Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we reported that amrinone increases isometric twitch force but relaxes K+-induced contracture in muscles from normal cat right ventricle. This study evaluated its effects on diseased cardiac tissue. Right-ventricular papillary muscles were obtained from cats with subacute right-ventricular failure (3-14 days after partial pulmonary-artery ligation) and studied in vitro during stimulation (0.5 Hz) and exposure to high-K+ Tyrode solution. Active isometric twitch force and rate of force development (dP/dt) were significantly lower in muscles from hearts with right-ventricular failure compared to control muscles. In addition, while time to peak force was not different, duration of the twitch was significantly longer. In contrast to its positive inotropic actions in control muscles, amrinone (5.3 X 10(-4) M) had no significant effects on twitch force and dP/dt in muscles from failed ventricles. Time to peak force was not changed by amrinone in either group, but unlike its action in control muscle, duration of the twitch was reduced in failed muscle. Amrinone reduced K+-contracture force similarly in both control and failed muscles. Isoproterenol (10(-6) M) significantly increased twitch force and dP/dt and reduced K+-contracture force in both muscle groups. Since amrinone appears to be a phosphodiesterase inhibitor, our data indicate that cyclic AMP (cAMP)-related relaxation processes, but not cAMP-related contractile processes, can be enhanced by phosphodiesterase inhibitors in experimental heart failure. Furthermore, amrinone's reduced positive inotropic effect in failed myocardium suggests that its improvement of ventricular function in patients reflects, in part, enhancement of relaxation.
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PMID:Enhanced relaxation and reduced positive inotropic effects of amrinone in ventricular muscle from cats with subacute heart failure. Implications for drug therapy. 298 64

The bipyridine derivative amrinone is a specific phosphodiesterase III blocking agent. In vitro and in vivo studies show a dose-dependent increase in myocardial contractility induced by amrinone. In patients with congestive heart failure, the inotropic and vasodilator effects of amrinone contribute to cardiac improvement. When amrinone is used, the increase in myocardial oxygen consumption due to increased contractility is offset by the reductions in preload and afterload. In hearts with very high wall tension, myocardial oxygen consumption may even decrease with amrinone. Amrinone therapy is not accompanied by significant increases in heart rate. Tachyphylaxis has not been observed. The elimination half-life ranges between 2.5 and 3.5 h. A large quantity of amrinone is excreted unchanged, and therefore in cases of renal impairment the possibility of cumulation exists. The main adverse reaction of amrinone is a reversible thrombocytopenia induced by a dose-dependent decrease in platelet survival time. Therefore, frequent platelet counts are necessary when amrinone is administered. Numerous studies in patients with chronic congestive heart failure confirmed the beneficial hemodynamic effects of amrinone. Experience in the treatment of acute perioperative heart failure with amrinone are still limited, but the present results are encouraging; an additive effect of amrinone to catecholamines seems especially promising in the therapy of severe postoperative low-cardia-output syndrome.
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PMID:[Amrinone (Wincoram)--a new positive inotropic and vasodilator agent]. 304 13

Isolated rabbit hearts were perfused normoxically or ischemically using the technique of Langendorff. The hearts were perfused with a modified Krebs-Henseleit solution, perturbated with 95% O2/5% CO2 or in case of ischemia with N2 which replaced the O2. The perfusion rate was 25 ml/min under normoxic and 2.5 ml/min under ischemic conditions. The oxygen pressure was about 65 kPa in the normoxic and about 6 kPa in the ischemic medium. Reperfusion of ischemic hearts was realized in some cases normoxically. During the ischemic perfusion and reperfusion LDH was released time depended into the perfusion medium and the aortic inflow pressure increased. The LDH release and the increase of the inflow pressure are strong correlated. Both parameters direct to ischemic myocardial lesions. Amrinone applied as bolus in the start period of ischemia or as an infusion during the ischemic and reperfusion time limited the release of LDH and the increase of the inflow pressure. The results were discussed as a direct protecting effect of amrinone against a myocardial ischemic lesion, which is in correspondence with the improving effects of amrinone on the ischemia caused heart failure of canines in vivo, shown by Campbell et al.
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PMID:The effect of amrinone on LDH release and perfusion pressure in isolated ischemic rabbit hearts. 322 85

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or 'refractory' despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation. Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma. Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pharmacokinetics and pharmacodynamics of newer inotropic agents. 330 72

Clinical trials with new inotropic, non-adrenergic agents with vasodilating properties have open new perspectives for the treatment of acute and chronic heart failure. If their mechanism of action is not exactly known, they are likely to increase C.AMP by phosphodiesterase inhibition. A clear distinction has to be made concerning short- and long-term administration of these drugs. Amrinone (A) has been administered to 10 patients with low postoperative cardiac output as unique inotropic therapy and to 34 patients in severe cardiogenic shock, despite optimal treatment. In the latter group, A was added to the preliminary drugs. In both groups of patients, hemodynamics improved significantly, except in 4 patients in group II, who died. Except in one case with thrombocytopenia and one with supraventricular dysrhythmias, no serious side-effects were noted. No long-term treatment has been carried out in our institution. The literature has widely reported that the new inotropic drugs used in class III and IV patients, are likely to increase patient's well-being and exercise capacity, but not life expectancy.
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PMID:New inotropic-vasodilating drugs in acute and chronic heart failure. 376 91

Amrinone is a new positive inotropic agent available in oral and intravenous preparations. Twelve patients with Stage III cardiac failure of ischaemic (6 cases), myocardial (5 cases) or valvular (1 case) origin, were treated with oral amrinone. The protocol included a complete clinical, radiological and biochemical work-up, an exercise stress test, cardiac catheterisation and echocardiography before entering the trial. The patients underwent clinical examination, stress testing and echocardiography at the 4th, 8th and 12th week of treatment with 300 mg daily of amrinone. Two patients had to be withdrawn from the trial because of thrombocytopaenia; one patient deteriorated and eventually died of pulmonary embolism. There was a marked improvement in the 8 patients who achieved the trial, with an average gain of 40 watts on exercise testing, a mean reduction of 16 mm Hg in diastolic pulmonary pressures, and an increase of 11 p. 100 in EF and velocity of circumferential fibre shortening. Four additional patients were given intravenous amrinone (1 cc/kg relayed with an infusion of 1 ng/kg/min). Ventricular end-diastolic pressures fell by 9 mm Hg and cardiac index rose by 1.02 1/min/m2. Tolerance was good with no arrhythmic complications or significant variations in mean arterial pressure or heart rate. Although certain reserves have to be made with regards of tolerance of oral amrinone, the drug would seem to be useful and effective in the intravenous form. Further studies are under way.
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PMID:[Effects of amrinone administered orally and by injection in heart failure]. 389 92

Hemodynamic effects of amrinone were studied in 2 groups of patients after open heart surgery. Group I consisted of 10 patients with moderate heart failure. In the absence of inotropic agents, their mean cardiac index (CI) was 2.02 +/- 0.41 liters/min/m2 and mean pulmonary capillary wedge pressure (PCWP) 19 +/- 3 mm Hg. Amrinone was administered 24 hours postoperatively by bolus injection (2 mg/kg) and by 12-hour infusions (20 micrograms/kg/min). Hemodynamic data and plasma concentrations were obtained 10 and 20 minutes after the bolus injection and at 1, 4, 8 and 12 hours during infusion. Significant beneficial changes were noted in CI, PCWP, right atrial pressure, systemic vascular resistance and pulmonary vascular resistance. Group II consisted of 5 patients in severe cardiogenic shock (mean CI 1.97 +/- 0.3 liters/min/m2, mean PCWP 28 +/- 8 mm Hg) despite adrenergic agonists in all patients and intraaortic counterpulsation in 2. After these measures, amrinone was given intravenously for 36 to 72 hours as additional inotropic support. Significant improvement was observed in CI, PCWP, right atrial pressure, systemic vascular resistance and pulmonary vascular resistance. Four patients in this group were discharged; 1 patient died after 5 days in acute renal failure and coma grade IV. No serious adverse effects of amrinone were observed in any group II patient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amrinone in the management of low cardiac output after open heart surgery. 402 58

Amrinone, a positive inotropic-vasodilator agent, was administered to anaesthetised dogs in an attempt to reverse heart failure induced by drugs possessing negative inotropic properties. Propranolol, a beta-adrenergic blocker; verapamil, a calcium slow-channel blocker procainamide, a type 1 antiarrhythmic agent; or sodium pentobarbital, a barbituate; administered as a bolus injection and/or infusion, produced a sustained depression in canine cardiac function. Cardiac depression was characterised by a greater than 40% reduction in cardiac contractile force (CF) and maximum left ventricular pressure development (LV dp/dtmax), a 30 to 50% reduction in cardiac output (CO) and concomitant increases in mean central venous or mean right atrial blood pressures (CVP, RAP, respectively). Amrinone, when administered intravenously as a bolus injection (1 or 3 mg X kg-1) plus an infusion (0.03 or 0.1 mg X kg-1 X min-1) reversed the depression in cardiac function by increasing CF, CO and LV dp/dtmax and decreasing preload CVP or RAP in all four drug-induced failure models. Due to the vasodilator properties of amrinone, afterload, total peripheral resistance (TPR), was reduced in verapamil and procainamide failures as well as in propranolol failure, the only model where TPR increases. In another model of heart failure, in which ouabain-induced arrhythmias preceded procainamide toxicity, amrinone was also an effective cardiotonic agent. Ouabain's inotropic effect was studied in propranolol-induced heart failure. Although an increase in LV dp/dtmax and a decrease in CVP were noted, ouabain (40 micrograms X kg-1 iv) increased TPR and had little effect on the depression in CF and CO. Drug-induced models of heart failure were useful pharmacological tools for evaluating the cardiotonic agent's ability to overcome severe cardiac depression. In propranolol-, verapamil-, procainamide-, and pentobarbital-induced cardiac toxicity, amrinone could be of therapeutic value.
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PMID:The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog. 404 15

It has been suggested that amrinone and AR-L57 enhance cardiac contractility either by inhibiting phosphodiesterase activity or altering Ca++ homeostasis. Because these novel agents are potentially useful in the management of heart failure, it was of interest to more clearly define their mechanism(s) of action. Amrinone and AR-L57 caused concentration-dependent increases in the contractile states of either perfused guinea-pig hearts or cultured rat cardiomyocytes. To determine whether these actions might result from an increase in sarcolemmal Ca++ movement, the effects of these agents on Ca++ accumulation were studied in a simple system, dog erythrocytes. Both agents promoted erythrocyte Ca++ accumulation in time and concentration-dependent manners, effects that resulted primarily from increased Ca++ entry. However, because these effects were not measurable at inotropic drug concentrations and were apparent only after a 30-min incubation, they did not provide an explanation for the inotropic effects of these agents. Amrinone and AR-L57 inhibited dog heart phosphodiesterase activity (isozyme III) with EC50 values of 23 and 420 microM, respectively; however, only the inotropic responses to amrinone were attenuated by the muscarinic agonist, carbachol, thereby implying a cAMP (cyclic AMP)-dependent mechanism. In cultured ventricular cells, concentrations of amrinone (2 X 10(-4) M) and AR-L57 (3 X 10(-5) M) that caused maximal inotropic responses were associated with the activation of glycogen phosphorylase, but neither drug significantly increased the activation state of cAMP-dependent protein kinase. To further probe the effects of these drugs on intracellular cAMP and Ca++ metabolism, their effects on protein phosphorylation were studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular basis for the cardiovascular activities of amrinone and AR-L57. 608 73

It has been reported recently that 5-amino-34,4'-bipyridine-6(1H)-one is a new positive inotropic agent that appears to offer significant advantages over the cardiac glycosides. The effects of this agent were studied in a modified heart-lung preparation which allows the measurement of coronary flow and oxygen consumption in addition to a controlled study of cardiac contractility. In two models of cardiac insufficiency the administration of 5 mg amrinone caused a marked increase in cardiac output and a considerable decrease in left atrial pressure with complete reversal of the failure. In addition, the drug produces a 78% increase in coronary flow. Amrinone produces in these preparations a proportionally larger increase in cardiac output than in oxygen consumption, thus this agent increases cardiac efficiency. These results suggest that this new compound could be very useful in the treatment of cardiac insufficiency in congestive heart failure.
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PMID:[Effects of amrinone, a new non-digitalic positive inotropic agent, on the efficiency and coronary circulation of the heart]. 651 40


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