The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice

PLOS ONE, Dec 2019

Objective The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. Methods The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Results Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. Conclusions These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

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The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice

et al. (2013) The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/ 4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice. PLoS ONE 8(2): e56867. doi:10.1371/journal.pone.0056867 The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice Florian Rieder 0 Britta Siegmund 0 Daniela S. Bundschuh 0 Hans-Anton Lehr 0 Stefan Endres 0 Andreas Eigler 0 Stefan Bereswill, Charite-University Medicine Berlin, Germany 0 1 Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich , Munich, Germany , 2 Department of Internal Medicine I, University of Regensburg , Regensburg, Germany, 3 Medical Department I, Charite Universita tsmedizin , Campus Benjamin Franklin, Berlin, Germany , 4 Takeda Pharmaceuticals International GmbH, Zurich, Switzerland, 5 Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois , Lausanne , Switzerland Objective: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. Methods: The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrinetreated animals, splenocytes were analyzed for interferon-c (IFNc) production and CD69 expression. Results: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-a (TNFa) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFa production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNc compared to no treatment in vivo. Conclusions: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice. - Funding: This study was partly supported by Takeda Pharmaceuticals International GmbH (formerly Nycomed GmbH), the employer of Daniela S. Bundschuh. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: This study was partly supported by Takeda Pharmaceuticals International GmbH (formerly Nycomed GmbH), the employer of Daniela S. Bundschuh. Roflumilast and pumafentrine are products of Nycomed and were synthesized by the Department of Chemistry at the Nycomed GmbH, Konstanz, Germany, a member of the Takeda Group. There are no further patents, products in development or marketed products to declare. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. . These authors contributed equally to this work. Inflammatory bowel disease (IBD) is characterized by a disturbed balance of pro- and anti-inflammatory cytokines. Tumor necrosis factor-a (TNFa), which is elevated in the intestinal mucosa of both of its entities Crohns disease (CD) and ulcerative colitis (UC) [1] plays a crucial role in the pathogenesis of IBD [2], a fact further underlined by the efficacious treatment of patients with CD and UC with anti-TNFa antibodies [3,4,5]. However, repeated administration of infliximab results in the production of auto-antibodies and antibodies against double-stranded DNA [3,4]. In addition, patients treated with infliximab are at an increased risk of concomitant infectious complications secondary to the sustained immune suppression [6]. Among the agents known to inhibit pro-inflammatory cytokine production rather than to block its biological function are cyclic adenosine-39,59-monophosphate (cAMP)-elevating PDE inhibitors. A major PDE isoenzyme family in mononuclear inflammatory cells, the main source of TNFa production, is PDE4 [7]. The specific inhibition of PDE4 with rolipram is 500-fold more potent in suppressing TNFa synthesis in human mononuclear cells compared to pentoxifylline [8]. PDE4 inhibitors have shown efficacy in the treatment of several chronic inflammatory disorders, including experimental colitis [9,10,11]. Unfortunately, the clinical use of rolipram a (...truncated)


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Florian Rieder, Britta Siegmund, Daniela S. Bundschuh, Hans-Anton Lehr, Stefan Endres, Andreas Eigler. The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice, PLOS ONE, 2013, 2, DOI: 10.1371/journal.pone.0056867