15 minutes reading time (3080 words)

    A New Look at the Old Drug - Aspirin

    Dr. Eva Todoroska
    Charles Sturt University - Mitchell

    History of the discovery of aspirin

    The history of aspirin (acetylsalicylic acid) begins with common, folk herbal remedies that were used by early 18th century pharmacologists to reduce fever. Fever is symptomatic of many diseases.

    The bark of the willow tree (Salix alba), meadowsweat plant (Spiraea ulmaria) and wintergreen plant (Gaultheria sp.) were all known to have antipyretic effects. Herbalists who discovered the curing potency of such plants were influenced by the belief that antidotes were often to be found in the vicinity of the causative agents of the disease. On occasions such a line of reasoning can be helpful as indeed willows and feverish illnesses are abundant in moist areas. Patients treated with herbal remedies obtained from the plants listed above benefited from them long before it could be explained why.

    Many years later, during the 19th century scientists have shown that willow tree bark, meadowsweat and wintergreen plants all contained derivatives of the chemical substance known at present as salicylic acid. Salicylic acid was identified as the active, bitter compound of the herbal antipyretic remedies. Willow bark contained a glycoside of salicyl alcohol (salicin), meadowsweat plant yielded ample quantities of oil containing salicylic acid and oil of wintergreen contained a methyl ester of salicylic acid. 

     The chemical era of the antipyretic drugs begins at the 19th century as French and German pharmacologists started to compete to find the active ingredient of willow bark (G. Weissmann, 1991). In 1828, Johann A. Buchner, a German pharmacologist from Munich, first isolated small amounts of low purity salicin from willow bark. A year later, H. Lerouz, a French chemist from Paris, improved an extraction procedure and obtained better yield - one ounce of salicin from three pounds of willow bark.

    In 1833, E. Merck, a pharmacist from Darmstad (Germany), was the first to obtain a pure preparation of salicin. Five years later in 1838, R. Piria, an Italian working with drugs in Paris, gave the name to the bitter crystaline substance with antipyretic properties and called it l'acide salicylique (willow acid) or salicylic acid - the name so well known to us today.

    In 1860 Hermann Kolbe, a professor of chemistry at Marburg University (Germany), achieved great success. Together with his young assistants he synthesized salicylic acid and it's sodium salt from phenol, carbon dioxide and sodium. One of his assistants, Frederick von Heyden, established in Dresden in 1874 the first large factory devoted to the production of synthetic salicylates. Soon, responding to public demand, more competitive factories were built and as a result the price of salicin was lowered by ten times from 1870 to 1874.

    What was the reason for the high demand for salicylates?
    In a parallel way to chemical discoveries, clinical medical reports have been accumulating which show that purified salicylic acid and salicin are of great value in the control of fevers caused by various conditions. Moreover the data suggests that salicylate-like drugs show fewer side-effects that were associated with application of quinine, which was routinely used as an antipyretic until the 1880s (Sneader, W., 1985). For example, Dr Carl Buss from Gallen (Switzerland) administered salicylic acid to typhoid patients. This treatment proved to be very effective as an antipyretic but it did not cure the typhoid infection. These findings, published in 1875, although not quite successful in curing typhoid, aroused widespread interest and initiated the use of salicylic acid as a popular antipyretic.

    Furthermore, in 1876 Franz Stricker and Ludwig Riess reported in one of the German medical journals (simultaneously with Thomas MacLagan who published his results in the British Lancet) that salicylate treatment provided substantial improvement in the health of patients suffering from acute rheumatic fever. Unfortunately this treatment can not eradicate long term consequences of rheumatic fever. We know at present that the explanation for that is the inability of salicylic acid to destroy streptococcal bacteria lodged in the joints of the rheumatic fever patients. Bacteria lodged in joints mount a long lasting inflammatory response which can only be alleviated by treatment with other groups of drugs known as antibiotics.

    Further efforts brought effective salicylic therapies for gout, chronic polyarthritis, rheumatoid arthritis and osteoarthritis. Successful as they were, they also brought some problems. The large doses of salicylic acid recommended in the treatment of rheumatic disorders severely upset the patients' stomachs and caused them to vomit. As it happens, one such patient was the father of Felix Hoffman, a German chemist who worked at the Bayer laboratories in Elberfield in Germany. Hoffmann senior suffered severe side-effects from taking high doses of salicylic acid to control his rheumatism. Hence he asked his son to find an alternative with fewer side effects. Felix Hoffmann searched the chemical literature and found a less troublesome derivative of salicylic acid - acetylsalicylic acid.

    Acetylsalicylic acid had been synthesized in 1853 by Charles Frederick von Gerhardt at Strassburg. This alternative drug proved to be more gentle to the stomach of the senior Mr Hoffmann and aroused great interest among Bayer company staff. After initial trials performed by the Bayer company on animals and later chemical trials on patients in Berlin hospitals, the properties of acetylsalicylic acid were published in 1899. Acetylsalicylic acid was shown to be as effective as salicylic acid but free of most of its unpleasant effects in every day use. Bayer Company marketed the drug under the commercial name of "Aspirin". The name derives from "a" for acetyl and "spirin" from the scientific name of the plant from which the drug was firstly purified - Spiraea ulmaria (meadowsweat plant).

    Later, after the Bayer Company managed to secure the large-scale production patent they intensively advertised the drug using for the first time an extensive mass mailing process as a tool to ensure aspirin's commercial success among medical practitioners.

    The success of aspirin brought great profits to the Bayer Company over the years. Its domination of the world pharmacological market was broken as a result of the First World War. The war in Europe served as an excuse for the infringement, by winning war countries, of the patent rights of the Bayer Company. This allowed British and American pharmacological companies to start their own big scale production of aspirin.

    Present State Of Knowledge About Aspirin

    The popularity of aspirin as an analgesic and antipyretic grew over the years and many further synthetic derivatives of salicylic acid were synthesized and tested with variable results. Also, very importantly, aspirin production gave rise to a strong pharmacological industry, which in a constant search for new drugs initiated a new era of synthetic drug therapies. This era extends to our times. Examples of the wide variety of modern nonsteroidal anti-inflammatory drugs that were developed over the years are presented in Figure 3.

    Despite the unquestioned success of salicylic acid and its formulations less upsetting to the stomach, it was not until 1938 when British gastroenterologists proved that there are still quite damaging consequences of prolonged usage of aspirin to the walls of a stomach. Then the latest modification to the drug was introduced. This was achieved by the use of a soluble form of aspirin - calcium aspirin, that could be dissolved in water before swallowing. The soluble aspirin does not allow lodging of tablets against the stomach walls and this lowers the chances of ulcer development.

    Further studies about the usage of aspirin, the most popular over-the-counter drug, have shown that it is not as safe a drug as it seemed at the time of its discovery. Upper gastrointestinal disease in the form of peptic ulcers, fibrosis of kidneys, abnormalities in the functioning of the liver, blood clotting abnormalities and hypersensitivity reaction in some patients have caused many medical practitioners to express concern (Roth, S.H., 1980). On the basis of such studies the prevalent view at present is that aspirin in therapeutic doses should not be taken over sustained periods of time without medical supervision.

    More than 200 years have elapsed from the discovery of aspirin and its wide use. It is known at present that aspirin exhibits a far wider range of effects on living organisms than was earlier postulated. It not only has antipyretic, analgesic and anti-rheumatic effects (Rose, B.S., 1991; Roth, S.H., 1980) but also in very low doses is used to treat and prevent heart attacks (Koutts, J., 1990) and to alleviate thrombosis (Hockings, B. 1990). Some other biological effects displayed by salicylates were also observed and according to G. Weissmann (1991) they are:

    • ability to dissolve skin corns;
    • initiation of loss of uric acid from kidneys;
    • inhibition of the clotting of blood;
    • induction of peptic ulcers;
    • promotion of fluid retention by the kidneys;
    • inhibition of ion transport across cell membranes;
    • ability to interfere with the activation of white blood cells;
    • interference with the production of ATP;
    • ability to activate dormant genes for heat-shock proteins in Drosophlia sp;
    • ability to induce flowering in plants such as impatiens and voodoo lily.

    This enormous range of effects observed by scientists made the explanation of aspirin's biochemical action quite a troublesome task. Some of the effects of aspirin are explained by the prostaglandin hypothesis, proposed in 1971 by J.R. Vane (Vane, J.R., 1971). This hypothesis is based on the ability of aspirin to block the synthesis of prostaglandins. Prostaglandins are local cellular hormones involved in the inflammatory response. The consequences of the absence of prostaglandins in various types of cells of the body enables us to explain the inhibition of the local inflammatory response, the reduction of the risk of heart attack and stroke, the hypersensitivity syndrome in some patients and the stomach irritation and ulceration. These phenomena will be discussed in some detail below. 

    Inhibition of Local Inflammatory Response
    Without aspirin, injured cells of various types synthesize and release local hormones - prostaglandins. As a result of their activity swelling, heat and pain occur in the injured area caused by local inflammatory reaction. In the presence of aspirin or some aspirin-like drugs this reaction does not develop. The presence of drugs inhibits prostaglandins synthesis by inactivating an enzyme prostaglandin synthase (PG synthase). PG synthase is required to transform a cell membrane component (arachidonic acid) into unstable prostaglandin precursors and then into stable forms of prostaglandins. A blockage of the PG synthase activity causes a lack of prostaglandins and there is no local inflammatory reaction (see figure 4).

     Reduction in the Risk of Heart Attack and Stroke.

    The potency of aspirin in the case of heart attacks and strokes is based on the dual role that it performs in the human body. The first is its ability to inhibit platelet (clotting particles of human blood) aggregation. Thus it has a "thinning" effect on blood and lowers the chance of incidental clot formation.The second involves aspirin's regulatory role in keeping the balance between synthesis of vasoconstricting and vasodilating agents. Both types of agents require prostaglandin precursors for their production. In the absence of aspirin, platelets are able to transform prostaglandin precursors into a highly potent vasoconstricting and platelet aggregating substance called thromboxane. This substance enhances the chances of clot formation leading to heart attacks or strokes. At the same time endothelial cells, that line blood vessels, use the same prostaglandin precursors to make a potent substance, a vasodilator - prostacyclin. Prostacyclin has an opposing effect to thromboxane and reduces the chance of heart attacks and strokes. Carefully calibrated does of aspirin can interfere with thromboxane production, while leaving prostacyclin synthesis unaffected. Lower doses (one tablet a day) of aspirin irreversibly inactivate platelet prostaglandin synthase, so they can not produce vasconstrictor - thromboxane. Endothelial cells of blood vessels, however, can make new PG-synthase and replace the PG-synthase inactivated by aspirin in a few days. The prostacyclin synthesis is hence recovered after a while. This uneven influence of aspirin on different cells (platelets and endothelial) tips the balance of the body toward the production of the vasodilator - prostacyclin and overall, lowers the risk of heart attacks and strokes (see figures 5-1 and 5-2).

    Hypersensitivity Syndrome in Some Patients

    In genetically susceptible individuals, the presence of aspirin and its blocking of prostaglandin synthase diverts (reason unknown) arachidonic acid from plasma membranes of various cells into other biochemical pathways. The competing enzyme - lipoxygenase that uses the same substrate as PG-synthase (in the form of arachidonic acid) transforms it into substances called leukotrienes. Leukotrienes are exceedingly irritating to surrounding tissues and cause a hypersensitivity reaction via their influence on various cells of the immune system (see figure 6).Stomach Irritation and UlcerationStomach irritation and ulceration is known to be the most troublesome of the side effects of aspirin therapy. Aspirin taken orally, especially if in an insoluble form, causes severe stomach irritation. Aspirin, by inhibiting the synthesis of prostaglandins in the stomach lining interfered with the control of local acid (HCl) production. Lack of prostaglandins has a dual effect on the stomach environment. It leads to overproduction of acid by the lining of a stomach and disturbs the synthesis of the mucous barrier that normally protects the stomach from self-digestion.

    All phenomena discussed above seem convincingly explained by their linkage with prostaglandins and their action. Vane's prostaglandin hypothesis evolved into some very useful practical applications. It has a great impact on public health via a novel preventative aspirin treatment of patients with a tendency to strokes and heart attacks. The prostaglandin hypothesis explains some of the effects of antithrombotic, analgesic and antipyretic effects of lower doses of aspirin. The higher doses,of aspirin required for the anti-inflammatory effect appear to work via a quite different mode of action, probably involving alterations in the structure of plasma membranes.

    As G. Weissmann reports in his review (Weissmann, G., 1991) that aspirin is capable of altering the uptake of fatty acids and their insertion into the membranes of human manocytes and macrophages. It inhibits anion transport across a variety of plasma membranes and interferes with stimulus response coupling in neutrophils. Neutrophils are the most abundant cells in acute inflammation. They are the first line of defence against foreign intruders and cause primary damage in the autoimmune response associated with rheumatoid arthritis. They release (when activated) enzymes called proteases that are able to break down proteins and cause damage to the surrounding tissues. It seems from data obtained by G. Weissmann and co-workers that aspirin interferes with the first step leading to the injury of tissues - namely with the process of adhesion of neutrophils to the surrounding cells. So in the presence of aspirin, the acute inflammatory response is suppressed, giving relief to arthritic patients. Research about this anti-inflammatory action of aspirin is in the preliminary stages and requires further experiments in order to collect data for a comprehensive understanding of its alternative action.

    In conclusion
    In retrospect, the discovery of aspirin initiated an important breakthrough in medical therapies. It initialised an era of wide drug treatment and laid foundation for the modern pharmacological industry.

    Aspirin unquestionably proved useful in the treatment of peripheral (local) pain, though its full analgesic potential is not yet understood. Claims about direct analgesic effects of aspirin on the central nervous system, observed by some medical practitioners, need to be researched further.

    The anti-inflammatory effect of aspirin seems partially to be achieved via inhibition of prostaglandin synthesis, but other modes of action are also quite feasible. Aspirin influence on the plasma membrane structure, ion transport, and ATP production implicates some other possible alternative pathways of its effects.

    Medical applications of aspirin in the treatment of strokes, heart attacks, thrombosis and arthritic disorders are well documented and helpful in the treatment of many people who otherwise would suffer serious discomfort or even death. Some of the effects achieved in the treatment of such disorders fit well into the prostaglandin hypothesis discussed earlier. But not all scientific data obtained by various researchers support this hypothesis and therefore further clarification through experimental work is required.

    Despite all the benefits associated with aspirin treatment, caution should be encouraged as knowledge about its various side-effects is accumulating with research in progress. The maxim "no drug is a safe drug" appears to have lasting validity and should be acted upon, encouraging caution in prescribing, as well as in the dosage of aspirin. Regular heavy use of aspirin can read to the hypersensitivity reaction, gastrointestinal irritation and bleeding. It can cause toxicity damage to the kidneys and liver or interfere with blood clotting. Such side effects are too serious to be treated lightly.

    Data gathered by Gerard Weissmann and co-workers (1991) about aspirin interference with the action of white cells involved in the body's general immunity reaction, not related to prostaglandin effects, imply far more complex and wider influence of aspirin on the anti-inflammatory physiological processes of the body.

    Vane's prostaglandin hypothesis although extremely valuable, seems to explain only one aspect of aspirin's ability to act upon the human body. So more than 200 years after discovery of this useful drug, its full spectrum of interactions with various cells of the body are still not completely known. A lot of research and further learning about aspirin is needed to allow for comprehensive understanding of its effects.

    References
    1. Hockings, B., Aspirin and Thombolytic Therapy in the Management of Acute Myocardial Infarction, "Australian Family Physician", Vol. 19, No. 7, July 1990, pp.1003-1009.
    2. Koutts, J., Aspirin and Coronary Heart Disease, "Australian Family Physician", Vol. 19, No. 2, February 1990, pp.217-221.
    3. Rose, B.S., Rheumatology in Retrospect, "Patient Management", October 1991, pp.51-52.
    4. Roth, S.H., "New Directions in Arthritis Therapy", PSG Publishing Company, Littleton, Massachusetts. 1980.
    5. Sneader, W., "Drug Discovery; the Evolution of Modern Medicines", John Wiley and Sons, Chichester, 1985.
    6. Vane, J.R., Inhibition of Prostaglandin Synthesis as Mechanism of Action for Aspirin-like Drug, "Nature-New Biology", Vol. 231, No. 25, pp.232-235, June 23, 1971.
    7. Weissmann, G., Aspirin, Scientific American, January 1991, pp.58-64.


    About the author

    Dr Eva Todoroska holds a M.Sc. in Biology (Hons) from the Warsaw University (Poland) and Ph.D. from the Polish Academy of Sciences for research on the mutagenesis and DNA repair processes in microorganisms. Before moving to Australia she spent two years in Rochester N.Y. (USA) as a Postdoctoral Fellow at the University of Rochester, Medical Centre doing research in the area of genetical engineering. She has published in the area of molecular biology and genetics. Since 1988 she has been employed as a lecturer at the School of Information Technology, Charles Sturt University - Mitchell. She teaches microbiology, genetics, anatomy and physiology to the students of the Environmental Technology Course, and Nursing Diploma and Degree Courses. 

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