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Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Severe Pulmonary Hypertension

Hossein Ardeschir Ghofrani, MD; Ralph Wiedemann, MD; Frank Rose, MD; Horst Olschewski, MD; Ralph Theo Schermuly, PhD; Norbert Weissmann, PhD; Werner Seeger, MD; and Friedrich Grimminger, MD
[+] Article and Author Information

From University Hospital, Justus-Liebig-University, Giessen, Germany.


Acknowledgments: The authors thank Dr. R.L. Snipes for linguistic editing of the manuscript and George Afram for technical assistance.

Grant Support: By the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 547).

Requests for Single Reprints: Hossein Ardeschir Ghofrani, MD, Department of Internal Medicine, University Hospital, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany; e-mail, ardeschir.ghofrani@innere.med.uni-giessen.de.

Current Author Addresses: Drs. Ghofrani, Wiedemann, Rose, Olschewski, Schermuly, Weissmann, Seeger, and Grimminger: Department of Internal Medicine, University Hospital, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany.

Author Contributions: Conception and design: H.A. Ghofrani, R. Wiedemann, H. Olschewski, W. Seeger, F. Grimminger.

Analysis and interpretation of the data: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Drafting of the article: H.A. Ghofrani, H. Olschewski, W. Seeger, F. Grimminger.

Critical revision of the article for important intellectual content: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Final approval of the article: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Provision of study materials or patients: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, W. Seeger, F. Grimminger.

Statistical expertise: H.A. Ghofrani, H. Olschewski, N. Weissmann, W. Seeger,

Obtaining of funding: H.A. Ghofrani, W. Seeger, F. Grimminger.

Administrative, technical, or logistic support: H.A. Ghofrani, R. Wiedemann, F. Rose, H. Olschewski, R.T. Schermuly, N. Weissmann, W. Seeger, F. Grimminger.

Collection and assembly of data: H.A. Ghofrani, R. Wiedemann, F. Rose, R.T. Schermuly, W. Seeger, F. Grimminger.


Ann Intern Med. 2002;136(7):515-522. doi:10.7326/0003-4819-136-7-200204020-00008
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Lung tissue is a rich source of phosphodiesterases. Phosphodiesterase-3 and phosphodiesterase-4 by hydrolyzation assist in degradation of cyclic adenosine monophosphate, and phosphodiesterase-5 assists in decay of cyclic guanosine monophosphate. The actions of these phosphodiesterases limit the vasodilatory effects of adenylate cyclase stimuli (such as prostanoids) and guanylate cyclase stimuli (such as nitric oxide) (17). Cross-talk between the cyclic adenosine monophosphate and the cyclic guanosine monophosphate pathways has been demonstrated; inhibition of phosphodiesterase-3 by cyclic guanosine monophosphate is the most prominent example (9). Moreover, phosphodiesterases may be up-regulated in response to increased second messenger levels as a negative feedback loop (9).

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Figures

Grahic Jump Location
Figure 1.
Hemodynamic responses to vasodilators.PPPP

Bars show the maximum changes from preintervention baseline values; error bars represent CIs. Analysis of variance with the Scheffé post-test for intergroup comparison indicated significant differences ( < 0.001); plus signs bracketed by horizontal bars show these relationships. NO = nitric oxide; NS = not significant; PVR/SVR = ratio of pulmonary vascular resistance to systemic vascular resistance. * < 0.001, † < 0.05, ‡ < 0.01 for differences between pretreatment and post-treatment values.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Time to decrease in pulmonary vascular resistance in response to vasodilator challenge.NO

Data are presented as the mean; error bars indicate CIs. Arrows indicate administration of therapy. The bars at the left of each panel show the maximum reduction in pulmonary vascular resistance caused by initial nitric oxide ( ) inhalation. Pretreatment baseline values are set at 100%.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Area under the curve ( AUC ) of reduction in pulmonary vascular resistance ( PVR ) in response to therapy.P

To assess mean AUCs and CIs (indicated by the error bars), we calculated the integral of difference between preintervention baseline values until pulmonary vascular resistance again reached 95% of baseline values or 120 minutes had passed. Analysis of variance with the Scheffé post-test for intergroup comparison indicated significant differences ( < 0.001); plus signs bracketed by horizontal bars demonstrate these relationships.

Grahic Jump Location

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Summary for Patients

Sildenafil (Viagra) May Help Improve Control of Pulmonary Hypertension

The summary below is from the full report titled “Combination Therapy with Oral Sildenafil and Inhaled Iloprost for Severe Pulmonary Hypertension.” It is in the 2 April 2002 issue of Annals of Internal Medicine (volume 136, pages 515-522). The authors are HA Ghofrani, R Wiedemann, F Rose, H Olschewski, RT Schermuly, N Weissmann, W Seeger, and F Grimminger. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine.

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