Aspirin From Tree Bark to Bayer by pengxiuhui

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									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
• It’s 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. He’s 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 Marlboro’s 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!

 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
     Rolling into A.D. times…
• 100 AD – Dioscorides, a Greek surgeon
  – “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
 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).
       “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
• 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 1700’s 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
• 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.
• 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.
           We’re 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
  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 … acetyl-
  salicylic 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
• 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 acetyl-
  salicylic 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 – couldn’t handle the
  sodium salicylate.
• A- Acetylation, SPIR – Spiraea ulmaria
  (meadowsweet), IN – that’s 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
Hoffman gets it done in the US too!
         History is written by the
• What’s a good history talk without a little
  conspiracy …
• Remember:
   – 1853 – French Chemist, Charles Frederich Gerhardt
     discovered the new compound … acetyl-salicylic acid
   – Hoffman - "his" Aspirin® was known throughout the
     world. He, however, lived unrecognized until his death
     on February 8, 1946
   – Aspirin supposedly produced in Hoffman’s lab in
     August, 1897 and patented in 1899.
    Who is Arthur Eichengrün?
• Jewish Scientist - Hoffman’s 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
• Not in the position in Nazi Era to report what he
  says is the truth about aspirin …
           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 1990’s when
  many of his claims were verified.
         So Back to Bayer …
• Mass production of
• Finally pill form in
  1900 as 500mg tablets.
• It’s 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 ½.
• 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
• 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 –
       Aspirin’s Second Career…
• 1980 – FDA approves use to            • 1997 – FDA broadens its
  reduce risk of stroke after TIA         recommendations in prevention
  in men. (Stroke, 1977), (NEJM 1978)     of stroke to include women w/
• 1982 –Sir John Vane awarded             TIA history, Men and women
  nobel prize for his work.               with minor stroke or MI history
• 1985 – FDA approves use of              - and in lower doses (NEJM 1991)
  ASA to prevent MI in pts with           .
  previous MI (NEJM 1983) or UA         • 1998 – FDA officially endorses:
  history (NEJM 1985).                      – Reduces risk of death in AMI
• 1996 – FDA proposes change                – Prevents recurrent CVA/TIA
  of label to include its use in            – Low Dose ASA reduces risk
  acute management of MI.                     MI or CVA
      Aspirin – Round Three…
• 1988 – Australian Surgeon G. Kune shows may
  reduce risk of colon cancer.
• 1991 – NEJM validates Dr. Kune’s 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.
          We’re almost done…
• So what about our patient
  from the beginning, Mr.
  Cinchona – should we
  give him an aspirin?
• What is his Framingham
• 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
• 2. Who is credited for
  discovering Aspirin?
• 3. What are two
  current medicinal uses
  of Aspirin?
Thanks to those who stayed awake!
• 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
• 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-
• 5.
• 6.

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