Phosphodiesterase 5 inhibitors for pulmonary hypertension.
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ABSTRACT:
SUBMITTER: Barnes H
PROVIDER: S-EPMC6354064 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension.
| S-EPMC6159440 | biostudies-literature
Project description:A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min-1·m-2 and pulmonary vascular resistance >400 dyn·s·cm-5 underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.
| S-EPMC5898946 | biostudies-literature
Project description:Chronic exposure to cold caused pulmonary arterial hypertension (cold-induced pulmonary hypertension [CIPH]) and increased phosphodiesterase-1C (PDE-1C) expression in pulmonary arteries (PAs) in rats. The purpose of this study is to investigate a hypothesis that inhibition of PDE-1 would decrease inflammatory infiltrates and superoxide production leading to attenuation of CIPH. Three groups of male rats were exposed to moderate cold (5±1°C) continuously, whereas 3 groups were maintained at room temperature (23.5±1°C, warm; 6 rats/group). After 8-week exposure to cold, 3 groups in each temperature condition received continuous intravenous infusion of 8-isobutyl-methylxanthine (8-IBMX) (PDE-1 inhibitor), apocynin (NADPH oxidase inhibitor) or vehicle, respectively, for 1 week. Cold exposure significantly increased right-ventricular systolic pressure compared with warm groups (33.8±3.2 versus 18.6±0.3 mm Hg), indicating that animals developed CIPH. Notably, treatment with 8-IBMX significantly attenuated the cold-induced increase in right ventricular pressure (23.5±1.8 mm Hg). Cold exposure also caused right-ventricular hypertrophy, whereas 8-IBMX reversed cold-induced right ventricular hypertrophy. Cold exposure increased PDE-1C protein expression, macrophage infiltration, NADPH oxidase activity, and superoxide production in PAs and resulted in PA remodeling. 8-IBMX abolished cold-induced upregulation of PDE-1C in PAs. Interestingly, inhibition of PDE-1 eliminated cold-induced macrophage infiltration, NADPH oxidase activation, and superoxide production in PAs and reversed PA remodeling. Inhibition of NADPH oxidase by apocynin abolished cold-induced superoxide production and attenuated CIPH and PA remodeling. In conclusion, inhibition of PDE-1 attenuated CIPH and reversed cold-induced PA remodeling by suppressing macrophage infiltration and superoxide production, suggesting that upregulation of PDE-1C expression may be involved in the pathogenesis of CIPH.
| S-EPMC4050371 | biostudies-literature
Project description: Not available
| S-EPMC6483682 | biostudies-literature
Project description: Not available
| S-EPMC7193764 | biostudies-literature
Project description:BackgroundAchieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients.ObjectiveTo Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH.MethodsWe carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response.ResultsTwo hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response.ConclusionMale sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.
| S-EPMC10503122 | biostudies-literature
Project description:Pulmonary Hypertension due to left heart disease is the most common type of Pulmonary Hypertension. Morbidity and mortality significantly increase once Pulmonary Hypertension is present. Treatment is aimed toward optimizing the underlying condition. Targeted therapy has been evaluated in small studies with mixed results. The goal of this systematic review is to identify the possible benefit and safety of Phosphodiesterase 5 inhibitors in Pulmonary Hypertension due to left heart disease with elevated pulmonary vascular resistance, diagnosed by right heart catheterization. Electronic searches using MEDLINE/PREMEDLINE, EMBASE, and The Cochrane Library were searched on 21 October 2018. Randomized clinical trials comparing Phosphodiesterase 5 inhibitors versus placebo in patients with proven Pulmonary Hypertension by right heart catheterization secondary to left heart disease (both heart failure with reduced ejection fraction and with preserved ejection fraction) and reported pulmonary vascular resistance were included. We identified 436 potentially relevant studies. After reviewing the titles and abstracts to exclude irrelevant articles, five randomized clinical trials were considered for the study. Sildenafil was well tolerated among all studies. Sildenafil was found to improve hemodynamics, exercise capacity, and quality of life in patients with elevated pulmonary vascular resistance. Phosphodiesterase 5 inhibitors therapy in patients with proven Pulmonary Hypertension due to left heart disease and elevated pulmonary vascular resistance by right heart catheterization may improve the quality of life, exercise capacity, and pulmonary hemodynamics. Further prospective randomized controlled studies are needed to confirm.
| S-EPMC7545768 | biostudies-literature
Project description:Purpose: One of the promising chemical groups for the development of new antihypertensive medicines, the action of which is associated with the inhibition of phosphodiesterase III (PDE3) activity, are phosphorylated oxazole derivatives (OVPs). This study aimed to prove experimentally the presence of the OVPs antihypertensive effect associated with decreasing of PDE activity and to justify its molecular mechanism. Methods: An experimental study of the effect of OVPs on phosphodiesterase activity was performed on Wistar rats. Determination of PDE activity was performed by fluorimetric method using umbelliferon in blood serum and organs. The docking method was used to investigate the potential molecular mechanisms of the antihypertensive action of OVPs with PDE3. Results: The introduction of OVP-1 50 mg/kg, as a leader compound, led to the restoration of PDE activity in the aorta, heart and serum of rats with hypertension to the values observed in the intact group. This may indicate the possibility of the development of vasodilating action of OVPs by the influence of the latter on the increase in cGMP synthesis due to inhibition of PDE activity. The calculated results of molecular docking of ligands OVPs to the active site of PDE3 showed that all test compounds have a common type of complexation due to phosphonate groups, piperidine rings, side and terminal phenyl and methylphenyl groups. Conclusion: The analysis of the obtained results both in vivo and in silico showed that phosphorylated oxazole derivatives represent a new platform for further studies as phosphodiesterase III inhibitors with antihypertensive activity.
| S-EPMC10278226 | biostudies-literature
Project description:Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
| S-EPMC10985131 | biostudies-literature
Project description:Background Pulmonary arterial hypertension (PAH) is a fatal disease characterized by pulmonary vascular remodeling and increased pulmonary artery pressure, leading to impaired lung oxygenation, right heart failure, and even death. Although great advances have been made in PAH-targeted medications for pediatric patients, the efficacy and safety of these treatments are controversial. Methods We retrieved relevant articles from electronic databases including PubMed, EMBASE, Web of Science, and Cochrane Library until 12 April 2022. To compare the effectiveness and safety of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 Inhibitors (PDE-5i), and prostaglandins (ProA) in the treatment of pediatric PAH, we investigated six hemodynamic parameters, four respiratory parameters, intensive care unit (ICU) stay duration, length of hospital stay, and two safety outcomes. Results A total of 27 randomized controlled trials (RCTs) were included in the meta-analysis with 1,574 pediatric participants. The duration of mechanical ventilation was shorter for patients using bosentan, sildenafil, and ProsA, compared with that for patients using the placebo. Bosentan helped to shorten more time for mechanical ventilation than ProsA did, while ProsA was more effective than sildenafil in this respect. As for the length of stay in the ICU, patients administered by ProsA or sildenafil needed shorter ICU stay, compared to those using the placebo, while ProsA was more effective for shortening ICU stay time. In light of safety outcomes, there was a statistically significant difference between the sildenafil and the placebo group. Sildenafil surpassed ProsA in reducing the incidence of pulmonary hypertension (PH) crisis. Conclusions ERAs were more effective than ProsA in shortening the duration of mechanical ventilation, while ProsA were better for shortening the duration of mechanical ventilation and ICU stay than PDE-5i. PDE-5i were found to generate more benefits in decreasing the occurrence of PH crisis, though further investigation is warranted. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=351505.
| S-EPMC9875131 | biostudies-literature