New therapies in asthma

  • R. D
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Abstract

Available treatment of asthma using inhaled corticosteroids and long-acting inhaled β2-agonists (LABAs) is highly effective and safe. Importantly, it is also relatively inexpensive. However, many patients remain poorly controlled despite the use of optimal treatment. Most advances in asthma therapy have been achieved by improving these drugs and more recently several promising once-a-day LABAs have been developed. New corticosteroids are also being developed with differential effect on trans-activation and trans-repression of pro-inflammatory transcription factors, thus giving them a better therapeutic index. The big challenge in asthma is posed by corticosteroid unresponsiveness which is relative and therefore requires high doses to achieve symptom control which inevitably leads to side-effects. One option being pursued is to develop activators of the nuclear enzyme histone-deactylase (HDAC)2 which is recruited to the gene initiation site of pro-inflammatory mediators. There is an increasing appreciation that asthma is not a single disease and is increasingly seen as a syndrome consisting of several phenotypes. So far, two relatively clear subsets have been identified: eosinophilic and neutrophilic forms of asthma. With this notion in mind, attempts are being made to develop more-specific inhibitors for a range of mediators with the hope that sub-phenotypes of asthma will be identified that respond well to either single mediator inhibitors or a combination of these. A number of cytokine modulators have been tested in clinical trials, the most notable example being anti-TNF inhibitors which is felt to be more relevant to neutrophilic asthma. Unfortunately, large clinical trials with TNF inhibitors have not found them to be very effective. Treatment with blocking antibody for the eosinophils growth factor, IL-5, has been slightly more effective, with early clinical trials showing that the treatment reduces the frequency of exacerbations in patients who have eosinophilia. Whilst the exact mechanisms leading to the development of these two subphenotypes is not fully understood, it is thought that eosinophilia represents a risk factor for exacerbations which has led to eosinophils counts in sputum being used as a guide to treatment; this has been beneficial in reducing exacerbations. Neutrophilic forms of asthma represent a special challenge because patients with neutrophilia tend not to respond well to corticosteroids, making them reliant on bronchodilators. Such patients' asthma may be driven by mechanisms that involve IL-17 which induces the production of neutrophil chemoattractants by the epithelium, which makes IL-17 and its chemo-attractant axis a target for novel therapies. The major unmet need in asthma is the treatment of infections. There are early indicators of antibiotic treatment (macrolides) being effective in the treatment of severe asthma. But the real hope comes from novel strategies aimed at the effects of viruses which are the cause of most acute exacerbations, both in milder and more severe forms of disease. Recent studies have identified a deficiency in type I interferons (IFN), the production of which by the bronchial epithelium - the prime target of virus infection - has been shown to be reduced when epithelial cells from asthmatic are grown in culture and infected ex vivo. This finding has raised hope that early administration of IFNβ, at a time when patients are suffering upper respiratory symptoms typical of a virus infection, could prevent spread of virus to the lower airways and thus prevent acute exacerbations. Early clinical trials of safety with IFNβ are encouraging and an international trial programme is underway to test whether this treatment is effective in moderate asthmatics treated with inhaled corticosteroids.

Author-supplied keywords

  • Asian
  • agonist
  • antibiotic therapy
  • asthma
  • blocking antibody
  • bronchus mucosa
  • clinical trial
  • corticosteroid
  • cytokine
  • drug megadose
  • enzyme
  • eosinophil
  • eosinophilia
  • epithelium
  • epithelium cell
  • ex vivo study
  • gene
  • growth factor
  • histone
  • hope
  • infection
  • interferon
  • interleukin 5
  • lower respiratory tract
  • macrolide
  • neutrophil
  • neutrophilia
  • patient
  • phenotype
  • risk factor
  • safety
  • side effect
  • society
  • sputum
  • therapy
  • transcription factor
  • tumor necrosis factor inhibitor
  • virus
  • virus infection

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Authors

  • Djukanovic R.

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