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The official Journal of Cardiological Society of India, Kerala Chapter
URL: http://keralaheartjournal.in/ojs/index.php/KHJ
A glimpse into Cardio Vascular History
History of Aspirin
Rajan Joseph Manjuran MD, DM, PGDHRM, FCSI, FICC, FIAE, FISE, FACC*
*Address for Correspondence: Prof. Dr. Rajan Joseph Manjuran MD, DM, PGDHRM, FCSI, FICC, FIAE, FISE, FACC,
Professor Emeritus of Cardiology, Pushpagiri Heart Institute, Thiruvalla.
E-mail: [email protected]
URL: http://keralaheartjournal.in/ojs/index.php/KHJ/article/view/74
Introduction
The discovery and development of antithrombotics
, antiplatelets, anticoagulants and fibrinolytics form one
of the most fascinating chapters in the history of medicine. It has one of the longest stories in drug discovery.
Many of these advancements in the discovery process
were made by individuals with little experience in the
field. The innovators belonged to diverse backgrounds.
The review will be limited to the most important drugs in
current use which have a story to tell.
The Fascinating Story of Aspirin
Aspirin is probably the mostly widely used drug
world over and most frequently prescribed antithrombotic agent1. The precursor of aspirin, salicylates was
observed in willow bark and other plant sources as old
a 2400 years ago by Hippocrates. The antipyretic and
antiinflammatory properties of willow leaves (Figure 1)
were first described by Galen2. The modern history of salicylates can be traced to Reverend Edward Stone of Oxfordshire, England in 17571. He described that bark of the
white willow tree (salixalba vulgaris) is a cure for febrile
illness [3]. The subsequent phase of aspirin development
occurred half a century later with the development of
chemistry and pharmacology1. The active principle in salicylates was isolated between 1826 and 1829 by Italian,
German and French workers4,5. It was named salicin4.
In 1838, Piria, a French scientist, isolated salicylic acid
from salicin5. In 1897, Felix Hoffman, a German Chemist modified salicylic acid to produce acetylsalicylic acid
which was named aspirin4 (a for acetyl, spir for spirsaure
or the genus spiraea and in as a popular suffix for drugs)2.
Aspirin was initially rejected because of an erroneous impression that it was cardiotoxic6. However, the drug was
introduced commercially few months later and was quickly accepted as analgesic / antipyretic.
Aspirin as an antithrombotic
As early as 1891, a German Scientist, Binz, observed
that salicylic acid caused mucosal bleeding in patients6.
In 1940 Karl Link showed that acetylsalicylic acid (ASA)
Kerala Heart Journal
Volume - 5
Issue - 2
can reduce prothrombin activity and published several
reports in 1943 related to its anticoagulant effect7. Gibson in 1948 first proposed the use of ASA for vascular
diseases8. LL Craven, an otorhinolaryngologist in private
practice in California in late 1940s noted that when his
tonsillectomy patients took aspirin containing medicine,
they bled excessively. In 1948 he started treating his older male patients with ASA to prevent myocardial infarction (MI). In 1950 he reported that none of 400 patients
on ASA had MI9. Craven published two more articles10,11
in which he reported that of more than 8000 patients on
aspirin none had myocardial infarction. He also observed
that ASA is useful in secondary prevention of MI10 and to
prevent stroke11. Craven initially recommended ASA to
all male patients between 30 and 90 years, though subsequently he prescribed aspirin for men between the ages
of 45 and 65 years12. To verify aspirins antithrombotic action, Craven ingested12 aspirin tablets daily which resulted in profuse nasal bleeding after 5 days12. Unfortunately,
Craven died of MI in 1957 less than a year after he published his last paper12.
Antiplatelet effect of Aspirin
By 1950 it was established that aspirin in high doses
caused bleeding by prolonging the prothrombin time13,14.
However, even low doses of aspirin which did not affect
the prothrombin time prevented coronary thrombosis12.
Because aspirin in high doses was associated with bleeding, many physicians in 1940s were prescribing aspirin
together with vitamin K12. In 1967, Weiss et al15 reported
that ASA caused inhibition of platelet activation by collagen. He thought that aspirin antiplatelet effect is due to
impaired adenosine diphosphate (ADP) release resulting
in defective platelet aggregation15,16. Weiss15,16 also observed that sodium salicylate did not have such effect
on ADP release or platelet aggregation. This suggested
that acetyl modification of salicylic acid (aspirin) resulted
in antiplatelet activity. Brien also confirmed this observation17. Weiss also noticed that aspirin had rapid and
irreversible antiplatelet effect which remained for the duration of the life of platelet. Although the work of Weiss
29
The official Journal of Cardiological Society of India, Kerala Chapter
Aspirin in Clinical trials
A large number of randomized, multicentric trials
were carried out to prove the efficacy of aspirin in preventing and treating cardiovascular disorders21. In 1988,
the second International Study of Infarct Survival (ISIS2) proved the value of aspirin in treating acute MI22. In
1989, Physicians Health Study established the value of
aspirin in primary prophylaxis against cardiovascular
disease23. The optimal effective dose of aspirin was an
area of controversy. A recent review of clinical trials and
aspirin dosage by James E Dalen24 indicates that 160mg/
day may be the most optimum dosage.
Conclusion:
The history of aspirin spans over two centuries.
Salicylates were initially used as analgesic antipyretic.
Acetylation of salicylic acid (Aspirin) was a watershed
event in the history of salicylates. Aspirin was detected
to have antithrombotic property through its antiplatelet
action. Aspirin is probably the most widely used medication because of its antiplatelet properties resulting in prevention and treatment of acute coronary syndrome and
occlusive stroke. Story of aspirin is unique in the history
of drug discovery.
Other Antiplatelets
Various other antiplatelets like clopidogrel, prasugrel (thienopyridines) and Glycoprotein IIb/III a receptor antagonists like abciximab, tirofiban and eptifibatide
have been recently developed. These drugs lack a history
like that of aspirin. The oldest antiplatelet drug, aspirin,
continues to retain the pride of place as the most frequently used antithrombotic.
References
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Mueller, RL, Scheidt S. History of Drugs for Thrombotic
Disease Discovery, Development and Directions for the future. Circulation 1994;89;432-449.
2.
Gross M, Greenberg LA; The salicylates: A critical Bibliographic Review New Haven, Conn: Hillhouse Press;
1948:1-8
3.
Stone E. An account of the success of the bark of the willow in the cure of agues.Philos Trans R SocLond (Biol).
1763;53:195-200
4.
Schindler PE. Aspirin Therapy New York, NY: Waler and
Company; 1978: 1-134
5.
Weissmann G. Aspirin. Sci Am. 1991:264:84-90
6.
Mann CC, Plummer ML. The Aspirin wars: Money, Medicine and 100 years of Rampant Competition. New York,
NY: Walker and Company; 1978:1-134.
7.
Link KP, Overman RS, Sullivan LOR, Nuebruier CF,
Scheel LD. Studies on hemorrhagic sweet clover disease.
Kerala Heart Journal
Volume - 5
Issue - 2
J Biol Chem. 1943;147:463-473.
8.
Gibson PC. Salicyclic acid for coronary thrombosis? Lancet
1948;1:965
9.
Craven LL. Acetylsalicylic acid, possible preventive of coronary thrombosis. Ann West Med Surg. 1950;4:95
10.
Craven LL. Experiences with aspirin (acetylsalicylic acid)
in the nonspecific prophylaxis of coronary thrombosis.
Miss Valley Med J. 1953;75:38-40
11.
Craven LL. Prevention of coronary and cerebral thrombosis. Miss Valley Med J. 1956;78:213-215.
12. Miner J, Hoffhines A. The Discovery of Aspirins Antithrombotic effects. Tex Heart Inst J 2007;34:179-86
13.
Combs FS, Highly CS, Warren HA. The magnitude of
salicylate hypothrombinemia.Proc Am Fed Clin Res
1945;2:57-8
14.
Clausen FW, Jager BV. The relation of the plasma salicylate level to the degree of hypothrombinemia J Lab Clin
Med 1946;31:428-436
15.
Weiss HJ, Aledoit LM. Impaired platelet connective tissue
reaction in man after aspirin ingestion Lancet 1967;2:495497
16.
Weiss HJ, Aledort LM, Kochwa S. The effect of salicylates
on the hemostatic properties of platelets in man. J Clin
Invest. 1968;47:2169-2180
17.
O Brien JR. Effect of Salicylates on human platelets. Lancet 1968;1:1431
18.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin like drugs Nature. 1971;2:743744
19.
Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol
1971;231:235-37
20.
Harrison MJG, Marshall J, Meadows JC, Russel RWR. Effect of aspirin in amaurosisfugax. Lancet 1971;2:743-744.
21. Antithrombotic Trialists Collaboration.
Collaborative
metaanalysis of randomized trials of antiplatelet therapy
for prevention of death, myocardial infarction and stroke
in high risk patients BMJ 2002;324:71-86.
22.
ISIS-2 collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,
187 cases of suspected acute myocardial infarction: ISIS-2
Lancet.1988;2:349-360
23. Final report on the aspirin component of the ongoing
Physician Health Study Research Group N Engl J Med
1989;321:129-35
24. McLean J:The thromboplastic action of cephalinAmJPhysiol 1916; 41:250-257
WILLOW BARK TREE
Picture Courtesy : Dr Sarita
and co workers15,16 demonstrated the antiplatelet effects
of aspirin, the specific molecular mechanism of aspirin effect was reported by John Vane in 197118. He stated that
aspirin inhibited prostaglandin synthetase which resulted in its antiplatelet effect. In 1982 Vane won the Nobel
Prize in Medicine for this work. Vane observation of antiplatelet effect of aspirin was confirmed by Smith and Willis19. Work of these scientists revealed that aspirin effects
on platelets is mediated through cyclooxygenase-1 (COX1) enzyme inhibition thereby reducing thromboxane-A2
synthesis. Harrison et al20 reported that ASA can prevent
cerebral transient ischaemic attacks.
Please cite this article as: Manjuran RJ. History of aspirin.
Kerala Heart J 2015;5 (2):28-29.