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)

Congestive heart failure may be produced by a variety of disorders, including dilated cardiomyopathy, hypertension, and ischemic heart disease. We have developed experimental models of these diseases, and found gene expressions of proinflammatory cytokines increased in the hearts of these animals. Various drugs for heart failure modulate the production of cytokines in experimental models of heart failure. Pimobendan, an inhibitor of phosphodiesterase III prolonged survival, attenuated inflammatory lesions, and decreased the production of cytokines and nitric oxide. Recent studies have shown that these inhibitory effects are due to inhibition of activation of NF-kappaB. In contrast, digitalis increased the production of cytokines and exacerbated myocarditis. Interleukin-10 prolonged survival, attenuated myocardial injury, and appears promising as a treatment of heart failure due to viral myocarditis. Endothelin-1 plays an important pathophysiological role in heart failure, and treatment with an endothelin antagonist had a cardioprotective effect in experimental models of heart failure.
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PMID:The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure. 1130 31

Pimobendan is an inotropic and vasodilating drug with phosphodiesterase (PDE) III-inhibiting and calcium-sensitizing effects. It may also have a bronchodilatory effect by inhibiting PDE III in airway smooth muscle. We tried a beta-blocker combined with low-dose pimobendan in 2 patients who had refractory heart failure of NYHA functional class III or IV with idiopathic dilated cardiomyopathy (DCM) and chronic obstructive pulmonary disease (COPD). Both of them had previously failed to tolerate beta-blocking drugs because of the exacerbation of bronchospasm. After pimobendan was administered at 1.25 to 2.5 mg daily, metoprolol could be successfully introduced from a low dose of 1.25 mg daily without decreasing the peak expiratory flow rate. Over the next 1 to 2 years, they have continued beta-blocker therapy. One is currently receiving 10 mg daily of bisoprolol and another is taking 15 mg daily of metoprolol, and both are in NYHA functional class II without worsening heart failure or COPD. The combination of beta-blocker with low-dose pimobendan may be helpful for patients with DCM and COPD, but further clinical investigation is required.
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PMID:Beta-blocker therapy combined with low-dose pimobendan in patients with idiopathic dilated cardiomyopathy and chronic obstructive pulmonary disease: report on two cases. 1237 5

For increasing myocardial contractility in patients with cardiac failure, catecholamines, phosphodiesterase-III (PDE) inhibitors, and calcium sensitizers are available. Improving myocardial performance with catecholamines and PDE inhibitors leads to increased intracellular calcium concentration as an unavoidable side effect. An increase in intracellular calcium can induce harmful arrhythmias and increases the energetic demands of the myocardium. Long-term trials with PDE inhibitors have raised concerns about the safety of positive inotropic treatment for cardiac failure. Calcium sensitizers are a new class of inotropic drugs. They improve myocardial performance by directly acting on contractile proteins without increasing intracellular calcium load. Thus, they avoid the undesired effects of an increased intracellular calcium load. Calcium sensitizers may enhance myocardial performance without increasing myocardial oxygen consumption and without provoking fatal arrhythmias. Two calcium sensitizers are available for the treatment of cardiac failure in men. Pimobendan is a drug with positive inotropic effects that additionally inhibits the production of proinflammatory cytokines. However, it exerts a significant inhibition of PDE at clinically relevant doses. Levosimendan is a calcium sensitizer with no major inhibition of PDE at clinically relevant doses. It opens ATP-dependent potassium channels and thus has vasodilating and cardioprotective effects. The most important studies of the long-term treatment of stable cardiac failure with pimobendan and on the short-term treatment of unstable cardiac failure with levosimendan are presented.
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PMID:The role of Ca++-sensitizers for the treatment of heart failure. 1450 45

Pimobendan, an oral inotropic drug with phosphodiesterase III-inhibitory activity, induces cAMP-dependent relaxation of vascular smooth muscle in the pulmonary artery, as well as in the systemic cardiovascular system. We report here a patient with severe primary pulmonary hypertension (PPH), who had developed right heart failure (New York Heart Association functional class IV) despite uptitrated intravenous epoprostenol, and who was treated with extremely low-dose (0.625-1.25 mg daily) pimobendan as an adjunct to prostacyclin therapy. The combination therapy of low-dose pimobendan, prostacyclin, intravenous epoprostenol and oral beraprost has been continued for over 2 years without occurrence of fatal arrhythmia, and her six-minute walk test has exceeded 400 m. We suggest that low-dose pimobendan may enhance the hemodynamic effect of prostacyclin in severe PPH.
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PMID:Low-dose systemic phosphodiesterase III inhibitor pimobendan combined with prostacyclin therapy in a patient with severe primary pulmonary hypertension. 1469 37

Inotropic agents are indispensable for the improvement of cardiac contractile dysfunction in acute or decompensated heart failure. Clinically available agents, including sympathomimetic amines (dopamine, dobutamine, noradrenaline) and selective phosphodiesterase-3 inhibitors (amrinone, milrinone, olprinone and enoximone) act via cAMP/protein kinase A (PKA)-mediated facilitation of intracellular Ca2+ mobilisation. Phosphodiesterase-3 inhibitors also have a vasodilatory action, which plays a role in improving haemodynamic parameters in certain patients, and are termed inodilators. The available inotropic agents suffer from risks of Ca2+ overload leading to arrhythmias, myocardial cell injury and ultimately, cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and cellular metabolism. Furthermore, they lose their effectiveness under pathophysiological conditions, such as acidosis, stunned myocardium and heart failure. Pimobendan and levosimendan (that act by a combination of an increase in Ca2+ sensitivity and phosphodiesterase-3 inhibition) appear to be more beneficial among existing agents. Novel Ca2+ sensitisers that are under basic research warrant clinical trials to replace available inotropic agents.
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PMID:Acute heart failure: inotropic agents and their clinical uses. 1705 76

Pimobendan, a calcium sensitizer and phosphodiesterase III inhibitor, has positive inotropic and vasodilatory properties. Its use in patients with naturally occurring congestive heart failure (CHF) has been studied in a number of blinded, randomized, multicenter clinical trials. It has been shown to improve quality of life, reduce heart insufficiency scores, and increase median survival times for patients with CHF due to dilated cardiomyopathy and myxomatous valvular disease. Although most studies have reported positive findings, some potential adverse effects have also been described. Studies are under way to further evaluate the effects of this novel positive inotrope and vasodilator in canine cardiac disease.
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PMID:Pimobendan and its use in treating canine congestive heart failure. 2210 50

Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacinginduced heart failure model.
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PMID:Comparative evaluation of calcium-sensitizing agents, pimobendan and SCH00013, on the myocardial function of canine pacing-induced model of heart failure. 2459 41

Pimobendan is a phosphodiesterase (PDE) inhibitor and calcium sensitizer with inotropic, lusitropic, and rasodilator properties used in the treatment of congestive heart failure. The mechanism of action is by inhibition of PDE III and V and by increasing intracellular calcium sensitivity in the cardiac myocardium. Pharmacokinetic and pharmacodynamic studies have been published in humans, dogs, and cats, but there are no studies in avian species. Pimobendan has been used in birds at the empirical dosage of 0.25 mg/kg q12h. To determine the pharmacokinetic parameters of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis), 3 pilot studies with 2 birds, each receiving 1, 3, and 10 mg/kg PO, provided the basis for the pivotal trials with 6 birds, each receiving 10 mg/kg PO using 2 different suspensions. Blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours after drug administration. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (HPLC/MS) by use of electrospray ionization. Because of the erratic and low concentrations of pimobendan, pharmacokinetic parameters were calculated using naive averaged analysis. Plasma concentrations after commercial pimobendan tablet suspension at 10 mg/kg reached a Cmax of 8.26 ng/mL at 3 hours with a terminal half-life of 2.1 hours, while concentrations after the bulk chemical suspension reached a Cmax of 1.28 ng/mL at 12 hours and had a terminal half-life of 2.3 hours. Further studies evaluating the effect of oral pimobendan in parrots are needed.
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PMID:Pharmacokinetics of single oral dose of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis). 2511 37

Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation. The purpose of this retrospective study was to evaluate the long-term survival of dogs with severe PH treated with SF and PB compared to SF alone. The use of PB in combination with SF did not result in a statistically significant increase in survival times in dogs with pulmonary hypertension secondary to chronic respiratory disease compared to SF alone.
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PMID:Retrospective evaluation of pimobendan and sildenafil therapy for severe pulmonary hypertension due to lung disease and hypoxia in 28 dogs (2007-2013). 2871 78


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