Disease relevance of Acardi

• Since the modulation of myocardial necrosis and contractile dysfunction by various proinflammatory cytokines may be partially mediated by the production of nitric oxide, the effects of pimobendan on the production ofproinflammatory cytokines and NO were investigated in an animal model of viral myocarditis involving heart failure [1].
• Calcium sensitization with pimobendan: pharmacology, haemodynamic improvement, and sudden death in patients with chronic congestive heart failure [2].
• Although Holter analysis at 14 days, but not at 6 months, indicated increased ventricular extrasystoles in pimobendan patients, these did not lead to serious clinical events [3].
• The finding that the mild tachycardia caused by pimobendan was not accompanied by an increase in MVO2 warrants investigation to evaluate its usefulness in the treatment of heart failure [4].
• A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy [5].

High impact information on Acardi

• Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group [6].
• Pimobendan has almost the same mechanoenergetic effects as dobutamine but slightly greater contractile economy and coronary vasodilation [7].
• We hypothesized that the effect of pimobendan (UD-CG 115 BS) to increase calcium sensitivity of contractile protein might result in less myocardial oxygen consumption (VO2) in comparison with dobutamine when they enhance ventricular contractility to the same extent [7].
• Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium [8].
• The purpose of this investigation was to determine whether a positive inotropic effect of the cAMP-phosphodiesterase (PDE) inhibitor pimobendan is observed in the failing human myocardium and to study whether other factors, such as an increase in the Ca2+ sensitivity of myofilaments, play a functional role in the increase in force of contraction [8].

Chemical compound and disease context of Acardi

• The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors [9].
• Correlations between the cardiovascular effects of pimobendan and plasma concentrations of the parent compound and of its major active metabolite, UD-CG 212 CL, in patients with congestive heart failure [10].
• Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs [11].
• 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 [12].
• Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs [13].

Biological context of Acardi

• Contractile force developed in the presence of 25 mM [K]o and 1 microM isoproterenol was increased further by addition of 50 microM pimobendan with no effect on the slow action potential [14].
• The stimulation of force and ATPase activity of the skinned heart muscle fibers could be accounted for by an effect of pimobendan on the affinity of the regulatory (low affinity, Ca2+-specific) binding sites of cardiac troponin C. Ca2+ binding to the "structural" high affinity sites of troponin C was slightly inhibited [14].
• Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis [1].
• In patients with chronic congestive heart failure, pimobendan produces a dose-dependent and prolonged decrease in pulmonary capillary wedge pressure and an increase in cardiac output [2].
• Systolic arterial blood pressure dropped from 126 +/- 20 mmHg to 111 +/- 14 mmHg (P less than 0.05) after the first enalapril tablet and from 123 +/- 16 mmHg to 112 +/- 13 mmHg (P less than 0.05) after the first pimobendan tablet [15].

Anatomical context of Acardi

• The results indicate that the positive inotropic actions of pimobendan, but not milrinone, may involve activation of the cardiac myofilaments by a direct effect involving an increased affinity of the regulatory site on troponin C for Ca2+ [14].
• Enantiomers of pimobendan and its demethylated metabolite in plasma and in red blood cells were measured [16].
• The novel insulinotropic mechanism of pimobendan: direct enhancement of the exocytotic process of insulin secretory granules by increased Ca2+ sensitivity in beta-cells [17].
• To examine the insulinotropic effect of pimobendan in pancreatic beta-cells, which have an intracellular signaling mechanism similar to that of cardiomyocytes, we measured insulin release from rat isolated islets of Langerhans [17].
• Different effects of aspirin, dipyridamole and UD-CG 115 on platelet activation in a model of vascular injury: studies with extracellular matrix covered with endothelial cells [18].

Associations of Acardi with other chemical compounds

• A combination of 10 microM dipyridamole with 2 microM pimobendan or UD CG 212 was markedly a more effective inhibitor of platelet aggregation than a high dose of either inhibitor alone [19].
• After oral administration of 1 mg/kg, compound 1, milrinone, and pimobendan were equipotent [20].
• Electrophysiological actions of the pimobendan metabolite, UD-CG 212 Cl, in guinea pig myocardium [21].
• Levosimendan and pimobendan reduced cerebral vascular resistance [22].
• The sites of action of three such compounds (pimobendan, sulmazole, isomazole) within the myofibril have been investigated [23].

Gene context of Acardi

• The contribution of CYP1A2 to pimobendan O-demethylation in human liver microsomes varied in the range of 18 to 76%, whereas CYP3A4 accounted for less than 10%, as calculated using the relative activity factor method [24].
• Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect [25].
• We conclude that CYP1A2 is one of the major enzymes responsible for the O-demethylation of pimobendan and CYP3A may make a minor contribution at clinically relevant concentrations of the drug [24].
• CONCLUSIONS: These findings suggest that the beneficial effects of pimobendan in viral myocarditis are partially mediated by the inhibition of both proinflammatory cytokine production and NO synthesis by iNOS [1].
• Interleukin-6 levels (7.1+/-0.8 vs. 9.2+/-1.9 pg/mg heart) were also lower in the mice treated with pimobendan [1].

Analytical, diagnostic and therapeutic context of Acardi

• There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01) [6].
• RESULTS: The survival of mice improved in a dose-dependent fashion such that a significant difference (p < 0.02) was found between the higher-dose pimobendan group (20 of 30 [66.7%]) and the control group (11 of 30 [36.7%]) [1].
• The pharmacodynamic effect of pimobendan was evaluated by echocardiography [16].
• After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h [26].
• The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers to measure ventricular pressures, and their effect on left ventricular dP/dt was compared with that of 1, pimobendan, and indolidan [27].

References