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Roflumilast for severe COPD becomes less effective: drug tolerance can develop over time


Roflumilast ( Daxas; Daliresp ), a drug approved to treat severe chronic obstructive pulmonary disease ( COPD ), increases the production of a protein that causes inflammation, which possibly results in patients developing a tolerance to the drug after repeated use and makes the drug less effective, according to researchers at Georgia State University, Kumamoto University and the University of Rochester Medical Center.

The findings, published in the Proceedings of the National Academy of Sciences USA, may help explain the development of tolerance to Roflumilast and may assist with developing new therapeutics to improve the efficacy of the drug.

COPD is the fourth-leading cause of death worldwide. This progressive disease causes airflow blockage and breathing-related problems, such as coughing that produces 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.

Roflumilast, a new drug class for the treatment of COPD, decreases the frequency of flare-ups or worsening of symptoms from severe COPD.

There is clinical evidence showing that patients could develop a tolerance if they keep taking repeated dosing of this drug.

Roflumilast was designed to inhibit the enzymatic activity of a protein called PDE4, but the study found the drug also undergoes a complicated, unwanted process to increase the production of PDE4B2. T
he surge of this protein increases inflammation in ways that are dependent and independent of enzymatic activity and may contribute to the patient developing a tolerance to Roflumilast.

The researchers concluded the drug, even at high concentrations, cannot fully suppress inflammation because it can’t suppress inflammatory response that is independent of enzymatic activity.
Over time, patients can develop a tolerance.

The researchers also identified an important protein called PKA-Cbeta, which can be targeted to reduce the unwanted production of PDE4B2.

In addition, researchers found Roflumilast works with the major bacterial pathogen that causes symptoms to worsen in severe COPD to increase production of the unwanted protein PDE4B2 in a synergistic manner. ( Xagena )

Source: Georgia State University, 2015

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