Download Understanding its origins and mechanism of action

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Acetylsalicylid acid – the active ingredient in Aspirin®:
Understanding its origins and mechanism of action
The origins of aspirin go back to ancient times. Greek physician Hippocrates (460–377
B.C.) was aware of the analgesic properties of willow bark juice, as was the Father of
Botany Theophrastus (372–287 B.C.). While the therapeutic properties of the willow were
forgotten by the medical profession of the Middle Ages, it continued to play an important
role in popular medicine. Herb specialists boiled up willow bark and gave their suffering
patients the bitter concoction. Not until 1763 did Reverend Edward Stone give a report to
the British Royal Society on experiments with salix bark extract conducted on 50 fever
patients. In 1829, salicin was crystallized by the French pharmacist, Pierre Joseph Leroux,
and the Italian chemist Raffaelle Piria further processed it into salicylic acid.
By the end of the 19th century, scientists were looking for a way to make salicylic acid (Fig. 1)
more tolerable. This approach was first successful in 1897: Legend has it that at Bayer’s
pharmaceutical laboratories, the young chemist Dr. Felix Hoffmann’s father had been
tortured by the pain of rheumatism for years, and Hoffmann wanted to help him. The
sodium salicylate used in his father’s therapy caused nausea because of its offensive
taste, so Hoffman looked for a method of modifying salicylic acid to make it more
tolerable. He was finally successful when he chose acetylation: He was able to
synthesize chemically pure and stable acetylsalicylic acid, or “aspirin” (Fig. 2). By
esterifying salicylic acid, the substance became more tolerable and less aggressive
towards mucosal membranes.
For a long time, scientists believed that acetylsalicylic acid inhibited pain by influencing
the central nervous system. Then, in 1971, the British pharmacologist Sir John Vane and
his research team demonstrated that aspirin actually inhibits the formation of certain
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prostaglandins and thromboxanes.1 Prostaglandins and thromboxanes are hormone-like
substances responsible for different processes in the body. Prostaglandins are mediators
of pain, fever and inflammation; thromboxanes are mediators of platelet aggregation.
They are derived from an essential fatty acid called arachidonic acid with the help of the
enzyme cyclooxygenase (COX). COX is available in two isoforms, COX-1 and COX-2.
Aspirin inhibits both the enzymes cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX2). By adding an acetyl group (−C(O)CH3) to an amino acid residue, the COX enzymes
lose their ability to transform arachidonic acid into prostaglandins. This has the effect of
blocking the channel in the enzyme and arachidonic acid cannot enter the active site of
the enzyme. By inhibiting this enzyme, the synthesis of prostaglandins is blocked. To
produce more prostaglandins, the body has to form new COX enzymes that are not
affected by aspirin, a process that may take several days.
In pain relief, aspirin inhibits COX-2 by blocking the active site of the enzyme due to
irreversible acetylation, and also by a reversible salicylate blockade. Consequently, this
prevents the synthesis of prostaglandins from arachidonic acid reducing pain, fever and
inflammation. In cardiovascular event prevention, aspirin inhibits COX-1 in platelets also
by blocking the active site of the enzyme due to irreversible acetylation. Again,
arachidonic acid cannot enter the active site of the enzyme and as a result, aspirin can
reduce platelet aggregation and can prevent blood from clotting.
Fig. 1 Salicylic acid
1
Fig. 2 Acetylsalicylic acid
Flower R, Gryglewski R, Herbaczyńska-Cedro K et al. Effects of anti-inflammatory drugs on prostaglandin
biosynthesis. Nat New Biol 1972;238(82):104–106.
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Contact:
Anne Coiley, phone +862 404-6314
E-mail: [email protected]
August, 2015
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This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer
Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to
material differences between the actual future results, financial situation, development or performance of the company
and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on
the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking
statements or to conform them to future events or developments.
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