Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells.
The phosphodiesterase 4 inhibitor (PDE4i) roflumilast has been approved in the US and EU for treatment of GOLD stage 3 and 4 chronic obstructive pulmonary disease (COPD). Inhaled β2 adrenoceptor agonist bronchodilators and anti-inflammatory glucocorticosteroids are also used as standard of care in COPD. We investigated the anti-inflammatory interaction of roflumilast in combination with long-acting β2 agonists (LABA), salmeterol or formoterol, or a glucocorticosteroid, dexamethasone, on cytokine production from LPS-stimulated human primary peripheral blood mononuclear cells (PBMC). Salmeterol or formoterol caused a concentration-dependent inhibition of tumor necrosis factor-α (TNFα) secretion with an IC50 of 0.33 pM (C.I. 0.006-19) and 34 pM (C.I. 13-87), respectively. When roflumilast was evaluated, the addition of salmeterol (1 nM) to roflumilast caused the IC50 for roflumilast to shift from 1.8 nM (C.I. 0.8-4) to 4.1 pM (C.I.0.3-69) (p < 0.01), and maximal inhibition increased from 72.5 ± 3.2% to 90.9 ± 3.1%. Addition of formoterol to roflumilast also produced an increased TNFα inhibition more than either drug alone (p < 0.05). The inhibition of TNFα production with salmeterol was both β2 adrenoceptor- and protein kinase A-dependent. Addition of roflumilast (10 nM) in the presence of dexamethasone increased the inhibition of LPS-induced TNFα and CCL3. Roflumilast in combination with salmeterol, formoterol, or dexamethasone increased the inhibition of LPS-induced TNFα from human PBMC, in an additive manner. Addition of roflumilast to either a β2 adrenoceptor agonist or a glucocorticosteroid may provide superior anti-inflammatory activity and greater efficacy in COPD patients and be dose sparing.
Respiratory Research, Gilead Sciences Inc., 199 East Blaine St., Seattle, WA 98102, USA. Stacey.Tannheimer@gilead.com
Stacey L
SL
Tannheimer
Eric A
EA
Sorensen
Aaron C
AC
Haran
Christopher N
CN
Mansfield
Clifford D
CD
Wright
Michael
M
Salmon
D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000068299:Salmeterol Xinafoate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D003521:Cyclopropanes; D004983:Ethanolamines; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; C424423:Roflumilast; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000420:Albuterol; D000068759:Formoterol Fumarate