- The Washington Times - Monday, August 25, 2003

Although medications can help keep asthma in check, heavy use of certain popular drugs actually can worsen the condition.

Researchers long have sought an explanation for this paradox and a new study might have uncovered the mechanism behind it, possibly paving the way for a treatment to help patients avoid the problem.

The drugs in question belong to a class known as short-acting beta-agonists, the most commonly used treatments for the condition, employed by millions of asthma sufferers.

Asthma causes inflamed and swollen airways that overreact when exposed to such substances as smoke, dust and pollen, constricting and shutting off airflow. Though beta-agonists can help reduce these symptoms, prolonged use of the drugs in some people appears to cause the opposite effect, actually closing air passages.

For severe asthmatics who require the medicine daily, this can lead to a downward spiral: Worsening symptoms lead them to use more medication, which in turn only exacerbates the condition.

“We’ve known for a number of years that constant use of beta-agonists in asthma … seems to be associated with odd physiological events, which may include a tendency to have worse or frequent flares of asthma,” Dr. Stephen Liggett, a physician at the University of Cincinnati and lead author of the study, told United Press International.

Solving this physiological puzzle is urgent because asthma can cause severe health problems if not controlled. Asthma-related problems account for more than half a million hospital stays each year and 14 deaths each day in the United States, according to the Asthma and Allergy Foundation of America in Washington. In addition, patients spend billions of dollars annually on asthma medications.

About half of the estimated 17 million asthmatics in the United States use beta-agonists on a regular basis and they all probably are at risk of experiencing the worsening paradox, Dr. Liggett says. “We think it’s probably using it on a very regular basis … like daily,” that can induce the reaction, he says.

Some researchers have postulated the problem could be due to the body becoming desensitized to the medications after repeated use. But Dr. Liggett, an asthma-sufferer himself, is convinced he has uncovered a better explanation.

As described in the Aug. 15 issue of the Journal of Clinical Investigation, Dr. Liggett and colleagues genetically altered mice in such a way their lungs behaved similarly to that of a person with severe asthma who uses the medications continuously. The beta-agonist drugs bind to and activate a receptor on lung cells. The mice were genetically manipulated so the receptor was constantly activated.

The research revealed persistent activation of the receptor — as heavy use of the beta-agonists would cause — is associated with a host of changes in the way the airway contracts that intensifies the constriction. This suggests continuous use of the medications might induce the same effect, Dr. Liggett says.

Dr. Liggett’s group further discovered the culprit for the constriction could be a chemical in the body called phospholipase C-beta or PLC. The constant activation of the receptor leads to production of the PLC enzyme, which seems to interfere with the relaxation signal and instead causes constriction of the airways.

Dr. Liggett thinks PLC could be targeted for additional therapies to help prevent the worsening paradox.

Stephanie Shore, a physiologist at Harvard University’s School of Public Health in Boston, who wrote an accompanying commentary on the study, says although the problem probably occurs in a minority of asthma patients, it still needs a solution.

“For most people, beta-agonists are fine and work really well, but there is a subset of people who, when given beta-agonists regularly, their symptoms can start getting worse rather than better,” Miss Shore says. “For that group, we need something else.”

Miss Shore put the prevalence of the paradox reaction at about 10 percent of asthmatics.

The AAFA has no exact numbers of how many asthmatics might be at risk of the paradox because it is not well-studied. But the organization’s perspective is that no patients should be using the beta-agonists so heavily they risk making their condition worse.

Daily use should be “a red-flag” for the patient, Mike Tringale, AAFA’s director of marketing and communication, says. Beta-agonists are designed to be emergency-response medications, so “if it’s at a point where [patients] are constantly using them, then they are constantly in an emergency situation and something is wrong,” he says. “They need to go back to their doctor and ask why they are using it so frequently” and develop a better management plan for their asthma, he says.

Miss Shore notes the findings of Dr. Liggett’s study still must be duplicated in humans before medications can be developed that act on PLC, but says Dr. Liggett’s data look promising.

A therapy based on PLC would not replace other asthma treatments, but would be used in conjunction with them, she says. “The idea would be that if we could target [PLC], you might be able to get rid of this adverse effect. We’re not going to take away the beta-agonists, but rather also do something else to prevent bad effects.”

Meanwhile, another alternative recently became available. The Food and Drug Administration approved the first in a new class of asthma treatments in June. The drug, Xolair, is manufactured by Genentech, a biotech company in San Francisco. It is intended for patients with moderate-to-severe asthma. The drug blocks the action of molecules in the body called IgE, which can trigger inflammation in the airways.

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