The effect duration of selective phosphodiesterase inhibitors in the guinea pig

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

“…The results described here establish a novel role for PDE4s in the Journal of Cell Science 117 (11) regulation of the actin cytoskeleton and, as a consequence, cell migration. These observations might contribute towards the understanding of PDE4 activity in immune cell migration during allergic airway diseases (Spina et al, 1998;Torphy et al, 1998;Giembycz, 2000). The results described here might also have impact on cancer therapy; deregulation of cell migration is pivotal to the invasive and metastatic properties of cancer cells, manipulation of PDE4 activity might provide a novel therapeutic cancer target.…”

“…For example, asthma is associated with the infiltration of eosinophils, whereas in chronic obstructive pulmonary disease (COPD) neutrophils are the major infiltrating cell type. 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).…”

“…PDE4 enzymes (reviewed in Conti et al, 2003;Houslay and Adams, 2003;Houslay et al, 1998) have recently attracted much interest, as PDE4 selective inhibitors, with rolipram being the archetypal example, appear to have both anti-inflammatory and antidepressant actions and are currently being developed as potential therapeutic agents for treating major diseases such as asthma, chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (Spina et al, 1998;Torphy et al, 1998;Giembycz, 2000). PDE4 inhibitors suppress the production of TNF-α, the generation of reactive oxide and the migration of eosinophils and neutrophils which characterise inflammatory lung disease (Spina et al, 1998;Torphy et al, 1998;Giembycz, 2000). In addition, the PDE4D gene has recently been associated with an increased susceptibility to ischemic stroke (Gretarsdottir et al, 2003).…”

The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

“…RPL554 and RPL565 both caused a concentration-and timedependent inhibition of contractile responses elicited by EFS. Of major importance was the finding that these compounds had a considerably longer duration of action against EFSinduced contractile responses than other PDE4 inhibitors (Spina et al, 1998), more reminiscent of the long-acting ␤ 2 - Fig. 8.…”

“…However, recent concerns regarding the safety of regular treatment with long-acting ␤-agonists (Martinez, 2005) and continued concerns about the safety of glucocorticosteroids provide a rational basis for the development of novel single molecular entities with both bronchodilator and anti-inflammatory activity. Among known PDE inhibitors, we have reported that trequinsin demonstrated a significantly longer duration of action against contraction of airway smooth muscle than a number of PDE4-selective inhibitors (Spina et al, 1998). In the present study, we describe the pharmacology of two novel long-acting trequinsin analogs, RPL554 and RPL565, in a variety of in vitro and in vivo assays of relevance to airway disease.…”