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Riociguat for treatment of pulmonary hypertension in COPD – a translational study


Alexandra Pichl, Natascha Sommer, Mariola Bednorz, Michael Seimetz, Stefan Hadzic, Stefan Kuhnert, Simone Kraut, Elsa T. Roxlau, Baktybek Kojonazarov, Jochen Wilhelm, Marija Gredic, Henning Gall, Khodr Tello, Manuel J. Richter, Oleg Pak, Aleksandar Petrovic, Matthias Hecker, Ralph T. Schermuly, Friedrich Grimminger, Werner Seeger, Hossein A. Ghofrani, Norbert Weissmann

European Respiratory Journal 2019; DOI: 10.1183/13993003.02445-2018

Abstract

Chronic obstructive pulmonary disease (COPD) which comprises the phenotypes of chronic bronchitis and emphysema is often associated with pulmonary hypertension (PH). However, currently no approved therapy exists for PH-COPD. Signalling of the nitric oxide/cyclic guanoside monophosphate (NO-cGMP) axis plays an important role in PH and COPD.

We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.

In mice with established PH and emphysema (after 8 months of cigarette smoke exposure) riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways, e.g.related to matrix metalloproteinases (MMPs). MMP activity was decreased in vivoby riociguat. In PH-COPD patients treated with riociguat (n=7) the pulmonary vascular resistance, airway resistance and circulating MMP levels decreased, while oxygenation at rest was not significantly changed.

Conclusions: Riociguat may be beneficial for treatment of PH-COPD. Further long-term prospective studies are necessary to investigate the tolerability, efficacy on functional parameters and the effect specifically on pulmonary emphysema in COPD patients.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Pichl has nothing to disclose.

Conflict of interest: Dr. Sommer has nothing to disclose.

Conflict of interest: Dr. Bednorz has nothing to disclose.

Conflict of interest: Dr. Seimetz has nothing to disclose.

Conflict of interest: Mr. Hadzic has nothing to disclose.

Conflict of interest: Dr. Kuhnert reports non-financial support from TEVA, personal fees from Chiesi, personal fees and non-financial support from GSK, personal fees and non-financial support from Novartis, personal fees from Berlin Chemie MENARINI, non-financial support from BAYER, non-financial support from ASTELLAS, personal fees from AstraZeneca, outside the submitted work; .

Conflict of interest: Dr. Kraut has nothing to disclose.

Conflict of interest: Dr. Roxlau has nothing to disclose.

Conflict of interest: Dr. Kojonazarov has nothing to disclose.

Conflict of interest: Dr. Wilhelm has nothing to disclose.

Conflict of interest: MSc Gredic has nothing to disclose.

Conflict of interest: Dr. Gall reports grants and personal fees from Actelion, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen Cilag, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and UnitedTherapeutics/OMT, outside the submitted work.

Conflict of interest: Dr. Tello has nothing to disclose.

Conflict of interest: Dr. Richter reports grants from United Therapeutics, grants and personal fees from Bayer, personal fees from Actelion, personal fees from Mundipharma, personal fees from Roche, personal fees from OMT, outside the submitted work; .

Conflict of interest: Dr. Pak has nothing to disclose.

Conflict of interest: Dr. Petrovic has nothing to disclose.

Conflict of interest: Dr. Hecker has nothing to disclose.

Conflict of interest: Dr. Schermuly has nothing to disclose.

Conflict of interest: Friedrich Grimminger

Conflict of interest: Dr. Seeger has received honoraria for consultant activities from Bayer, United Therapeutics, and Liquidia , outside the submitted work.

Conflict of interest: Dr. Ghofrani reports personal fees from Actelion, Bayer, GSK, Novartis, Pfizer, personal fees from Actelion, Bayer, GSK, MSD Merck Sharpe & Dohme, Novartis, Pfizer, personal fees from Actelion, Bayer, GSK, Novartis, Pfizer, personal fees from Actelion, Bayer, GSK, MSD Merck Sharpe & Dohme, Novartis, Pfizer, grants from Deutsche Forschungsgemeinschaft (DFG), outside the submitted work.

Conflict of interest: Dr. Weissmann has nothing to disclose.

sumber : https://erj.ersjournals.com/content/early/2019/03/27/13993003.02445-2018

 
 

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