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The History of Asthma Drugs from Astra Pharmaceuticals and AstraZeneca R&D In this AZ-Air section Dr Selroos summarizes the history of asthma treatments from an AstraZeneca perspective. AstraZeneca has been involved in the development of selective beta-agonists (terbutaline), inhaled glucocorticosteroids (budesonide), long-acting beta-agonists (the clinical development of formoterol), and the combination product Symbicort® (budesonide/formoterol). During the journey starting in the 1960'ies AstraZeneca has been driving and supporting several new treatment concepts in asthma with these drugs, not least in several large landmark studies - eventually leading to a better understanding of the disease and its treatment. However, first a little glimpse into the very early treatments of asthma staring over 2000 years ago. The word "Asthma" originates from the Greek word asqma, which stands for "short breathes" or "gasp for breath". Treatment of asthma existed long before AstraZeneca and goes back to ancient India, China and Greek. It is known that the inhabitants of the Indus valley long before the Christian era attempted to relieve respiratory symptoms by inhaling fumes originating from burning thorn apples. The ancient Greeks, e.g. Hippokrates, recommended vapor inhalation. The apparatus used by the Greeks consisted of a lidded pot with a reede through which the vapor escaped. The vapor was inhaled after it had passed through sponges that cooled it. In the nineteenth century, inhalation therapy was introduced to the western world with the use of Datura stramonium, a congener of atropin (1). D.Stramonium also became available as asthma cigarettes.
In 1860 Salter wrote in his text book: "The cure of asthma by violent emotions is more sudden and complete than by any other remedy whatever….I think, too, that mental emotions act, if I may express it, as a nervous derivative" (2). This was the introduction of treatment by stimulants in the history of asthma. Later on Salter also advocated the use of belladonna (3), again an atropin containing drug. Around the turn of the century adrenal extracts and adrenalin were introduced for the treatment of asthma (4-6). A prolongation of the effect of adrenalin was achieved with the introduction of ephedrine (7). The pulmonary effects of theophylline were published in the mid 1930´ies (8,9) and this drug is still used in the treatment of obstructive lung diseases. It is obvious that the effects of the adrenal substance described by Solis-Cohen (5) were in fact effects of a corticosteroid. The isolation of the active agent, cortisone, was achieved by Kendall and his co-workers, but its further characterization and synthesis proved to be a slow process. It took further 16 years before cortisone was used in rheumatoid arthritis (1948). Within a year it was administered intramuscularly in bronchial asthma (1950). In the 1950´ies high doses of oral or intramuscular formulations were given to patients, but the side-effects became quite obvious and severe. Today oral (prednisolone, methylprednisolone) and parenteral (mainly hydrocortisone) glucocorticosteroids are only used in association with acute severe attacks of asthma. In the early 1940´ies an analogue to adrenalin with bronchodilating properties was identified - isoprenaline (10). Work with isoprenaline made a great impact on the development of our understanding of a- and ß-receptors and the separation between ß1- and ß2 a-receptors. Isoprenaline was widely used in the treatment of asthma but the concomitant -receptor stimulating properties resulted in cardiac side effects which were sometimes fatal. The follow-up substance, orciprenaline, was still not a ß2 -selective agonist. |
