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

In recent years, the better understanding of the pathobiology and pathogenesis of pulmonary arterial hypertension (PAH) has led to the development of new drugs for its treatment. Epoprostenol, which was the first drug approved for PAH, has shown an improvement in the survival at 3 years in patients with primary pulmonary hypertension. Recently, the Food and Drug Administration has approved two new compounds, Bosentan (an oral, non-selective endothelin receptor blocker) and Treprostinil (a subcutaneous prostacyclin analog). At least three multicenter, international studies are currently in progress. These studies include the use of a diet supplement rich in arginine (nitric oxide precursor), the evaluation of an endothelin A-receptor blocker (Sitaxsentan), and the evaluation of Sildenafil (a 5-phosphodiesterase inhibitor). As long as research continues to scrutinize the pathogenesis of this disease, clues to possible new therapies are warranted.
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PMID:[What is new in the treatment of pulmonary artery hypertension?]. 1296 61

For some years drugs of several different classes have been available in Germany for the treatment of pulmonary arterial hypertension (PHT): prostanoids, endothelin-receptor antagonists and phosphodiesterase inhibitors. To-date all relevant studies have consistently shown improvement in the 6-minute walking test (Iloprost, Treprostinil, Bosentan, Sitaxentan, Ambrisentan, Sildenafil). Results have not been consistent when the end-point has been an improvement in New York Heart Association (NYHA) class III or in the time to clinical worsening. Despite the good safety data for all drugs approved in Germany in the treatment of PHT, there are some clinically relevant interactions and significant contraindications. The availability of several options demands a detailed knowledge of studies to optimize safety and success in the treatment of PHT. Placebo-control mortality studies are not available for ethical reasons for those drugs that have been approved in Germany. But cohort analyses using historical survival rates have demonstrated a impressive improvement in survival of patients with PHT. Although there has been great progress in the treatment of PHT, a cure of this grave disease is not yet possible.
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PMID:[Specific drugs for the treatment of pulmonary arterial hypertension - current status]. 1881 92

Patients with Eisenmenger syndrome form a small percentage of congenital heart disease patients. The rarity of this syndrome, combined with its complex pathophysiology, account for the insufficient understanding of the principles underlying its proper treatment. The main clinical symptoms are: cyanosis due to secondary erythrocytosis, resulting in increased blood viscosity, iron deficiency anemia (enhanced by unnecessary phlebotomies), blood clotting disturbances, heart failure and serious supraventricular and ventricular arrhythmias. Recent decades have seen developments in pulmonary hypertension pathophysiology which have led to the introduction of new groups of drugs: prostacycline analogs (Epoprostenol, Treprostinil, Beraprost, Illoprost), phosphodiesterase inhibitors (Sildenafil, Tadalafil), endothelin receptor antagonists (Bosentan, Sitaxantan, Ambrisentan) and nitric oxide. These drugs should be administered to patients in III-IV NYHA class. Despite successful early results, the therapeutic effect on patients with Eisenmenger syndrome has not been conclusively established. Our therapeutic efforts should be directed mainly towards preventing complications. As a rule, we should avoid agents with no established therapeutic efficacy and try to alleviate symptoms without any additional risk, so as not to disrupt the existing clinical balance.
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PMID:Therapeutic methods used in patients with Eisenmenger syndrome. 1995 85

Multiple conditions result in development of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is the subclassification of pulmonary hypertension, in which known or unknown underlying conditions lead to similar intrinsic alterations in the pulmonary vasculature. PAH is a progressive condition characterized by restricted blood flow through the pulmonary circulation leading to poor survival in the absence of effective therapy. Over the last two decades, new therapeutic agents have substantially improved the course and prognosis for PAH patients. Three available classes of drugs, ie, prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors provide multiple options for treatment of PAH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors are administered orally, whereas prostacyclin therapies are delivered by continuous intravenous or subcutaneous infusion, or as aerosols by nebulization. Because of the risks and inconveniences associated with administration, prostacyclins are typically reserved for patients with more advanced disease or progression despite oral therapy. Inhaled administration may be a safer and easier route for prostacyclin administration. Treprostinil is a prostacyclin analog that has been demonstrated to be effective when administered by continuous subcutaneous or intravenous infusion, and more recently by nebulization.
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PMID:Inhaled treprostinil and pulmonary arterial hypertension. 2119 32

Treprostinil, a stable prostacyclin analogue used in the treatment of pulmonary arterial hypertension, is in development as a sustained release oral tablet, treprostinil diolamine (United Therapeutics Corp, Research Triangle Park, NC). As combination therapy yields additional benefit in pulmonary arterial hypertension, treprostinil diolamine may be used with sildenafil, a phosphodiesterase-5 inhibitor. This study was designed to evaluate the presence of a pharmacokinetic drug interaction between treprostinil diolamine and sildenafil. Treprostinil is primarily metabolized by cytochrome (CYP) P450 2C8 with minor contribution from CYP2C9. Sildenafil is metabolized by CYP3A4 with minor contribution from CYP2C9. Eighteen healthy volunteers were randomized to receive 4.5 days each of (1) treprostinil diolamine alone, (2) sildenafil alone, and (3) combination treprostinil diolamine and sildenafil in an open-label, 3-period, 3-sequence crossover study. The geometric mean ratio (90% confidence intervals) for combination/agent alone of steady state area under the concentration-time curve and peak concentration (Cmax) were 0.972 (0.824-1.145) and 1.030 (0.900, 1.1-9), respectively, for treprostinil diolamine and were 0.881 (0.804-0.966) and 0.910 (0.876-0.946), respectively, for sildenafil. The results suggest lack of a metabolic interaction between treprostinil diolamine and sildenafil, as geometric mean ratio 90% confidence intervals were within 0.8-1.25. Combination therapy was well tolerated but had slightly higher rates of nausea, headache, and extremity pain than monotherapy.
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PMID:Lack of a pharmacokinetic interaction between treprostinil diolamine and sildenafil in healthy adult volunteers. 2342 88

Pulmonary arterial hypertension (PAH) remains a progressive disease without a cure, despite the development of several treatment options over the past several decades. Its management strategy consists of the endothelin receptor antagonists (ambrisentan, bosentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (epoprostenol, treprostinil, iloprost). Treprostinil, a stable prostacyclin analog, displays vasodilatory effects in the pulmonary vasculature, as well as antiplatelet aggregation properties. Clinical practice guidelines recommend oral endothelin receptor antagonist or phosphodiesterase inhibitor therapy in mild to moderate PAH. Epoprostenol is specifically suggested as first-line therapy in moderate to severe PAH patients (ie, World Health Organization/New York Heart Association functional class III-IV). However, treprostinil may be an alternative option in these severe PAH patients. The longer half-life and stability at room temperature with treprostinil may be associated with lower risk of pulmonary hemodynamic worsening as a result of abrupt infusion discontinuation and less frequent drug preparation. These characteristics make treprostinil an attractive alternative to continuous infusion of epoprostenol, due to convenience and patient safety. The purpose of this review is to evaluate the safety and efficacy of continuous infusion of treprostinil as well as the inhaled and oral routes of administration in PAH.
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PMID:Clinical utility of treprostinil in the treatment of pulmonary arterial hypertension: an evidence-based review. 2501 85

Pulmonary arterial hypertension (PAH) is a progressive condition that can lead to right ventricular failure and death. Treprostinil is a prostacyclin analogue that has proven clinical efficacy in patients with PAH. Difficulties in the administration of inhaled and parenteral prostacyclins led to the development of extended-release treprostinil diolamine for oral use. Limited data exist on the transition to oral treprostinil. The purpose of this case series is to describe the transition from subcutaneous or inhaled treprostinil to oral treprostinil in the outpatient setting. With the current availability of oral prostacyclins and prostacyclins analogues, most transitions to oral therapy are done in the hospital setting resulting in increased cost and risk of hospital-acquired infections. Four patients on background phosphodiesterase type 5 therapy with baseline World Health Organization functional class (WHO FC) II PAH were transitioned at home. Three of the 4 patients were safely transitioned as outpatients and maintained WHO FC II status at 10 and 12 months. The fourth patient had worsening right heart failure and was admitted within 2 months of the transition and started back on parenteral prostacyclin therapy. The 6-minute walk distance (6MWD) increased in patients transitioning from inhaled therapy and decreased in the patient transitioning from subcutaneous therapy. The most common adverse event was nausea.
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PMID:Transition From Subcutaneous or Inhaled Treprostinil to Oral Treprostinil at Home in Patients With Pulmonary Arterial Hypertension: A Retrospective Case Series. 2846 60