Novel Therapies for Asthma - Advances and Problems

Abstract

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.

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

“…In preliminary studies, a second LDV mimetic modeled after BIO-1211, IVL745, caused only a modest reduction in sputum eosinophils in human patients with mild-to-moderate atopic asthma following inhalation and had no effect on the early or late asthmatic response to inhaled allergen or markers of airway inflammation [118]. The futures of IVL745 and another α4β1 antagonist, compound HMR 1031, under investigation by Sanofi-Aventis in phase II trials of asthma, are unclear [117,119]. HMR 1031 is a potent α4β1 small molecule antagonist that selectively blocks binding of α4β1 to VCAM-1 and fibronectin [120].…”

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

“…Local anti-inflammatory properties of GCs make them a first-choice medication for asthma (Walsh 2005) and rheumatoid arthritis (Boers 2004). However, there is considerable individual variation in sensitivity to GCs (Hearing et al 1999), which may affect the outcome of GC treatment.…”

Enhancement of the release of inflammatory mediators by substance P in rat basophilic leukemia RBL-2H3 cells

“…These differences in the activation of MAPK pathway are possibly due to different responses in cell types. Nevertheless, these MAPK-activated mediators are targets of current asthmatic therapy consisting of anti-histamines, LT antagonists, anti-inflammatory glucocorticoid, and humanized monoclonal antibodies against IgE and IL-4 [37].…”