Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Beta-adrenergic stimulants (Dobutamine and Dopamine) and recently introduced phosphodiesterase inhibitors (PDI) such as Amrinone, Milrinone, Enoximone and Piroximone are the principal inotropic agents for the treatment of acute cardiac failure. Most of the hemodynamic effects of these drugs are comparable, but peripheral vasodilatation is more marked with PDI. A potential advantage of the latter group is the lack of development tolerance, which occurs within 48 to 72 hours after beta-stimulants. On simultaneous administration, additive effects can be observed. Short term clinical results with PDI are good, especially in patients with postoperative cardiocirculatory failure, including cardiogenic shock. In contrast, long-term oral treatment with Amrinone, Milrinone and Enoximone in recent studies was disappointing. Efficacy was not superior to Digoxin, and unwanted side effects were frequent. Intermittent instead of continuous administration of positive inotropic agents should be evaluated in patients with severe congestive heart failure not responding to vasodilators and diuretics.
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PMID:[New positive inotropic drugs in acute and chronic heart failure]. 135 9

The hemodynamic effects of dobutamine, milrinone, and a combination of both drugs were compared intra-individually in 14 patients with severe heart failure (NYHA III: n = 9; NYHA IV: n = 5). Dobutamine (maximum dose: 9 micrograms/kg/min) and milrinone (0.5 micrograms/kg/min) each induced a comparable increase in stroke volume index (21 to 29 resp. 21 to 30 ml/m2; mean values; p less than 0.001) and reduction in pulmonary capillary wedge pressure (29 to 22 resp. 28 to 21 mm Hg; p less than 0.001), as well as in systemic (1846 to 1218 resp. 1858 to 1276 dyn s/cm5; p less than 0.001) and pulmonary vascular (301 to 195 resp. 293 to 216 dyn s/cm5; p less than 0.001) resistances. The heart rate rose significantly after dobutamine (92 to 107 min-1; p less than 0.05), but did not change after milrinone (94 to 95 min-1; ns). Neither drug had a significant effect on systemic arterial pressures. The combination of milrinone and dobutamine induced a further significant rise in stroke volume index (37 ml/m2; p less than 0.01) when compared to either drug alone. The combination also caused an additional fall in pulmonary capillary wedge pressure (14 mm Hg; p less than 0.01), as well as in systemic (799 dyn s/cm5; p less than 0.001) and pulmonary (133 dyn s/cm5; p less than 0.001) vascular resistances. When compared to dobutamine alone, the combined therapy did not significantly change the heart rate and systemic arterial pressures. The combined administration of a beta-adrenergic agonist and a phosphodiesterase inhibitor induces beneficial hemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Additive effects of milrinone and dobutamine in severe heart failure]. 162 7

To contrast the effect of increasing blood calcium concentrations on the cardiovascular actions of intravenous beta-adrenergic agonists and phosphodiesterase inhibitors, 46 patients recovering from aortocoronary bypass surgery received either dobutamine or amrinone both in the presence and absence of a calcium infusion. Cardiac output, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure, heart rate, and blood ionized calcium concentration were measured before and during infusions of dobutamine (2.5 and 5.0 micrograms/kg/min) and amrinone (0.75 mg/kg bolus + 10 micrograms/kg/min or 2.25 mg/kg bolus + 20 micrograms/kg/min). After the initial dobutamine infusion period, patients were randomly and blindly assigned to receive either a calcium or placebo infusion, and the dobutamine infusions were repeated. Because of the long duration of amrinone's actions, the amrinone maintenance infusion was continued while randomized, blinded infusion of either calcium or placebo was added. Dobutamine (5 micrograms/kg/min) increased cardiac output from 7.1 +/- 0.3 L/min to 9.1 +/- 0.4 L/min, and increased heart rate from 93 +/- 4 beats/min to 107 +/- 4 beats/min. Systemic vascular resistance decreased and stroke volume increased. Dobutamine had no significant effects on other hemodynamic values. Amrinone (2.25 mg/kg bolus + 20 micrograms/kg/min) increased cardiac output from 5.6 +/- 0.4 L/min to 6.9 +/- 0.5 L/min, and increased heart rate from 87 +/- 3 beats/min to 98 +/- 3 beats/min. Amrinone decreased mean arterial pressure, systemic vascular resistance, pulmonary artery occlusion pressure, central venous pressure, and pulmonary artery pressure. Calcium infusion increased arterial pressure (8 to 13 percent) but had no significant effects on any other hemodynamic parameters. Calcium reduced the increase in cardiac output produced by dobutamine by 30 percent, but it did not alter the cardiotonic actions of amrinone. Thus, calcium inhibits the cardiotonic actions of certain beta-adrenergic agonists, most likely by interfering with signal transduction through the beta-adrenergic receptor complex.
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PMID:Calcium inhibits the cardiac stimulating properties of dobutamine but not of amrinone. 172 65

A model of heart failure produced by rapid ventricular pacing in the conscious dog instrumented with a conductance catheter to monitor instantaneous left ventricular volume has been developed. This experimental model is capable of analysis of the left ventricular pressure-volume relationship on a beat-to-beat basis, and has been used to assess ventricular function serially in the progress of heart failure and effects of pharmacological intervention. In seven dogs the magnitude of cardiotonic effects were significantly attenuated after development of heart failure. These findings support the concept that in the failing heart there is subsensitivity to beta-adrenergic stimulation in proportion to the severity. The failing heart was characterized by incomplete left ventricular relaxation. Dobutamine improved left ventricular early relaxation but did not affect chamber distensibility. In contrast new phosphodiesterase inhibitor, E-1020, improved ventricular distensibility with less marked changes in active relaxation; improved left ventricular relaxation appeared to be mediated by increased systolic shortening with enhancement of internal restoring forces, and improved distensibility by accelerated function of sarcoplasmic reticulum through increased intracellular cyclic AMP.
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PMID:Mechanics of contraction and relaxation of the ventricle in experimental heart failure produced by rapid ventricular pacing in the conscious dog. 191 38

Forty patients developed low cardiac output states after surgery for mitral valve disease or with associated cardiac disease and were randomly allocated to two treatment groups, one group to receive Dobutamine (D) and the other Enoximone (E), a phosphodiesterase inhibitor. Haemodynamic assessment covered a 24 hour period but treatment was continued for as long as was necessary. An improvement was observed from the 15th minute of treatment. At the second hour, the cardiac index had increased by 55% in Group E and by 59% in Group D whilst the heart rate increased by only 12% in Group E compared to 30% in Group D. The right and left heart filling pressures decreased by 25 to 27% in the 2 groups. The systemic arterial resistances fell by 36 to 37% without any significant changes in systemic or pulmonary arterial pressures. No significant difference was demonstrated in the haemodynamic responses to Dobutamine and Enoximone in this study. The duration of treatment was significantly shorter in Group E than in Group D (59 +/- 22 hrs vs 86 +/- 49 hrs) as was the patient's stay in the intensive care unit (92 +/- 37 hrs vs 155 +/- 129 hrs). The duration of assisted ventilation was the same in the two groups. These results suggest that Enoximone is as effective as Dobutamine in the treatment of low cardiac output after mitral valve surgery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Comparison of the hemodynamic effects of dobutamine and enoximone in the treatment of low cardiac output after valvular surgery]. 214 36

Low cardiac output in acute heart failure can result in a functional impairment of organs, when tissue hypoxia occurs and cardiogenic shock develops. To restore cardiac output, various forms of therapy can be considered. Fluid replacement is sometimes beneficial in acute situations where oedema can reduce effective plasma volume. Vasodilators are often contra-indicated in shock, when arterial pressure is usually low. Inotropic therapy consists primarily of the administration of adrenergic agents. Dopamine and noradrenaline can be indicated in severe hypotension, to maintain coronary perfusion. Dobutamine is the catecholamine of choice to increase myocardial contractility. However, decreased responsiveness of the myocardial receptors to adrenergic stimulation rapidly becomes an important limitation. Phosphodiesterase inhibitors represent an interesting option to increase contractility, also by increasing cyclic AMP levels in the myocardium. In this respect, the combination of phosphodiesterase inhibitors with adrenergic agents is attractive. The additional vasodilatory properties of these agents can contribute to the increase in cardiac output with limited risk of further reduction in arterial pressure. In 13 patients with cardiogenic shock persisting despite the use of adrenergic agents, the addition of enoximone, 0.5 mg/kg, resulted in significant increases in cardiac index and stroke volume index and a significant decrease in pulmonary artery balloon occlusion pressure without consistent change in mean arterial pressure. In 8 patients, a second infusion of 0.5 g/kg amplified these effects. All but one of these patients survived the episode of cardiogenic shock, and 5 patients were discharged alive. In some cases, even lower doses of enoximone resulted in dramatic increases in cardiac output and oxygen transport in patients already treated with dobutamine with limited success.
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PMID:The role of enoximone in the treatment of cardiogenic shock. 217 30

The aim of inotropic therapy is to increase the force of myocardial fibre shortening by improving the availability of calcium to the contractile proteins. Digitalis remains the most widely used drug, but its positive inotropic effects are weak and the therapeutic index is low. Dobutamine is the most useful catecholamine because the most cardioselective and it induces the least increase in myocardial oxygen consumption. There are three groups of new inotropic agents: sympathomimetics: pirbuterol and prenalterol are effective in the short term but tolerance is usually observed within a few weeks. Salbutamol and terbutaline have only been assessed in acute studies, phosphodiesterase inhibitors (MDL 17043, MDL 19025) are powerful inotropic agents in the short and medium term. ARL 115 has mainly been studied by parenteral administration, Amrinone has a largely unknown mode of action, but is a very effective positive inotropic drug; its side-effects limit it as age. However, its derivative, milrinone, seems to be more inotropic and less toxic. The new inotropic drugs currently under assessment are active in the short term but their long-term efficacy and side-effects are still little known. The ideal inotropic agent remains to be discovered.
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PMID:[Positive inotropic agents. Generalities and classification]. 286 22

The drugs, new and old, useful in the treatment of acute cardiac failure, are reviewed in the light of its pathophysiological mechanisms and of the biochemical aspects of myocardial contraction. Two major classes of drugs are considered, those that stimulate cell membrane adenylcyclase, i.e. beta-agonists (dopamine, dobutamine and dopexamine) and alpha-agonists (glucagon, forskolin, calcium agonists) and those that inhibit the cellular phosphodiesterases, i.e. bipyridine derivatives (amrinone and milrinone) and imidazolone derivatives (fenoximone and piroximone). Virtually, all the inotropic agents act by increasing the entry of calcium into the cell by increasing the intracellular AMPc concentration. Dopamine has a dose-related triphasic activity. At low doses, stimulation of renal dopaminergic receptors increases renal blood flow, glomerular filtration rate and sodium clearance. At moderate doses, dopamine stimulates, for the most part, cardiac beta-adrenergic receptors. Higher doses stimulate alpha-1-adrenergic receptors, with an increase in systemic arterial and venous pressures. Dobutamine exerts a potent positive inotropic action, with little effect on vascular tone and less tachycardia than with other catecholamines, resulting in only a slight increase in myocardial oxygen consumption. The dopamine analogue, dopexamine, increases renal blood flow, myocardial contractility and produces peripheral vasodilation. The haemodynamic effects of phosphodiesterase inhibitors are similar to those of dobutamine, except that these drugs are vasodilators, their positive inotropic properties are weak and their haemodynamic effects persist for at least 8 h after a single dose in heart failure patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Use of new inotropic agents in the treatment of acute cardiac failure]. 289 79

The peak hemodynamic effect and hormonal response of the phosphodiesterase inhibitor enoximone (MDL 17,043) were compared with those of dobutamine in 10 patients with severe congestive heart failure. Both agents significantly (p less than 0.05) increased cardiac index, stroke volume index and heart rate. Enoximone tended to decrease mean systemic arterial and pulmonary artery wedge pressures (0.05 less than p less than 0.1), whereas dobutamine did not. Both agents decreased systemic vascular resistance (p less than 0.05). The increase in heart rate was greater with dobutamine than with enoximone (p less than 0.05). Plasma renin activity increased significantly with dobutamine (from 11.3 +/- 13.5 to 17.8 +/- 15.0 ng/ml/hour, p less than 0.01) and with enoximone (from 13.6 +/- 18.3 to 16.6 +/- 18.8 ng/ml/hour, 0.05 less than p less than 0.1). Dobutamine suppressed plasma norepinephrine level (p less than 0.05) and enoximone did not. Neither agent affected the plasma vasopressin level. These data demonstrate a similar acute hemodynamic and hormonal profile for both enoximone and dobutamine. Further, dobutamine, like other beta agonists, provokes renin secretion and may do so to a greater extent than enoximone.
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PMID:Comparative hemodynamic and hormonal response of enoximone and dobutamine in severe congestive heart failure. 294 27

Intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fibers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopamine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors. In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients. The primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythmias have been reported less commonly. However, clinically significant proarrhythmic effects associated with these agents appear to occur rarely, and, at conventional doses, intravenous inotropic agents are relatively safe with respect to proarrhythmic effects.
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PMID:Electrophysiologic and proarrhythmic effects of intravenous inotropic agents. 756 5


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