Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary hypertension leading to right heart failure can be related to primary lung disease or hypoventilation. Idiopathic pulmonary hypertension is a progressive disease with poor prognosis. Therapy of idiopathic pulmonary hypertension includes: oxygen, calcium channel blockers, diuretics, anticoagulants, prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to chronic thrombotic or embolic disease should be treated with vasodilatators. The potent vasodilatators are: prostacyclin PGI2, prostacyclin analogue and endothelin receptor antagonists. For patients with idiopathic PAH classified as NYHA III (New York Heart Association) bosentan is recommended, whereas for patients classified as NYHA IV--epoprostenol. Combination therapy is an emerging therapeutic option in PAH. In BREATH-2 (Bosentan Randomised Trial of Endothelin Antagonist Therapy for PAH) study the efficacy and safety of combining bosentan and epoprostenol given orally was investigated. No significant difference was established between treatment groups in 6-minutes walking distance or NYHA functional class. However other study investigating the combination of bosentan and prostacyclin analogue showed clinical improvement. Additional bosentan therapy may also reduce the epoprostenol dose and therefore decrease its side-effects. Interventional procedures: atrial septostomy and lung transplantation are indicated in patients with advanced NYHA class III and IV symptoms and refractory to available medical treatment. However, currently no management potent enough to cure pulmonary arterial hypertension is available. The introduction of new class of drugs allowed for the improvement of quality of life and overall survival. The choice of drug depends on a variety of factors including accessibility, approval status and patient's preferences.
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PMID:[Treatment of pulmonary hypertension]. 1854 Jan 80

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Conventional treatment is based on non-specific drugs (warfarin, oxygen, diuretics). Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, functional class, exercise tolerance, haemodynamics, echocardiographic parameters and quality of life measures. Intravenous prostacyclin, was the first introduced drug for treatment of PAH and remains the first-line treatment for the most severe patients. Since then the list of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Novel drugs have also shown promise in experimental trials and are likely to be added to the list of options. This article reviews the current treatments strategies for PAH.
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PMID:Current pharmacological treatment of pulmonary arterial hypertension. 1869 Aug 74

Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO2 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l x min(-1) x m2 +/- 0.7 to 4.2 l x min x m2 +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.
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PMID:Intravenous tezosentan and vardenafil attenuate acute hypoxic pulmonary hypertension. 1880 Sep 59

Pulmonary arterial hypertension (PAH) is a devastating disease that is characterized by a high mortality. The pathogenesis of PAH is multifactorial. In addition to hereditary factors (e. g., BMPR2 mutations), numerous environmental factors may trigger the onset and progression of the disease. An imbalance between vasoconstrictive and vasodilative factors leads to vasoconstriction in the pulmonary circuit, resulting in an increase of pulmonary vascular resistance and pulmonary artery pressure. Alterations of several signaling pathways (i. e.; endothelin, nitric oxide and prostacyclin pathways) contribute to an increase of pulmonary vascular tone, and these pathways represent the targets of the current therapeutic interventions. However, PAH is increasingly recognized as a chronic proliferative disease particularly of the small pulmonary arteries, that is primarily characterized by morphological changes of the vascular wall ("vascular remodeling"). These changes are particularly induced by peptide growth factors such as platelet-derived growth factor (PDGF) that elicit their signals via activation of membrane-bound receptor tyrosine kinases (RTK). Accordingly, there is both experimental and clinical evidence for a therapeutic efficacy of tyrosine kinase inhibitors (TKI), which provide the basis for "reverse remodeling" strategies and indeed represent a promising novel approach for the treatment of PAH. Epidermal growth factor (EGF), soluble guanylate cyclase (sGC), and phosphodiesterase type 1 (PDE1) may represent additional future target molecules. PAH leads to progressive right heart failure which determines the outcome of PAH patients. The pathomechanisms of right heart failure should therefore also be considered for the development of novel therapeutic concepts.
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PMID:[Novel concepts in the pathobiology of pulmonary arterial hypertension]. 1881 87

Pulmonary arterial hypertension (PAH), previously known as primary pulmonary hypertension, is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. Recently dramatic advance in medical therapy including prostanoids, endothelin-receptor antagonists, phosphodiesterase 5 inhibitors, has occurred, and American College of Chest Physicians(ACCP) Evidence-Based Clinical Practice Guidelines have been proposed, followed by several guidelines for treatment of pulmonary hypertension in our country. Additionally several reports have provided utility of combination therapy. This article summarizes recent medical therapy for PAH including updated ACCP guidelines in 2007, further advance, and recommended therapeutic approach for PAH, available in our country.
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PMID:[Recommended guideline for the use of medical therapy in pulmonary hypertension]. 1905 32

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE-5). Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and haemodynamics in patients with symptomatic pulmonary arterial hypertension (PAH). There is however, no data describing the clinical consequences of sudden cessation of sildenafil treatment. In this series, 9 patients with NYHA Class II-IV PAH who were stable on 2 months of sildenafil monotherapy, had their sildenafil ceased to accommodate a 2-week washout period, required for enrollment in research involving an endothelin receptor antagonist. Six minute walk distance (SMWD) and clinical assessments were performed before cessation of sildenafil, and again 2 weeks later. Over the course of this 2-week washout period, 6 of the 9 patients reported increased breathlessness and fatigue, 1 of these was hospitalized with worsening right heart failure. The SMWD fell in 6 patients, with falls of greater than 100 m recorded in 4 patients. This was accompanied by a worsening of NYHA Class from 2.5 +/- 0.2 to 3.1 +/- 0.1 (mean +/- SEM, p = 0.01). These data indicate that sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. We recommend that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil.
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PMID:Clinical deterioration after sildenafil cessation in patients with pulmonary hypertension. 1918 60

Pulmonary hypertension is characterized by a progressive increase in pulmonary arterial pressure in association with dilatation and hypertrophy of the right ventricle, causing gradual reduction in ejection fraction. The increase in mean pulmonary arterial pressure may be passive, due to increased downstream pressure, hyperkinetic due to increased cardiac output, or due to increased pulmonary vascular resistance resulting from changes in the pulmonary vessels. In an advanced stage of pulmonary hypertension there may be right ventricular dilatation and hypertrophy, tricuspid regurgitation and septal deviation, with consequent effects on cardiac function. Clinical symptoms are not specific. Until recently, the treatment of pulmonary hypertension was limited to anticoagulation, supplementary oxygen and high-dose calcium channel blockers, in association with diuretics and digoxin where indicated. Recently approved treatments are nitric oxide, sildenafil--a phosphodiesterase-5 inhibitor, analogs of prostacyclin, and nonselective and selective endothelin receptor inhibitors. Surgery and anaesthesia pose a significant risk for patients with pulmonary hypertension. Right ventricular failure, persistent postoperative hypoxia and coronary ischaemia are among the potential postoperative complications.
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PMID:[Pulmonary hypertension]. 1951 79

Congenital heart disease can predispose individuals to pulmonary vascular remodeling as a result of the abnormality in pulmonary blood flow and pressure that accompanies the specific congenital defect being considered. Pulmonary arterial hypertension associated with congenital heart defects is an important determinant of functional capacity and survival, especially when the Eisenmenger's state of reversed shunt is present. The likelihood of right ventricular dysfunction and failure increases with the degree of pulmonary artery pressure. Thus, the aim of disease management in this patient population should be to prevent or improve right heart failure. Current therapies that modify the progression of pulmonary vascular disease-including endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids-should be considered carefully in patients with congenital heart disease-associated pulmonary hypertension. The risks and benefits of altering the balance of pulmonary vascular resistance to systemic vascular resistance must be weighed for each patient.
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PMID:Pulmonary hypertension complicating congenital heart disease. 1956 32

Treatment of pulmonary arterial hypertension (group 1 of clinical classification) has been recently characterized by important progresses, particularly in pharmacological therapy. Only until few years ago, patients with pulmonary arterial hypertension were treated with non-specific drugs, such as diuretics and digoxin for right heart failure and calcium-channel blockers in the minority of cases, responders to the acute vasoreactivity test. In addition, use of oral anticoagulant treatment was supported by uncontrolled studies. In the last 15 years (in particular in the last 8 years) different randomized controlled trials assessing the functional, clinical and hemodynamic efficacy of three classes of targeted drugs (prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) with pulmonary vascular dilating and antiproliferative effects have been performed. This information has allowed the proposal of an evidence-based treatment algorithm. Treatment starts with general measures (physical activity, fertility control, respiratory tract infection, etc.) and supportive therapy (anticoagulant therapy, diuretics, oxygen, digoxin). Patients who respond to the acute vasoreactivity test (10% of idiopathic form) are treated with high doses of calcium-channel blockers, non-responders with targeted therapies either on monotherapy or combination. Usually an oral active drug is initiated and a second compound of a different class is combined in case of non-satisfactory response to the first treatment. Combination therapy should be performed only in specialized centers with large experience on use of targeted therapies and their relevant side effects. In case of failure of medical therapy, possible options are balloon atrial septostomy and/or listing for lung or heart-lung transplantation. As available treatments do not constitute a cure for pulmonary arterial hypertension, further progresses are expected in the near future.
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PMID:[Pulmonary arterial hypertension. Part II: Medical and surgical treatment]. 1960 8

Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.
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PMID:Emerging therapies for the treatment of pulmonary hypertension. 2021 70


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