Novel therapies for asthma--advances and problems.
It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with anti-histamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-gamma are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.
Walsh
Garry M
GM
Asthmatic & Allergic Inflammation Group, School of Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. g.m.walsh@abdn.ac.uk
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D016503:Drug Delivery Systems; D006633:Histamine Antagonists / Q000627:therapeutic use; D006801:Humans; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D008168:Lung / Q000473:pathology; D008407:Mast Cells / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D016207:Cytokines; D006633:Histamine Antagonists; D020024:Leukotriene Antagonists