patient

from the beginning, Mr.

Cinchonashould we

give him an aspirin? What is his Framingham

risk?

Age67, Smoker, Chol

160, SBP 137 = 20% Hx of CVA

Hx of colon polyps


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Thanks to those who stayed awake!


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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 Dec23-30.

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. HistoricalArticle. Journal Article]Nursing Standard. 13(21):33-4, 1999 Feb 10-16.

5. http://www.aspirin.com/world_of_aspirin_en.html 6. http://www.bayeraspirin.com/press/factsheets/aspirin_history.pdf
http://www.aspirin.com/world_of_aspirin_en.htmlhttp://www.bayeraspirin.com/press/factsheets/aspirin_history.pdfhttp://www.bayeraspirin.com/press/factsheets/aspirin_history.pdfhttp://www.aspirin.com/world_of_aspirin_en.html

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