A drug used to treat severe chronic obstructive pulmonary disease (COPD) becomes less effective over time as patients develop a tolerance for the medication.

That’s the conclusion of researchers from Georgia State University, Kumamoto University in Japan, and the University of Rochester Medical Center. Their study was published today in Proceedings of the National Academy of Sciences.


Researchers said the drug roflumilast increases the production of a protein that causes inflammation. That change causes a tolerance to develop and makes the drug less effective after repeated use.

"There is clinical evidence showing that patients could develop a tolerance if they keep taking repeated dosing of this drug, but why or how has been unknown. If we can figure out why people have a tolerance, we can probably improve the therapeutics," said Dr. Jian-Dong Li, director of the Institute for Biomedical Sciences at Georgia State University. 

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The Food and Drug Administration approved roflumilast (Daliresp) in 2011. It’s used to decrease the frequency of flare-ups or worsening of symptoms in severe COPD.

The drug is designed to inhibit the activity of a protein called PDE4. But researchers found that roflumilast also increases production of another protein called PDE4B2. The surge in this protein causes the destructive inflammation.

Researchers compared the reaction to a fire extinguisher that puts out a fire but at the same time adds gasoline to the flames.

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"The patient keeps taking the drug and over time, you give more drug and you produce more target protein, which is even more counterproductive for suppressing inflammation," Li said in a press release.

COPD is the fourth-leading cause of death worldwide. The progressive disease causes airflow blockage and breathing-related problems, such as coughing with large amounts of mucus, wheezing, shortness of breath, and chest tightness.

Cigarette smoking is the leading cause of COPD, according to the National Heart, Lung and Blood Institute.

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