Inhibitors of PDE3 and PDE4 have been studied in animal mode

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 NBI-34060 structure 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 endpoints. First, local effects at the sites of inflammation were examined. There, the clinical activity was determined with a semiquantitative scoring system that has been described as a reliable marker of pathologic changes during the disease course. Roflumilast dose-dependently alleviated the clinical course of colitis. Pumafentrine improved the clinical score at the dose of 5 mg/kg/d. Comparable results were seen in the shortening of the colon as a morphometric surrogate for the degree of inflammation. TNFa is a key GSK137647A cytokine in human IBD. The local TNFa expression was measured ex vivo as described previously. Roflumilast and pumafentrine both significantly reduced the synthesis of TNFa in the colon. However this suppression was stronger in the pumafentrine versus roflumilast treated animals. These observations may further support that TNFa is only one example for cytokines being involved in this experimental model of colitis, amongst other inflammatory mediators possibly modulated by the PDE inhibitor. Further studies should address this hypothesis, by testing the involvement of additional cytokines in this model. Surprisingly, no significant change on the histologic score was observed with both substances. This was not in concordance with previous reports, which showed a close relation between crypt lesions and clinical activity. This coul