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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a novel positive inotropic agent, toborinone ((+/-)-1-[3,4-dimethoxy-benzylamino)-2-hydroxypropoxy]-2(1H)-quinolinone , CAS 128667-95-8, OPC-18790, on myocardial oxygen consumption were examined in pacing-induced heart failure dogs. Ten dogs were ventricularly paced at 260 beats/min for 10 days to induce heart failure. Five of them were controls and the remaining five were given toborinone. Dogs were anesthetized with halothane, and cardiac functions, hemodynamics and myocardial oxygen consumption were measured. The peak of the first derivative of left ventricular pressure (LV dP/dtmax), cardiac output (CO) and mean blood pressure (mBP) were significantly decreased, and left ventricular end-diastolic pressure (LVEDP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP) and mean pulmonary arterial pressure (mPAP) were also significantly increased after 10 days of rapid ventricular pacing. Toborinone (5 and 10 micrograms/kg/min) dose-dependently increased LV dP/dtmax, coronary blood flow (CBF) and CO and decreased LVEDP and systemic vascular resistance (SVR) without increasing myocardial oxygen consumption in the pacing-induced heart failure dogs. These results suggest that toborinone may be useful for the management of chronic and congestive heart failure.
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PMID:Effects of toborinone on myocardial oxygen consumption in pacing-induced heart failure dogs. 900 82

The effects of toborinone (OPC-18790) and milrinone on cardiac function and energetics were compared in microembolized guinea pig hearts. Male guinea pig hearts were perfused according to the Langendorff method and microembolization was induced by injecting microspheres. The hearts were then treated with toborinone (10 microM), milrinone (4 microM), and vehicle. Energy metabolism in hearts was assessed by 31-phosphorus magnetic resonance spectroscopy (31P-MRS). Microembolization produced a decrease in coronary perfusion flow (CPF), left ventricular developed pressure (LVP), and peak LVdP/dt by about 50% concomitantly with a decrease in creatine phosphate (PCr) and ATP and an increase in inorganic phosphate (Pi) and Pi/PCr ratio. Toborinone and milrinone increased peak LVdP/dt, an index of contractility, by 15 +/- 2% and 18 +/- 3%, respectively. Milrinone increased heart rate (HR) by 22 +/- 4% but toborinone did not change HR. Toborinone did not change PCr, ATP, Pi, Pi/PCr, and intracellular pH (pHi) compared with the vehicle. On the other hand, milrinone decreased PCr and increased Pi and Pi/PCr compared with toborinone or vehicle. These results suggest that the different effects between toborinone and milrinone on energy metabolism in microembolized hearts may be due to the difference of chronotropic action between these drugs. Thus toborinone, a positive inotropic agent without chronotropic action, may be effective in acute treatment of ischemic heart failure.
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PMID:Comparative study of toborinone (OPC-18790) and milrinone on energy metabolism in microembolized guinea pig hearts. 940 58

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.
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PMID:Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery. 1041 65

Toborinone (OPC-18790, Otsuka Pharmaceutical Co. Ltd, 2(1H) -quinolone,6-[3-[ [3,4-dimethoxyphenyl)methyl] amino]-2-hydroxy prop oxyl]-,(.+-.)-) is a novel iv. inotropic agent. Positive inotropic effects are produced by PDE inhibition with the resulting increase in cAMP and intracellular calcium levels. Unlike other inotropic agents that increase cAMP, there is an absence of positive chronotropic effects, which are attributed to prolongation of the action potential due to blockade of delayed rectifier currents. There is also marked venous and arterial vasodilating properties. The absence of heart rate increases results in decreased myocardial oxygen consumption compared with conventional inotropes. Studies in human heart failure patients have been consistent with previous work in animal studies, confirming the effects of toborinone as being positive inotropy (relatively weak), marked arterial and venous vasodilatation and absence of increase in myocardial oxygen consumption. Data regarding safety in larger clinical trials, particularly regarding arrhythmias, is at present unavailable. This information will determine whether this agent becomes an accepted iv. therapeutic option for congestive heart failure.
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PMID:Clinical overview of the novel inotropic agent toborinone. 1106 Jul 31

Toborinone is an inotropic agent with a moderate coronary vasodilatory action, but lacking direct chronotropic action, under development by Otsuka. A marketing application has been filed in Japan [269634], and it has entered phase III trials in the US for the treatment of cardiac failure [170668]. The effects of toborinone in 48 patients with moderate to severe CHF have been evaluated in a multicenter, double-blind study. Patients received either placebo or 1.25, 2.5, 5 or 10 microg/kg/min toborinone via a 6-h infusion. Based on efficacy criteria (25% increase in cardiac index and/or 25% decrease in pulmonary capillary wedge pressure), 25, 58, 92 and 100% of patients receiving 1.25, 2.5, 5 or 10 microg/kg/min toborinone, respectively, had a clinically significant improvement in hemodynamic status after 6 h of infusion, compared to only 17% of patients taking placebo [284078]. A phase I trial of toborinone in 20 healthy Japanese volunteers showed that the drug was well-tolerated. Another phase I trial in 10 patients with congestive heart failure showed that the drug improved ventricular performance without sympathomimetic stimulation of the myocardium [279819]. In anesthetized dogs, the cardiovascular effects of toborinone were unaffected by procainamide and lidocaine, suggesting that it can be used clinically with these antiarrhythmic agents for the treatment of heart failure [175267]. Toborinone did not aggravate adverse effects such as arrhythmias, and can be combined with ACE inhibitors, nitrates and diuretics for the treatment of heart failure [175268].
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PMID:Toborinone Otsuka Pharmaceutical Co Ltd. 1846 98