Aspirin: From Tree Bark to Bayer

1
Aspirin From Tree Bark to Bayer A Drug for the
Ages

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

2
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.

3
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.

4
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?

5
What is ASPIRIN?

6
Ahhh, Molecular Sructures and for those that
loved playing with the models in orgo

7
Visual Daily Double
8
Visual Daily Double Worth One Bag of Swedish
Fish
                                               
                     

• Who Dat?

9
That is Correct!

• Hippocrates
• 460 BC - 377 BC

10
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.

11
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'

12
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 ...

13
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.

14
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.

15
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.

16
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!

17
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).

18
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.

19
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.)

20
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.

21
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.
  

22
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.

23
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.

24
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 .

25
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.

26
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.

27
Finally, a new kindler gentler ASA!

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

28
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.

29
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 an
  alternative to still being used sodium salicylate.

30
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.

31
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!

32
Patent Submission Get out your glasses!
33
Hoffman gets it done in the US too!
34
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.

35
Who is Arthur Eichengrün?

• 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

36
Eichengrün 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, Eichengrün 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.

37
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.

38
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").

39
And the Hits just keep on Comin!

• 1900 - Bayer releases water soluble tablets
  first drug sold in this form, cuts cost in ½.
• 1911 Bayer refutes imposter aspirins, advertises
  its ASA as the true aspirin Ironically also
  states DOES NOT AFFECT THE HEARTgtgtgtgtgtgtgtgtgtgt
• 1912 Kafka mentions aspirin in his letters to
  Bauer.
• 1915 Aspirin available without a prescription.

40
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.

41
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.

42
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."

43
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

44
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.

45
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.

46
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

47
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?

48
Thanks to those who stayed awake!
49
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 10-16.
• 5. http//www.aspirin.com/world_of_aspirin_en.html
  
• 6. http//www.bayeraspirin.com/press/factsheets/as
  pirin_history.pdf