Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.

01 Mar 2008·European Respiratory JournalQ1 · MEDICINE

Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition

Q1 · MEDICINE

Article

Author: Grimminger, F. ; Dony, E. ; Lai, Y.-J. ; Schermuly, R. T. ; Pullamsetti, S. S. ; Schudt, C. ; Savai, R. ; Seeger, W. ; Ghofrani, H. A. ; Weissmann, N. ; Flockerzi, D. ; Dumitrascu, R.

Phosphodiesterase (PDE) inhibitors are currently under investigation for the therapy of pulmonary hypertension.The present study was designed to investigate chronic effects of oral pumafentrine, a mixed selective PDE-3/4 inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension in rats.Treatment with pumafentrine (10 mg·kg−1daily) from week 4 to 6 after a single injection of MCT (60 mg·kg−1) partially reversed pulmonary hypertension and right heart hypertrophy in rats. In addition, small pulmonary arterial muscularisation, media hypertrophy and decrease in lumen area were largely reversed. Inhibition of smooth muscle proliferation under pumafentrine was demonstratedin vivoas was a pro-apoptotic effect of pumafentrine on vascular cells. Moreover, pumafentrine dose-dependently increased cyclic adenosine monophosphate levels and inhibited proliferation of cultured pulmonary arterial smooth muscle cells.In conclusion, oral pumafentrine partially reverses monocrotaline-induced pulmonary hypertension, lung vascular remodelling and right heart hypertrophy in rats.

PLoS ONEQ3 · CROSS-FIELD

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

Q3 · CROSS-FIELD

ArticleOA

Author: Stefan Endres ; Hans-Anton Lehr ; Andreas Eigler ; Daniela S. Bundschuh ; Florian Rieder ; Britta Siegmund

OBJECTIVEThe 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.METHODSThe 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.RESULTSRoflumilast 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.CONCLUSIONSThese series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

100 Deals associated with Pumafentrine

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	US	ALTANA Pharma AG	-
Psoriasis	Phase 2	EU	-	-
Pulmonary Disease, Chronic Obstructive	Phase 2	EU	-	-
Pulmonary Disease, Chronic Obstructive	Phase 2	-	ALTANA AG	-
Asthma	Discovery	-	ALTANA AG	-

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