Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a beta-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT(1)) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT(1) antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of beta-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional beta -adrenoceptors, may give it additional benefits to selective beta(1)-adrenoceptor antagonists. Celiprolol and bucindolol are not the beta-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor alpha antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.
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PMID:Present and future pharmacotherapy for heart failure. 1208 91

The past decade has realized remarkable advances in the treatment of pulmonary arterial hypertension (PAH), a progressive and potentially fatal disease. A small proportion of patients will have a dramatic hemodynamic response to acute vasodilator testing performed at the time of right heart catheterization and may be candidates for calcium channel blocker therapy. The vast majority of patients with PAH will not benefit from calcium channel blockers and should be treated with one of the three US Food and Drug Administration-approved therapies for PAH; bosentan, treprostinil, or epoprostenol. Because of the ease of administration relative to other therapies, the majority of patients with functional class III symptoms should be treated with the oral nonselective endothelin antagonist bosentan. Randomized controlled trials with treprostinil have demonstrated improvements in exercise endurance and hemodynamics. Patients who are critically ill, with functional class IV symptoms, should be started on epoprostenol because it is the most rapidly effective therapy. Intravenous epoprostenol improves exercise endurance, quality of life, hemodynamics, and survival in PAH. Investigational therapies on the horizon include phosphodiesterase inhibitors, prostacyclin analogues with alternative delivery routes (eg, inhaled, oral), and selective endothelin A receptor antagonists. The future of PAH therapy will likely include combinations of these therapies based on the multiple mechanisms of action.
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PMID:Pulmonary Arterial Hypertension: New Management Options. 1549 62

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, exercise tolerance, functional class, haemodynamics, echocardiographic parameters and quality of life measures. Since the introduction of continuous intravenous prostacyclin, the treatment armamentarium 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. Selective endothelin-A receptor antagonists have shown promise in clinical trials and are likely to be added to the list of options. As the number of medications available for PAH continues to increase, treatment decisions regarding first-line therapy, combination treatments, and add-on strategies are becoming more complex. This article reviews the current treatments strategies for PAH and provides guidelines for its management.
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PMID:Current treatment strategies for pulmonary arterial hypertension. 1611 93

Pulmonary arterial hypertension (PAH) is a progressive disorder with a poor prognosis. It is characterized by sustained elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). It is defined hemodynamically by a mean PAP over 25 mm Hg, a pulmonary arterial wedge pressure of 15 mm Hg or less (which excludes left sided lesions), and a PVR of 3 or more Wood units (240 dyn.sec.cm-5). Patients are limited by exertional dyspnea, pre- or true syncope, chest pain, and edema/ascites when right heart failure supervenes. PAH afflicts predominantly young women and the diagnosis is often delayed. Three processes contribute to progressive arterial narrowing: vasoconstriction, vascular remodeling, and thrombosis in situ. The diagnosis of PAH must be confirmed and its etiology must be identified before appropriate therapy can be instituted. Right heart catheterization is necessary to establish the diagnosis, severity, and prognosis of PAH and to ascertain its etiology and to evaluate vasoreactivity, which guides therapy. Treatment of PAH includes vasodilators, supplemental O2, anticoagulation, diuretics, digoxin, intravenous inotropic therapy for decompensated right ventricular failure, and lung or combined heart-lung transplantation for those patients who continue to deteriorate with a poor quality of life despite pharmacologic therapy. Calcium channel blockers are beneficial in a small minority of patients. Prospective, controlled, randomized trials of approved vasodilator agents have enrolled a large proportion of women (70-85%). Agents such as the endothelin-1 receptor antagonist bosentan, the phosphodiesterase-5 inhibitor sildenafil, and the prostanoids have been shown to improve symptoms, exercise capacity, and, in most instances, delay clinical worsening. The clinical outcomes of patients with PAH have improved with the judicious use of contemporary therapies.
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PMID:Pulmonary arterial hypertension and women. 1705 80

Until in the early nineties, pulmonary arterial hypertension (PAH) was a uniformly fatal disease, with a median life expectancy of approximately 2.5 years. Uncontrolled studies showed that a small proportion of patients responded to high-dose calcium channel blockers, retrospective studies supported the use of anticoagulant therapy and heart-lung or lung transplantation remained the only option. In 1996, a 3-month randomised, placebo-controlled trial showed that chronic intravenous epoprostenol (synthetic prostacyclin) improved functional state, exercise capacity, haemodynamics, and even survival in patients with idiopathic PAH. Similar benefits were subsequently reported and extended to all PAH categories, and confirmed with more stable prostacyclin analogues administered subcutaneously (treprostinil), by inhalation (iloprost), or even orally (beraprost). In the early 2000s, two randomised controlled trials showed efficacy of the oral intake of the dual endothelin A/B receptor antagonist bosentan. Two selective endothelin-A receptor antagonists, sitaxsentan and ambrisentan, are being developed. Finally, a randomised controlled trial has established the therapeutic efficacy of phosphodiesterase-5 inhibition with sildenafil, introducing a third signalling pathway to be targeted by the pharmacological treatment of PAH. Another phosphodiesterase-5 inhibitor, tadalafil, is already being evaluated. While all these treatments have markedly improved the lives of PAH patients, they have not offered yet a cure of the disease. Multi-drug approaches are now under evaluation, with more ambitious therapeutic goals. Alternative approaches with stem cells, RhoA-Rho-kinase inhibitors, platelet derived growth factor inhibitors and vasoactive intestinal peptides are being considered.
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PMID:Expert opinion on available options treating pulmonary arterial hypertension. 1792 81

Systemic sclerosis (systemic scleroderma) is a chronic connective tissue disease of unknown etiology that causes widespread microvascular damage and excessive deposition of collagen in the skin and internal organs. Raynaud phenomenon and scleroderma (hardening of the skin) are hallmarks of the disease. The typical patient is a young or middle-age woman with a history of Raynaud phenomenon who presents with skin induration and internal organ dysfunction. Clinical evaluation and laboratory testing, along with pulmonary function testing, Doppler echocardiography, and high-resolution computed tomography of the chest, establish the diagnosis and detect visceral involvement. Patients with systemic sclerosis can be classified into two distinct clinical subsets with different patterns of skin and internal organ involvement, autoantibody production, and survival. Prognosis is determined by the degree of internal organ involvement. Although no disease-modifying therapy has been proven effective, complications of systemic sclerosis are treatable, and interventions for organ-specific manifestations have improved substantially. Medications (e.g., calcium channel blockers and angiotensin-II receptor blockers for Raynaud phenomenon, appropriate treatments for gastroesophageal reflux disease) and lifestyle modifications can help prevent complications, such as digital ulcers and Barrett esophagus. Endothelin-1 receptor blockers and phosphodiesterase-5 inhibitors improve pulmonary arterial hypertension. The risk of renal damage from scleroderma renal crisis can be lessened by early detection, prompt initiation of angiotensin-converting enzyme inhibitor therapy, and avoidance of high-dose corticosteroids. Optimal patient care includes an integrated, multidisciplinary approach to promptly and effectively recognize, evaluate, and manage complications and limit end-organ dysfunction.
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PMID:Systemic sclerosis/scleroderma: a treatable multisystem disease. 1895 73

Current knowledge about the pathogenesis of Raynaud's phenomenon (RP) results in novel approaches for therapy. Vasospasm without endothelial damage is thought to be the main cause for primary RP. The pathogenesis of secondary forms of RP is supposed to be initiated primary by endothelial damage. The aim of the review is to present main groups of medications as well as non-pharmacological regimen, that are used for the treatment of RP. The necessity of immediate assessment and treatment in severe forms of the disease with digital ulcers is highlighted. The mild forms of primary RP can be controlled by non-pharmacologic approaches. If the effect is insufficient, medications of first choice are calcium channel blockers. In the severe forms of the disorder, intravenous infusion of prostacyclin as well as endothelin-1 receptor antagonists and specific inhibitors of phosphodiesterase-5 are the treatment of choice. Treatment in the future may include selective blockers of alpha-2c adrenergic receptors, inhibitors of protein tyrosine kinase and Rho-kinase, as well as calcitonin gene-related peptide.
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PMID:New lines in therapy of Raynaud's phenomenon. 1903 2

Systemic sclerosis-related pulmonary arterial hypertension (PAH) is a severe disease affecting about 1000 patients in France. In 2008, all scleroderma patients are screened for PAH by a yearly cardiac Doppler ultrasonography. The pathogenesis of systemic sclerosis-related PAH is poorly known but it seems that besides common arteriolar remodeling (media hypertrophy, intimal thickening, endothelial proliferation), venular lesions suggesting obstructive venous disease and inflammatory lesions may be also be involved. Prostacyclin and analogues, phosphodiesterase-5 inhibitors (sildenafil) and endothelin-1 receptor antagonists are proposed as specific treatments for systemic sclerosis-related PAH. Unlike bosentan, which is non-selective, inhibiting both ETA and ETB receptors, sodium sitaxentan is highly selective for ETA receptors; this could favor pulmonary vasodilation.
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PMID:[Pulmonary arterial hypertension related to systemic sclerosis in 2008]. 1908 Dec 17

Pulmonary hypertension (PH) is an important complication in the natural history of chronic obstructive pulmonary disease (COPD). Its presence is associated with reduced survival and greater use of healthcare resources. The prevalence of PH is high in patients with advanced COPD, whereas in milder forms it might not be present at rest but may develop during exercise. In COPD, PH is usually of moderate severity and progresses slowly, without altering right ventricular function in the majority of patients. Nevertheless, a small subgroup of patients (1-3%) may present with out-of-proportion PH, that is, with pulmonary arterial pressure largely exceeding the severity of airway impairment. These patients depict a clinical picture similar to more severe forms of PH and have higher mortality rates. PH in COPD is caused by the remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating agents (nitric oxide, prostacyclin) and increased expression of growth factors. Products contained in cigarette smoke play a critical role in the initiation of pulmonary endothelial cell alterations. Recognition of PH can be difficult because symptoms due to PH are not easy to differentiate from the clinical picture of COPD. Suspicion of PH should be high if clinical deterioration is not matched by the decline in pulmonary function, and in the presence of profound hypoxaemia or markedly reduced carbon monoxide diffusing capacity. Patients with suspected PH should be evaluated by Doppler echocardiography and, if confirmed, undergo right-heart catheterization in those circumstances where the result of the procedure can determine clinical management. To date, long-term oxygen therapy is the treatment of choice in COPD patients with PH and hypoxaemia because it slows or reverses its progression. Conventional vasodilators are not recommended because of their potential detrimental effects on gas exchange, produced by the inhibition of hypoxic pulmonary vasoconstriction and their lack of effectiveness after long-term treatment. In the subgroup of patients with out-of-proportion PH, new specific therapy available for pulmonary arterial hypertension (PAH) [prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors] may be considered in the setting of clinical trials. The use of specific PAH therapy in COPD patients with moderate PH is discouraged because of the potential detrimental effect of some of these drugs on gas exchange and there are no data demonstrating their efficacy.
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PMID:Pulmonary hypertension in patients with chronic obstructive pulmonary disease: advances in pathophysiology and management. 1953 34

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


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