A comparison of the inhibitory activity of PDE4 inhibitors on leukocyte PDE4 activity in vitro and eosinophil trafficking in vivo

Abstract

Phosphodiesterase (PDE) 4 inhibitors have been shown to inhibit eosinophil PDE4 activity in vitro and accumulation of eosinophils in experimental airways inflammation. However, direct effects on eosinophil trafficking have not been studied in detail and it is not known if activity in vitro translates into efficacy in vivo. In the present study, we compared the activity of five PDE4 inhibitors in vitro and against trafficking of 111In‐eosinophils in cutaneous inflammation in the guinea‐pig. The rank order of potency for inhibition of PDE4 activity in guinea‐pig eosinophil, neutrophil and macrophage, and human neutrophil lysates was RP73401>SB207499>CDP840>rolipram>LAS31025. On TNFα production by human PBMC, all inhibitors with the exception of rolipram showed potency similar to their effect on neutrophil lysates. In a brain cerebellum binding assay, the rank order of potency at displacing [3H]‐rolipram was RP73401>rolipram>SB207499>CDP840>LAS30125. Trafficking of 111In‐eosinophils to skin sites injected with PAF, ZAP or antigen in sensitized sites was inhibited by oral administration of all PDE4 inhibitors. The rank order of potency was RP73401=rolipram>LAS31025>SB207499>CDP840. With the exception was RP73401, which was the most potent compound in all assays, there was no clear relationship between activity of PDE4 inhibitors in vitro and capacity to inhibit eosinophil trafficking in vivo. Thus, we conclude that in vitro activity of PDE4 inhibitors does not predict in vivo efficacy in an experimental model of eosinophil trafficking. British Journal of Pharmacology (1999) 126, 1863–1871; doi:

Antidepressant-like effects of PDE4 inhibitors mediated by the high-affinity rolipram binding state (HARBS) of the phosphodiesterase-4 enzyme (PDE4) in rats

“…Piclamilast has been reported to be among the most potent PDE4 inhibitors in peripheral tissues in vitro and for displacing [ 3 H]-rolipram binding to brain cerebellar preparations (Cooper et al 1999). It also is 400-fold more potent than rolipram in terms of binding to the HARBS (Zhao et al 2003a).…”

Airway function and reactivity, leukocyte influx and nitric oxide after inoculation with parainfluenza-3 virus: effects of dexamethasone or rolipram

“…Elevated cAMP levels suppress inflammatory cell activation and the release of leukotrienes, PAF, TNFa, cytokines (IL-2, IL-4, IL-5 and IL-8) and eicosanoids [22]. Elevated cAMP through PDE4 inhibition by rolipram also explains the reduction in eosinophils in BALF since rolipram has been shown to inhibit eosinophil trafficking in vivo [39].…”

PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration

“…PDE4 inhibitors can attenuate neutrophil/eosinophil migration into the lung in models of these diseases (Spina et al, 1998;Torphy et al, 1998;Giembycz, 2000). In particular, it has been demonstrated that rolipram inhibits eosinophil chemotaxis in vitro (Alves et al, 1996;Tenor et al, 1996) and trafficking to sites of inflammation in vivo (Cooper et al, 1999). Rolipram also suppresses many aspects of neutrophil function including adhesion to endothelial cells (Derian et al, 1995).…”