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Inactive Ingredient in Asthma Inhaler Drug May Counteract Inhaler Benefits, According to University of Pittsburgh Study

PITTSBURGH, March 23, 2004 An inactive agent, used in inhalers to treat asthma, can reverse the beneficial anti-inflammatory effects of inhaled steroids, according to a study presented today at the annual meeting of the American Academy of Allergy, Asthma and Immunology, in San Francisco, Calif.

Albuterol, in a class of medications called beta-agonists, is combined with steroids and is used to prevent and treat breathing problems caused by asthma and other lung diseases. It relaxes and opens the muscle surrounding air passages in the lungs, making it easier to breathe.

However, the study, presented by Bill Ameredes, Ph.D., research assistant professor of medicine and assistant professor of cell biology and physiology, in the division of pulmonary, allergy and critical care medicine at the University of Pittsburgh School of Medicine, may explain the paradoxical airway constriction and worsening of asthma in patients with continued use of beta-agonists.

The research team of the Asthma, Allergy and Airway Research Center here at Pitt has had a long interest in mechanisms of beta-agonists, particularly due to the paradoxical responses to albuterol experienced by some asthmatics, that are severe enough to land them in the emergency department, Dr. Ameredes said.

One potential explanation is that long-term repeated usage of albuterol may result in accumulation of the (S)- isomer of albuterol, which we know persists in the body 3-4 times longer than the beneficial (R)- isomer, which is normally metabolized in about three hours. Since the combination of steroid and beta-agonist therapy is prescribed for the long term for many asthmatics, we believed that it was reasonable to study the interaction of these compounds from the perspective of the isomers, he said.

Like other beta-agonists, chemically synthesized albuterol is typically called a racemic mixture. It is composed of 50 percent of the active version, or isomer, designated as (R)- albuterol, which binds to the beta-receptors and produces airway dilation, and 50 percent inactive isomer, designated as (S)- albuterol, thought to result in no airway dilation.

In the past, it was not feasible to separate these isomers from each other in the synthetic process. However, recent advances have allowed separation, testing and clinical administration of these compounds.

In contrast to other studies focusing on contractile properties of airway smooth muscle, the Pittsburgh researchers tested human airway smooth muscle cells to determine whether the different isomers of albuterol either amplified or nullified the anti-inflammatory effects of a simultaneously applied steroid.

Our findings indicated that (R)- albuterol in combination with dexamethasone reduced human airway smooth muscle cell production of an important pro-inflammatory chemical signal. Thus, the anti-inflammatory effects of the steroid were amplified by the active isomer of the beta-agonist, Dr. Ameredes said.

Importantly, we also found that (S)- albuterol did not have these effects, and in fact, resulted in increased production of the same pro-inflammatory cell signal. Thus, the reductions normally produced by the steroid were nullified by the inactive isomer of the beta-agonist. These results indicate that (S)- albuterol may diminish the beneficial anti-inflammatory effects of steroids by a mechanism that is not currently understood, and suggest that some of the paradoxical responses observed in asthmatics may derive from the pro-inflammatory effects of the (S)- isomer, he added.

Although we need to do further studies to understand the mechanisms behind these findings, they suggest that we need to give some consideration to the possibility that current combination therapies involving racemic beta-agonists may not be realizing their full potential, Dr. Ameredes said. It is possible that future focus on the therapeutic and non-therapeutic effects of isomers may reveal new combinatorial applications that can be beneficial to many sufferers of obstructive inflammatory lung diseases like asthma.

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