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Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells.
Pulm Pharmacol Ther 2012; 25(2):178-84PP

Abstract

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.

Authors+Show Affiliations

Respiratory Research, Gilead Sciences Inc., 199 East Blaine St., Seattle, WA 98102, USA. Stacey.Tannheimer@gilead.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22306235

Citation

Tannheimer, Stacey L., et al. "Additive Anti-inflammatory Effects of Beta 2 Adrenoceptor Agonists or Glucocorticosteroid With Roflumilast in Human Peripheral Blood Mononuclear Cells." Pulmonary Pharmacology & Therapeutics, vol. 25, no. 2, 2012, pp. 178-84.
Tannheimer SL, Sorensen EA, Haran AC, et al. Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells. Pulm Pharmacol Ther. 2012;25(2):178-84.
Tannheimer, S. L., Sorensen, E. A., Haran, A. C., Mansfield, C. N., Wright, C. D., & Salmon, M. (2012). Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells. Pulmonary Pharmacology & Therapeutics, 25(2), pp. 178-84. doi:10.1016/j.pupt.2012.01.003.
Tannheimer SL, et al. Additive Anti-inflammatory Effects of Beta 2 Adrenoceptor Agonists or Glucocorticosteroid With Roflumilast in Human Peripheral Blood Mononuclear Cells. Pulm Pharmacol Ther. 2012;25(2):178-84. PubMed PMID: 22306235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells. AU - Tannheimer,Stacey L, AU - Sorensen,Eric A, AU - Haran,Aaron C, AU - Mansfield,Christopher N, AU - Wright,Clifford D, AU - Salmon,Michael, Y1 - 2012/01/28/ PY - 2011/07/29/received PY - 2011/12/22/revised PY - 2012/01/13/accepted PY - 2012/2/7/entrez PY - 2012/2/7/pubmed PY - 2012/7/24/medline SP - 178 EP - 84 JF - Pulmonary pharmacology & therapeutics JO - Pulm Pharmacol Ther VL - 25 IS - 2 N2 - 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. SN - 1522-9629 UR - https://www.unboundmedicine.com/medline/citation/22306235/Additive_anti_inflammatory_effects_of_beta_2_adrenoceptor_agonists_or_glucocorticosteroid_with_roflumilast_in_human_peripheral_blood_mononuclear_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1094-5539(12)00008-9 DB - PRIME DP - Unbound Medicine ER -