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Monday 02 January 2006

Anti-Asthma Medications: Too Much of a Good Thing?

By: JCI News Release

In an unusual paradox, asthmatics that are chronically treated with bronchodilating beta-agonist medications such as albuterol, ventolin, and salbutamol may ultimately develop increased sensitivity to airway constriction and experience exacerbation of their condition.

A study by Stephen Liggett and colleagues at the University of Cincinnati in the August 15, 2003 issue of the Journal of Clinical Investigation (JCI) describes a responsible mechanism for this adverse reaction and reveals a potential new therapeutic target in the treatment of asthma.

Inhaled selective beta-agonists are the most widely used treatment for the acute relief of asthma symptoms. Administered to asthmatic patients via an inhaler, nebulizer, in tablet or liquid form, or injection, they cause airway relaxation and reduced airway responsiveness to nonspecific contractile stimuli. This is achieved by drug binding to the beta2-adrenergic receptor (beta2AR). Despite the ability of these agents to immediately reverse airway obstruction, there has been ongoing concern that the use of these drugs may be associated with harmful outcomes. Some, but not all, studies have revealed that regular scheduled use (e.g., multiple times daily, every day) of inhaled beta-agonists has resulted in a loss of control over the condition, which can manifest as longer asthmatic attacks and and post-treatment airway hyperresponsiveness.

To date, the evidence has suggested that a desensitization of the beta2AR is responsible. Liggett and colleagues suggest an alternative explanation. The authors demonstrate that persistent high-level activation of the beta2AR leads to increased expression of phospholipase C- beta (PLC-beta) in airway smooth muscle, inducing a crosstalk between beta2AR signaling pathways that ultimately results in airway hyperresponsiveness.

In their accompanying commentary, Stephanie Shore and Jeffrey Drazen from the Harvard School of Public Health and Brigham and Women's Hospital in Boston, Massachusetts, discuss additional explanations for the bronchoconstricting effects associated with chronic beta2AR stimulation. The commentary authors state that "it is interesting to note that the adverse effects of regular beta-agonist use can be observed even weeks after their withdrawal, at a time when beta2AR desensitization should be resolved". These authors also indicate that studies of regular beta-agonist use have reported adverse effects only in subjects with a particular mutation in the beta2AR. The impact of this mutation has not been fully examined in any cell type.

Liggett and his research team suggest that therapeutics targeting PLC-beta may have substantial benefit in the treatment of asthma, particularly when chronic beta-agonist use is prescribed. Shore and Drazen suggest that it is possible that this is "just the tip of the iceberg" and that "understanding the panoply of beta2AR-mediated events in airway smooth muscle might lead to the design of new agonists that avoid negative effects of beta 2AR activation while enhancing events that lead to relaxation".

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