Reproterol – A Monomolecular Combination of Orciprenaline and Theophylline: Novel Aspects of Its Mode of Action in Asthma

Abstract

Background and Objective: Reproterol is a monomolecular combination of orciprenaline and theophylline used as β-adrenergic agonist to induce bronchodilation in bronchial asthma. Since the mechanism of action of reproterol has not been investigated so far, its potential anti-inflammatory activity in asthma remains still unknown. Therefore, we have studied in vitro whether the theophylline component of the reproterol molecule might enhance the stimulatory effect of the β-adrenoceptor on cAMP production resulting in suppression of inflammatory mediator production. Methods: The effects of reproterol, orciprenaline and theophylline (10^–9–10^–5 M) on spontaneous cAMP (5 × 10⁴ cells/30 min)- and on LPS (10 μg/ml)-stimulated LTB₄ production (10⁵ cells/4 h) were determined in normal monocytes in vitro. Results: Production of cAMP (n = 9) was significantly augmented in a dose-dependent manner by orciprenaline (30 ± 8%) and theophylline (28 ± 10%), but mostly by reproterol (127 ± 8%) at 10^–5 M. Despite incubation with propranolol, significant stimulation of cAMP production was notable following reproterol therapy. Production of LTB₄ was significantly inhibited by reproterol (–48 ± 14%) and less by theophylline (–28 ± 10%), but was stimulated by orciprenaline (+20 ± 8%) at 10^–5 M. Conclusion: We conclude that reproterol exerts a strong stimulatory effect on monocyte cAMP production and a suppressive effect on LTB₄ production possibly due to a synergistic mode of action on adenylate cyclase activity and inhibition of phosphodiesterases. More clinical studies in bronchial asthma will be needed to determine whether these results may translate into clinically relevant effects.

Reproterol: Beta-2-Agonist, Theophylline,or Both?

“…Similar actions such as a reduction of eosinophils in the bronchial mucosa and a reduced infiltrate with CD4+ T lymphocytes have also been reported for cromoglycate [12]. Thus, while the results of Juergens et al [6]suggest that the action of the fixed combination of reproterol and cromoglycate might in fact have been mediated by the triple alliance of a β 2 -agonist, theophylline and cromoglycate, this finding also raises the question how to differentiate the possible anti-inflammatory actions of cromoglycate from those of the theophylline-like moiety of reproterol. As the authors correctly point out, further in vivo studies are needed to answer whether these findings bear any in vivo relevance.…”

“…In this issue of Respiration , Juergens et al [6]report an interesting observation about the mode of action of the aforementioned reproterol. Using classical pharmacological methods, they were able to demonstrate that reproterol increases the generation of cAMP in isolated peripheral blood monocytes in vitro more effectively than does orciprenaline.…”

Essential fatty acids and the brain: possible health implications

“…In fact LTB 4 has been identi®ed in in¯ammatory exudates in arthritis [142] and cystic ®brosis [71] and in the epidermis of patients with psoriasis [141]. Leukotrienes C 4 -D 4 -E 4 have also been identi®ed in several models of in¯ammation, in particular, hypersensitivity disorders such as asthma [61]. Therefore, those agents or dietary interventions capable of reducing the synthesis of LTB 4 will play an important role in reducing the inammatory components that accompany various pathological processes.…”

Inhibition of Proinflammatory Tumor Necrosis Factor-α-Induced Inducible Nitric-Oxide Synthase by Xanthine-Based 7-[2-[4-(2-Chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-Nitrobenzene)piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) in Rat Trachea: The Involvement of Soluble Guanylate Cyclase and Protein Kinase G

“…The role of PDE4 inhibition in anti-inflammation and on COX-2 expression has been described in non-TSMCs (Juergens et al, 1999;Jimenez et al, 2004). PDEIs suppressed IL-1-induced NO release and iNOS mRNA expression (Geng et al, 1998;Beshay and Prud'homme, 2001).…”