Therapy Analysis - Asthma
From corticosteroids to leucotriene agonists and beyond
The history of corticosteroid treatment for asthmatics
Asthma is a common disease, and the number of sufferers seems to be on the rise. Asthma affects one in five households in the UK, of which 5.2 million are seeking treatment. Each year, there are approximately 4 million consultations, of which 74,000 are hospital admissions. The total annual cost in the UK is in the region of £2 billion, with direct costs to the UK NHS of £889 million. Of this, difficult-to-manage asthma alone costs the NHS £680 million. For such a common and growing disease, there is a surprising lack of innovation within the pharmaceutical industry, with common current therapeutics having been longestablished and few genuinely novel pharmacological interventions having been discovered.
It was in 1900 that Solomon Solis- Cohen, a physician from Philadelphia, discovered that orally-administered dried adrenal extract improved asthmatic symptoms. This ground-breaking discovery led to the birth of adrenaline and sympathomimetics as bronchodilators. However, the clinical efficacy observed by Solis- Cohen is most likely due to the steroid content, as adrenaline is not absorbed in significant amounts from the gastrointestinal tract. Exactly 50 years after, the Nobel Prize for Medicine and Physiology was awarded to Kendall and Reichstein for the independent isolation and synthesis of cortisol. Six months later, Boardley and colleagues at Johns Hopkins University further showed that intramuscular injections of adrenocorticotropic hormone (ACTH) over 3 weeks dramatically reduced eosinophilic sputum, and showed that oral cortisone, widely used to treat inflammatory diseases, ameliorated clinical symptoms in severe asthmatics.
Subsequently, the UK Medical Research Council initiated the first ever placebo-controlled clinical trial in asthma to assess corticosteroid efficacy, although, somewhat surprisingly, the results were disappointing. This was later attributed to the low dose of cortisone used, inclusion of chronic obstructive pulmonary disease (COPD) patients, and a lack of welldefined parameters of lung function. Despite these poor results, oral steroids became popular for the treatment of severe asthma. However, with the continued growth of evidence of serious side-effects, such as central obesity, increased susceptibility to infections, metabolic disturbances and osteoporosis, inhaled formulations of cortisol and dexamethasone were developed to reduce systemic side-effects. These were found to have very little clinical benefit due to poor topical efficacy, leading to the discovery of beclometasone dipropionate (BDP) and betametasone-17-valerate, topically-active steroids. These inhaled steroids were not only effective in reducing patient need for oral corticosteroids, but also became first-line therapy due to their clinical effectiveness. Their widespread use resulted in major reductions in asthma morbidity and mortality.
