proven useful for preclinical testing of new compounds for the therapy of human IBD. Among the PDE isoforms PDE3 and PDE4 were identified as the predominant cAMP-hydrolyzing PDE in human inflammatory cells. SGI-7079 Elevation of intracellular cAMP by inhibition of PDE4 is associated with a broad anti-inflammatory activity in vitro, including suppression of TNFa and IFNc, and induction of IL- 10. A combined inhibition of PDE3 and PDE4 may result in overadditive effects on anti-inflammatory cellular functions. Early PDE4 inhibitors have successfully been tested in animal models of experimental arthritis, autoimmune encephalomyelitis, and respiratory inflammatory diseases, where PDE4 inhibitors resulted in reduced inflammatory cell infiltrates and expression of pro-inflammatory cytokines. In humans, however, the clinical use of early PDE4 inhibitors was limited by their tolerability profile. Roflumilast showed anti-inflammatory activity in animal models and in humans, was more potent than the early PDE4 inhibitors rolipram and cilomilast, but was well tolerated. By combining PDE3 and PDE4 inhibitors in vivo the benefits of over-additive effects may apply as described in vitro. Dual selective inhibitors of PDE3 and PDE4 have been studied in animal models of asthma or experimental pulmonary hypertension. Recent data from the literature suggest that inhibition of PDE4 might provide a novel approach in the therapy of IBD in humans. The PDE4 inhibitors rolipram, mesopram and tetomilast improved DSS-colitis in a preventive, therapeutic and chronic setting. Rolipram had a stronger anti-inflammatory activity compared to pentoxyphylline in the acute DSS-colitis model. In humans the oral once daily administration of tetomilast has been tested for mild to moderately active UC in a randomized controlled trial. While a post hoc analysis suggested efficacy of tetomilast in UC patients with high disease activity, the primary end point did not reach statistical significance. In our study, we focused the investigations of the selective PDE4 inhibitor roflumilast and the dual-selective PDE3/4 inhibitor pumafentrine on two VX-765 customer reviews endpoints. First, local effects at the sites of inflammation were examined. There, the clinical activity was determined with a semiquantitative scoring system that h
