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Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases.

Giembycz MA, Newton R - F1000Prime Rep (2015)

Bottom Line: This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose.In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy.Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary 3820 Hospital Drive NW, Calgary, Alberta Canada T2N 1N4.

ABSTRACT
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

No MeSH data available.


Related in: MedlinePlus

An example of a conjugated inactive long-acting β2-adrenoceptor agonist glucocorticoid pro-drugA phosphorylated form of salmeterol (blue) is shown conjugated to a derivative of the glucocorticoid, desisobutyryl-ciclesonide (pink). In vivo, the phosphate and ester bonds (in black) are cleaved (scissors) by alkaline phosphatase and esterases respectively to yield the active components in a 1:1 ratio. Adapted from [97].Abbreviations: LABA, long-acting β2-adrenoceptor agonists.
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fig-002: An example of a conjugated inactive long-acting β2-adrenoceptor agonist glucocorticoid pro-drugA phosphorylated form of salmeterol (blue) is shown conjugated to a derivative of the glucocorticoid, desisobutyryl-ciclesonide (pink). In vivo, the phosphate and ester bonds (in black) are cleaved (scissors) by alkaline phosphatase and esterases respectively to yield the active components in a 1:1 ratio. Adapted from [97].Abbreviations: LABA, long-acting β2-adrenoceptor agonists.

Mentions: A pro-drug is an inactive or weakly active molecule that typically undergoes enzymatic activation in vivo [94]. The patent literature contains several claims for mutual inhaled pro-drugs consisting of a glucocorticoid and a LABA [95,96]. An example is shown in Figure 2 in which salmeterol is conjugated to a derivative of the inhaled glucocorticoid, desisobutyryl-ciclesonide. This particular pro-drug is activated by alkaline phosphatase and an esterase, which are enriched in the lung relative to saliva and plasma. In theory, conjugated pro-drugs of this form would ensure co-deposition and selective activation in the lung with an improved side-effect profile.


Potential mechanisms to explain how LABAs and PDE4 inhibitors enhance the clinical efficacy of glucocorticoids in inflammatory lung diseases.

Giembycz MA, Newton R - F1000Prime Rep (2015)

An example of a conjugated inactive long-acting β2-adrenoceptor agonist glucocorticoid pro-drugA phosphorylated form of salmeterol (blue) is shown conjugated to a derivative of the glucocorticoid, desisobutyryl-ciclesonide (pink). In vivo, the phosphate and ester bonds (in black) are cleaved (scissors) by alkaline phosphatase and esterases respectively to yield the active components in a 1:1 ratio. Adapted from [97].Abbreviations: LABA, long-acting β2-adrenoceptor agonists.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4335793&req=5

fig-002: An example of a conjugated inactive long-acting β2-adrenoceptor agonist glucocorticoid pro-drugA phosphorylated form of salmeterol (blue) is shown conjugated to a derivative of the glucocorticoid, desisobutyryl-ciclesonide (pink). In vivo, the phosphate and ester bonds (in black) are cleaved (scissors) by alkaline phosphatase and esterases respectively to yield the active components in a 1:1 ratio. Adapted from [97].Abbreviations: LABA, long-acting β2-adrenoceptor agonists.
Mentions: A pro-drug is an inactive or weakly active molecule that typically undergoes enzymatic activation in vivo [94]. The patent literature contains several claims for mutual inhaled pro-drugs consisting of a glucocorticoid and a LABA [95,96]. An example is shown in Figure 2 in which salmeterol is conjugated to a derivative of the inhaled glucocorticoid, desisobutyryl-ciclesonide. This particular pro-drug is activated by alkaline phosphatase and an esterase, which are enriched in the lung relative to saliva and plasma. In theory, conjugated pro-drugs of this form would ensure co-deposition and selective activation in the lung with an improved side-effect profile.

Bottom Line: This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose.In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy.Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Pharmacology, Snyder Institute of Chronic Diseases, Cumming School of Medicine, University of Calgary 3820 Hospital Drive NW, Calgary, Alberta Canada T2N 1N4.

ABSTRACT
Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option for individuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids are due to their ability to suppress inflammation by modulating gene expression. While inhaled glucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe disease in whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled glucocorticoid. This so-called "combination therapy" is often effective and clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and another class of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy of inhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled glucocorticoid/LABA combination therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent therapeutics that was not previously possible.

No MeSH data available.


Related in: MedlinePlus