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      Allopurinol in Patients with Pulmonary Hypertension Associated with Chronic Lung Disease

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          Abstract

          Background

          Oxidative stress (OS) has been implicated in the development of pulmonary hypertension (PH) and ventricular hypertrophy. Xanthine oxidase is a well-recognised source of reactive oxygen species, which lead to OS. The aim of this proof of concept study was to assess whether allopurinol (xanthine oxidase inhibitor) would reduce right ventricular mass (RVM) in patients with PH-associated chronic lung disease (PH-CLD).

          Methods

          We conducted a randomised, double-blind, parallel-group, placebo-controlled trial in patients with PH-CLD (93% COPD, 7% IPF) who were randomly assigned to receive allopurinol or placebo for 12 months. The primary outcome was the mean change in RVM, as assessed by cardiac magnetic resonance imaging (CMRI). Secondary outcomes included quality of life (QOL), spirometry and six-minute walk test (6MWT).

          Results

          Seventy-one patients were recruited: mean age 71 years, mean pulmonary arterial pressure 30 mm Hg, FEV 1 60% and resting SpO 2 96%. After 12 months, there was no significant difference in the change in RVM from baseline (allopurinol 1.85g vs placebo 0.97g with mean difference 0.88g, CI −4.77 to 3.01, p =0.7). There were also no significant changes in other cardiac parameters measured on MRI, in QOL, spirometry and 6MWT. Subgroup analysis showed that allopurinol significantly reduced RVM compared to placebo with -6.16g vs 0.75g and mean difference 6.92g (CI 1.14 to 12.69, p = 0.02) in COPD patients with more severe airflow limitation.

          Conclusion

          Allopurinol had no overall impact on patients with PH-CLD but had potential benefit in COPD patients with more severe airflow limitation.

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          Most cited references 30

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          Role of oxidative stress in cardiac hypertrophy and remodeling.

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            "Natural history" of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease.

            The prognostic value and the evolution of pulmonary hypertension (PH) in patients with markedly hypoxemic chronic obstructive pulmonary disease (COPD), treated or not with long-term oxygen therapy (LTOT), has been extensively investigated. However, little is known in patients with mildly or moderately hypoxemic COPD not requiring LTOT. Therefore, we assessed the evolution of pulmonary hemodynamics in 131 patients with stable COPD by performing two right heart catheterizations at a mean (+/- SD) time interval of 6.8 +/- 2.9 yr. At inclusion (T0), no patient had PH (i.e., the mean pulmonary artery pressure [Ppa] at rest was 30 mm Hg during a steady-state 40-W exercise. Group 2 patients compared with group 1 patients had a significantly higher resting Ppa (16 +/- 3 mm Hg versus 14 +/- 2 mm Hg, p = 0.001). At the second catheterization, 33 (25%) patients (9 of 55 in group 1, 24 of 76 in group 2, p = 0.048) showed a resting Ppa > 20 mm Hg, but PH was generally mild, ranging from 20 to 42.5 mm Hg. The mean Ppa at second evaluation was 16 +/- 5 mm Hg in group 1 and 19 +/- 7 mm Hg in group 2 (p = 0.01). The patients who developed resting PH at the second catheterization (T1) had higher resting and exercising Ppa (p = 0.001 and p = 0.002, respectively), and significantly lower resting and exercising Pa(O(2)) (p = 0.005 and p = 0.012, respectively) at T0. Logistic regression analysis showed that resting and exercising Ppa were independent predictors (at T0) for the subsequent development of PH (p = 0.029 and p = 0.027, respectively). The patients who developed resting PH (T1) had a significantly worsening of Pa(O(2)) (from 63.5 mm Hg at T0 to 60 mm Hg at T1, p = 0.047), whereas the Pa(O(2)) as a mean was stable in the remainder (69.5 mm Hg at T0 and T1). These results show the following. The progression of Ppa over time in patients with COPD with mild to moderate hypoxemia is rather slow, the average change for the group as a whole being of + 0.4 mm Hg/yr. Only about 25% of patients with COPD with mild to moderate hypoxemia and without resting PH at the onset will develop PH during a 6-yr follow-up. The patients with exercising PH at the onset have a significantly increased risk of developing PH over time. Only resting and exercising Ppa at the onset are independently related to the subsequent development of PH. However, in individual cases, the models of linear or logistic regression do not allow a pertinent prediction of the level of Ppa or the presence of PH at the second right heart catheterization.
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              Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study.

              Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH). This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist. Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks. Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index. When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008). Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                copd
                copd
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove
                1176-9106
                1178-2005
                25 August 2020
                2020
                : 15
                : 2015-2024
                Affiliations
                [1 ]Division of Molecular and Clinical Medicine, University of Dundee , Dundee DD1 9SY, UK
                [2 ]Department of Respiratory Medicine, Victoria Hospital, NHS Fife , Kirkcaldy KY2 5AH, UK
                [3 ]Scottish Centre for Respiratory Research, Medical Research Institute, University of Dundee , Dundee DD1 9SY, UK
                [4 ]Department of Radiology, University of Cambridge , Cambridge CB2 0QQ, UK
                [5 ]Imaging Science and Technology, University of Dundee , Dundee DD1 9SY, UK
                Author notes
                Correspondence: Brian J Lipworth Scottish Centre for Respiratory Research, Medical Research Institute, University of Dundee, Ninewells Hospital , DundeeDD1 9SY, United KingdomTel +44 1382 383188 Email b.j.lipworth@dundee.ac.uk
                Article
                260917
                10.2147/COPD.S260917
                7457596
                © 2020 Liu-Shiu-Cheong et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 2, Tables: 18, References: 35, Pages: 10
                Funding
                Funded by: the British Heart Foundation;
                The present study was funded by the British Heart Foundation (Grant no: PG/14/6/30592). They had no role in study design, data collection, analysis and interpretation; in the writing of the manuscript; nor in the decision to submit the manuscript for publication.
                Categories
                Original Research

                Respiratory medicine

                pulmonary hypertension, right ventricle, allopurinol, chronic lung disease

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