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)

Pulmonary arterial hypertension (PAH) is a rare condition characterised by elevated pulmonary arterial resistance leading to right heart failure. PAH can be sporadic (idiopathic PAH, or primary pulmonary hypertension), familial (caused by germline BMPR2 mutations, a type II member of the TGFbeta receptor superfamily), or related to other conditions including connective tissue disease, congenital heart disease, human immunodeficiency virus infection, portal hypertension, appetite suppressant exposure... Idiopathic PAH has a prevalence of 2 per million per year in France. The lack of specificity of PAH symptoms (mostly dyspnea) presumably lead to underdiagnosis of this condition. Echocardiography is the investigation of choice for non-invasive screening. Measurement of hemodynamic parameters during right-heart catheterism is mandatory to establish the diagnosis (mean pulmonary artery pressure >25 mmHg and pulmonary artery wedge pressure <12 mmHg). Acute pulmonary vasodilator testing should be performed with nitric oxide or prostacyclin during right-heart catheterization. Recent advances in the management of PAH including continuous intravenous prostacyclin infusion and endothelin receptor antagonists have improved markedly the patients' prognosis. Novel treatments such as inhaled iloprost and type 5 phosphodiesterase inhibitors have to be further evaluated in this setting. Lung transplantation is the last option for patients deteriorating despite medical treatment.
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PMID:[Pulmonary arterial hypertension]. 1504 92

Pulmonary hypertertension (PHT) is a rare disease defined by increased resistance of the pulmonary arteries inevitably leading to right heart failure if specific treatment is not given. This disease can occur sporadically (idiopathic or primary PHT), within a familial context (familial PHT, BMPR2 gene mutation), or occur as a complication of other diseases (connective tissue disease, congenital cardiomyopathy, human immunodeficiency virus infection, portal hypertension, use of anorexigenic agents). The incidence of primary PHT is 2 million cases per year, probably an underestimation due to the low specificity of clinical signs, predominantly exercise-induced dyspnea. Recent therapeutic advances (prostacyclin and endothelin receptor antagonists administered in continuous infusion) have improved the prognosis of this orphan disease. Inhaled iloprost and type 5 phosphodiesterase inhibitors should be evaluated for this indication. Lung transplantation is reserved for patients unresponsive to medical treatment.
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PMID:[Pulmonary hypertension: from genetics to treatments]. 1554 47

Systemic sclerosis (scleroderma) is considered as the most severe connective tissue disease. It is characterized by an abnormal immune activation, a vasculopathy and a fibrosis of the skin and of multiple internal organs. Numerous progress in the understanding of the pathogenesis with identification of key molecules have permit to introduce novel treatments that improve the management of some aspects of the disease. ACE inhibitors are effective in resolving renal crisis. Cyclophosphamide is useful for treatment of fibrosing alveolitis. Prostaglandins, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors permit to improve the treatment of the vascular complications (digital ulcerations, pulmonary arterial hypertension) of scleroderma.
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PMID:[Pathogenic mechanisms in systemic sclerosis and their therapeutical consequences. Part 2: treatment]. 1671 Nov 51

Vascular acrosyndromes constitute a common reason for physician visits. They are associated with connective tissue disease; for example, 90% of patients with scleroderma experience Raynaud's phenomenon. The rheumatologist must strive to establish the diagnosis, to identify a potential underlying cause, and to prescribe effective treatment when the symptoms are incapacitating. Raynaud's phenomenon is the acrosyndrome most commonly encountered by rheumatologists. The diagnosis of Raynaud's phenomenon rests on clinical grounds. Nailfold capillaroscopy and immunological tests are useful chiefly for determining the cause. Calcium-channel antagonists are the treatment of reference for Raynaud's phenomenon. Drugs introduced over the last few years for severe refractory forms include prostacyclin and its derivatives, endothelin receptor antagonists, and phosphodiesterase inhibitors. These drugs were developed as a result of new knowledge on the pathogenesis of Raynaud's phenomenon. Acrocyanosis, which is extremely common, and erythromelalgia are the other main vascular acrosyndromes.
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PMID:Raynaud's phenomenon. 1721 39

Raynaud's phenomenon is a common disorder with vasospasm of the digital arteries causing pallor with cyanosis and/or rubor. It can be primary (idiopathic), where it is not associated with other diseases, or secondary to several diseases or conditions, including connective tissue diseases, such as scleroderma and systemic lupus erythematosus. Raynaud's is often mild enough to not require treatment; however, with secondary Raynaud's there is not only vasospasm but also fixed blood vessel defects so the ischaemia can be more severe. Complications can include digital ulcers and could, rarely, lead to amputation. Treatment is often non-pharmacological including avoiding cold and smoking cessation. Calcium channel antagonists, such as nifedipine, are often considered when treatment is needed; however, adverse effects of these drugs can include hypotension, vasodilatation, peripheral oedema and headaches. Other treatments have been studied in randomised, controlled trials including classes of drugs, such as angiotensin II inhibitors, selective serotonin reuptake inhibitors, phosphodiesterase-5 inhibitors (e.g. sildenafil), nitrates (topical or oral; the latter can be limited by adverse effects, such as flushing, headache and hypotension), and for more serious Raynaud's or its complications prostacyclin agonists may be used. There are two large studies that demonstrate that endothelin receptor blockade with bosentan can reduce the number of new digital ulcers in scleroderma patients. However, it does not affect the healing period. Thus, Raynaud's is common and often requires non-pharmacological treatment. When secondary Raynaud's is suspected, such as Raynaud's with an older age at onset or other features of connective tissue disease, then an appropriate history, physical examination and laboratory tests may be indicated to reach an appropriate diagnosis. There have been advances in pharmacological treatment, but some of the treatments are limited by adverse effects.
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PMID:The diagnosis and treatment of Raynaud's phenomenon: a practical approach. 1735 12

Systemic sclerosis (SSc) is a severe fibrotic multiorgan connective tissue disease. Vascular abnormalities such as fingertip ulcers and Raynaud's syndrome as well as involvement of organs including the lungs, heart, kidney and the gastrointestinal tract are prominent features of the disease. There are currently no disease modifying drugs available that can modify the course of the disease. In this review we will discuss medications that have been found to be effective in improving specific organ involvement due to SSc. For the treatment of gastroesophageal reflux disease (GERD), proton pump inhibitors are effective agents. In the setting of clinically significant gastrointestinal dysmotility, metoclopramide, erythromycin and octreotide may be beneficial. Small bowel bacterial overgrowth should be treated with oral antibiotics. Angiotensin converting enzyme inhibitors are the first-line agents for acute renal crisis. A variety of treatment options are available for Raynaud's phenomenon and include calcium channel blockers, iloprost (i. v.), losartan, fluoxetine and sildenafil. Fingertip ulcers can be prevented by using the endothelin receptor antagonist bosentan. The therapeutic options for treatment of pulmonary hypertension associated with SSc include bosentan, sildenafil and various prostacyclin analogs (eg, epoprostenol, treprostinil, iloprost). Sitaxentan, ambrisentan and new phosphodiesterase-5 inhibitors could be new options for therapy as well. Therapeutic options for interstitial lung fibrosis include cyclophosphamide, however, clinical effects are mild to moderate. Methotrexate has been used to treat skin fibrosis and can be beneficial when arthritis is present.
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PMID:[Systemic sclerosis]. 1855 72

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

Red blood cell distribution width (RDW), a widely available biomarker, independently predicts adverse outcomes in left-sided heart failure. The relation between RDW and death in pulmonary hypertension (PH) is unknown. In a prospective study of 162 consecutive patients with PH, RDW was recorded during initial diagnostic right-sided cardiac catheterization, and patients were followed for 2.1 +/- 0.8 years to determine vital status. Demographic, clinical, laboratory, and hemodynamic variables were compared by tertile of RDW. Cox proportional-hazards models were used to determine whether RDW was independently associated with death, and the prognostic utility of RDW was compared to that of other laboratory predictors, including N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP). Of the 162 study patients, 78% were women, and 62% had pulmonary arterial hypertension. The mean age was 53 +/- 15 years, and most patients had severe PH (mean pulmonary artery pressure 48 +/- 13 mm Hg). The highest tertile of RDW predicted death (univariate hazard ratio 4.86, 95% confidence interval 1.37 to 17.29, p = 0.015; multivariate hazard ratio 2.4, 95% confidence interval 1.02 to 5.84, p = 0.045, after adjusting for age, gender, diabetes mellitus, connective tissue disease, diuretic use, phosphodiesterase inhibitor use, hemoglobin, mean corpuscular volume, and blood urea nitrogen [BUN]). Of the laboratory data, only RDW, BUN, and NT-pro-BNP were associated with death on univariate analysis. When RDW, BUN, and NT-pro-BNP were entered into a multivariate model, only RDW was still associated with death (p = 0.037 for RDW, p = 0.18 for BUN, and p = 0.39 for NT-pro-BNP). Adding NT-pro-BNP to RDW did not improve the prediction of mortality. In conclusion, RDW is independently associated with death in patients with PH and performs better as a prognostic indicator than NT-pro-BNP.
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PMID:Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. 1973 26

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO(2) at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice.
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PMID:Pulmonary veno-occlusive disease: recent progress and current challenges. 2045 32

Pulmonary hypertension is a heterogeneous hemodynamic and pathophysiological state that is observed in a number of clinical conditions, which have been divided into six diagnostic groups. Although the increase in pulmonary pressure observed in these clinical groups may be similar, underlying disease mechanisms, diagnostic methods, and prognostic and therapeutic consequences are completely different. Pulmonary arterial hypertension is associated with several rare conditions that have comparable clinical and hemodynamic characteristics and exhibit virtually identical anatomical and pathological alterations in the lung microcirculation. These conditions include idiopathic and familial forms of the disease and disease forms associated with connective tissue disease, congenital heart defects involving systemic-to-pulmonary arterial shunts, portal hypertension, and HIV infection. It has been shown that treatment with specific drugs (e.g. prostanoids, endothelin-receptor antagonists and phosphodiesterase type-5 inhibitors) is effective in these patients and that these drugs can also be administered in various combinations. An evidence-based treatment algorithm has been developed for these patients. In patients with pulmonary hypertension due to left heart disease or lung disease, treatment focuses on the underlying condition and there is no convincing evidence that agents approved for pulmonary arterial hypertension are effective. For patients with chronic thromboembolic pulmonary hypertension, the treatment of choice is pulmonary endarterectomy. However, drugs intended specifically for the treatment of pulmonary arterial hypertension may be considered in inoperable cases or after suboptimal surgery.
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PMID:Current therapeutic approaches to pulmonary arterial hypertension. 2051 28


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