Historical Background

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Cromolyn and nedocromil are members of the chromone group of chemical compounds. The chemical formula for chromone is 5:6 benz-1:4 pyrone (2) (Fig. 1). In 1968, disodium cromoglycate (DSCG) or CS combined with isoproterenol was introduced in the United Kingdom as the first antiinflammatory medication used in asthma (3-5). The addition of the bronchodilator was done to prevent bronchoconstriction that can occur with inhalation of a sodium salt (4). By 1973, cromolyn was approved by the Food and Drug Administration (FDA) for the treatment of asthma and in 1983 for the treatment of allergic rhinitis (5). Khellin (2) was the first identified chromone, which was extracted from seeds of the plant Amni visnaga, the same plant from which cromolyn was derived. It was used as a diuretic and smooth muscle relaxant, especially for the relief of ureteric colic. In 1947, Anrep et al. (6) reported the clinical utility of khellin for the treatment of asthma. Multiple compounds were synthesized using the khellin molecular structure as a starting point. Two other chromones, K18 and GR4 (Fig. 2), used in the sensitized guinea pig lung with antigen challenge prevented the release of histamine and slow-releasing substances of anaphylaxis (SRS-A) (7).

Dr. Roger Altounyan discovered cromolyn in 1964 after many trials with other chromone compounds. As a young child he had a history of atopy

Khellin Structure
Figure 2 Chemical structure of early chromones: K18, GR4, and K84.

and eczema, and later he developed severe chronic asthma (2). In his early experiments he performed bronchial allergen challenges on himself to induce bronchoconstriction. Pretreatment of himself with K18 and GR4 demonstrated a 50% and 70% protection, respectively, against allergen challenge. In 1963, a K84 compound provided 57% protection when administered one hour prior to allergen challenge, but subsequent studies failed to reproduce these observations. This discovery led to a desire to perform human trials aimed at clarifying any therapeutic effectiveness of this compound to treat asthmatics. Since the drug was effective prior to inhalation of antigen in the preliminary observations, the first human trial involved prolonged administration of K84 prior to antigen challenge. Disappointingly, this trial of K84 in one adult patient showed no improvement in his asthma symptoms. Further analysis determined that the protection from allergen challenge in the initial K84 experiments might be due to an "impurity" in the compound. Eventually it was determined that two K84 molecules, joined

Nedocromil sodium

Figure 3 Chemical structure of khellin, Cromolyn sodium, and nedocromil sodium.

at the —5 position (Fig. 3), were responsible for the clinical observations. Thus, a new bischromone, CS, was brought to clinical medicine (7). A second molecule known as GR4 was the starting compound that led to the synthesis of the monochromone, nedocromil sodium.

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