Dr. Jian-Dong Li. Credit: Georgia State University
Roflumilast, a drug recently approved in the United States 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 on March 23 in the Proceedings of the National Academy of Sciences, 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, was approved by the U.S. Food and Drug Administration in 2011 to decrease the frequency of flare-ups or worsening of symptoms from severe COPD. The drug is known commercially as Daliresp.
"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 and a Georgia Research Alliance Eminent Scholar in Inflammation and Immunity.
It is important to develop new therapeutics to improve the efficacy of roflumilast because there is no effective therapeutic for severe COPD, Li said.
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. The 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.
"We found there is some inflammatory response which cannot be suppressed by the drug because it has little to do with the enzyme activity," Li said. "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. Over time, we develop a tolerance."
The researchers also identified an important protein called PKA-Cβ, which can be targeted to reduce the unwanted production of PDE4B2.
In addition, they 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.
Li said the counterproductive activity of roflumilast is similar to using a fire extinguisher to bring down a fire, but at the same time, the fire extinguisher itself is increasing the amount of flammable material causing the fire.
Explore further: About 1 in 7 older adults has some form of lung disease: CDC
More information: Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi , PNAS,
http://ift.tt/1N7zI4w
Medical Xpress on facebook
Related Stories
Roflumilast improves lung function after 6 months compared with placebo
Roflumilast was associated with significant improvements in lung function in patients with moderate and severe chronic obstructive pulmonary disease (COPD) after 6 months of treatment compared with placebo.
Phosphodiesterase 4 inhibitors have only marginal benefits for people with COPD
Giving patients with chronic obstructive pulmonary disease (COPD) newly available oral phosphodiesterase 4 (PDE4) inhibitors, roflumilast or cilomilast, improves lung function and reduces the likelihood of a flareup, but ...
About 1 in 7 older adults has some form of lung disease: CDC
(HealthDay)—Nearly 15 percent, or about one out of seven, middle-aged and older U.S. adults suffer from lung disorders such as asthma or chronic obstructive pulmonary disease (COPD), health officials said ...
Asthma vs. COPD, similar symptoms—different causes and treatment
Coughing, wheezing and shortness of breath are symptoms asthma sufferers are used to. They are also the symptoms of chronic obstructive pulmonary disease (COPD). For sufferers, as well as physicians, it can be difficult to ...
Vitamin D reduces lung disease flare-ups by over 40 percent
Vitamin D supplements can reduce COPD lung disease flare-ups by over 40% in patients with a vitamin D deficiency - according to new research from Queen Mary University of London. COPD (chronic obstructive pulmonary disease) ...
Recommended for you
Combination therapy boosts antiviral response to chronic infection
A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer.
Biotechnologists develop gene therapy for erectile dysfunction
Erectile dysfunction is a taboo subject among men. No one likes to talk about it. But the fact is that as men age, an increasing number will suffer from erectile dysfunction. From the age of 30, the number ...
Researchers explore mechanism to stop ageing
As medicine has improved, we are increasing our ability to treat disease and improve longevity. The deterioration of the body with age, though, is a whole other matter.
New treatment for scaffold creates healthier engineered bladder tissue
A new technique to create tissue-engineered bladders has been shown to decrease scarring and significantly increase tissue growth. The bladders are produced using scaffolds coated with anti-inflammatory peptides. ...
Research team discovers backup system that helps sustain liver during crisis
Scientists from Montana State University and Sweden have discovered an antioxidant system that helps sustain the liver when other systems are missing or compromised.
'Missing culprit' in heart failure identified
Working with lab animals and human heart cells, scientists from Johns Hopkins and other institutions have identified what they describe as "the long-sought culprit" in the mystery behind a cell-signaling ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here to reset your password.
Sign in to get notified via email when new comments are made.
Dr. Jian-Dong Li. Credit: Georgia State University
Roflumilast, a drug recently approved in the United States 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 on March 23 in the Proceedings of the National Academy of Sciences, 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, was approved by the U.S. Food and Drug Administration in 2011 to decrease the frequency of flare-ups or worsening of symptoms from severe COPD. The drug is known commercially as Daliresp.
"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 and a Georgia Research Alliance Eminent Scholar in Inflammation and Immunity.
It is important to develop new therapeutics to improve the efficacy of roflumilast because there is no effective therapeutic for severe COPD, Li said.
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. The 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.
"We found there is some inflammatory response which cannot be suppressed by the drug because it has little to do with the enzyme activity," Li said. "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. Over time, we develop a tolerance."
The researchers also identified an important protein called PKA-Cβ, which can be targeted to reduce the unwanted production of PDE4B2.
In addition, they 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.
Li said the counterproductive activity of roflumilast is similar to using a fire extinguisher to bring down a fire, but at the same time, the fire extinguisher itself is increasing the amount of flammable material causing the fire.
Explore further: About 1 in 7 older adults has some form of lung disease: CDC
More information: Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi , PNAS,
http://ift.tt/1N7zI4w
Medical Xpress on facebook
Related Stories
Roflumilast improves lung function after 6 months compared with placebo
Roflumilast was associated with significant improvements in lung function in patients with moderate and severe chronic obstructive pulmonary disease (COPD) after 6 months of treatment compared with placebo.
Phosphodiesterase 4 inhibitors have only marginal benefits for people with COPD
Giving patients with chronic obstructive pulmonary disease (COPD) newly available oral phosphodiesterase 4 (PDE4) inhibitors, roflumilast or cilomilast, improves lung function and reduces the likelihood of a flareup, but ...
About 1 in 7 older adults has some form of lung disease: CDC
(HealthDay)—Nearly 15 percent, or about one out of seven, middle-aged and older U.S. adults suffer from lung disorders such as asthma or chronic obstructive pulmonary disease (COPD), health officials said ...
Asthma vs. COPD, similar symptoms—different causes and treatment
Coughing, wheezing and shortness of breath are symptoms asthma sufferers are used to. They are also the symptoms of chronic obstructive pulmonary disease (COPD). For sufferers, as well as physicians, it can be difficult to ...
Vitamin D reduces lung disease flare-ups by over 40 percent
Vitamin D supplements can reduce COPD lung disease flare-ups by over 40% in patients with a vitamin D deficiency - according to new research from Queen Mary University of London. COPD (chronic obstructive pulmonary disease) ...
Recommended for you
Combination therapy boosts antiviral response to chronic infection
A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer.
Biotechnologists develop gene therapy for erectile dysfunction
Erectile dysfunction is a taboo subject among men. No one likes to talk about it. But the fact is that as men age, an increasing number will suffer from erectile dysfunction. From the age of 30, the number ...
Researchers explore mechanism to stop ageing
As medicine has improved, we are increasing our ability to treat disease and improve longevity. The deterioration of the body with age, though, is a whole other matter.
New treatment for scaffold creates healthier engineered bladder tissue
A new technique to create tissue-engineered bladders has been shown to decrease scarring and significantly increase tissue growth. The bladders are produced using scaffolds coated with anti-inflammatory peptides. ...
Research team discovers backup system that helps sustain liver during crisis
Scientists from Montana State University and Sweden have discovered an antioxidant system that helps sustain the liver when other systems are missing or compromised.
'Missing culprit' in heart failure identified
Working with lab animals and human heart cells, scientists from Johns Hopkins and other institutions have identified what they describe as "the long-sought culprit" in the mystery behind a cell-signaling ...
User comments
Please sign in to add a comment. Registration is free, and takes less than a minute. Read more
Click here
to reset your password.
Sign in to get notified via email when new comments are made.
0 comments:
Post a Comment