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

Heart failure remains a major therapeutic problem with a poor prognosis despite therapy with digitalis, diuretics and vasodilator drugs. Because impaired myocardial contractility is a principal feature of persistent heart failure, the development of phosphodiesterase inhibitors, e.g. milrinone, has presented important therapeutic possibilities. Milrinone exerts both positive inotropic and vasodilator activity, and improves systemic haemodynamics by increasing left ventricular stroke volume and decreasing left ventricular filling pressure and systemic vascular resistance. In addition to improving systolic pump function, milrinone has also been shown to improve impaired diastolic relaxation of the failing heart. Importantly, treatment with milrinone does not significantly increase myocardial oxygen consumption. In moderate to severe heart failure (NYHA class III and IV), intravenous and oral milrinone have been shown not only to produce acute haemodynamic improvement but also to relieve the associated symptom of breathlessness, with improvement in quality-of-life indices. In placebo-controlled, double-blind studies oral milrinone has enhanced exercise tolerance and increased total body oxygen consumption in mild (class II), moderate and severe heart failure. There is no evidence of a substantial pro-arrhythmic effect or other significant non-cardiovascular side-effects associated with the use of milrinone. The possibility of improved survival, which is still the ultimate goal of therapy with phosphodiesterase inhibitors, remains to the studied. Similarly, the role of these agents in the management of mild heart failure, alone or in addition to therapy with diuretics and angiotensin-converting enzyme (ACE) inhibitors, warrants further evaluation.
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PMID:Therapeutic achievements of phosphodiesterase inhibitors and the future. 268 Apr 98

Atrial natriuretic peptide (ANP) induces potent diuretic/natriuretic, vasorelaxing and aldosterone inhibitory effects. Increased plasma levels in congestive heart failure (CHF) have been reported. The aim of this study was to investigate plasma immunoreactive ANP (ir-ANP) levels during acute treatment of CHF. Seven patients with CHF underwent cardiac catheterization. Ir-ANP plasma levels were followed up to two h after administration of an orally given phosphodiesterase inhibitor (Milrinone); a substance with positive inotropic and peripheral vasodilating properties. In all patients cardiac output increased and cardiac filling pressures decreased markedly. Initially high ir-ANP plasma levels decreased. Our patients did not have an increased blood volume. It is concluded that plasma ir-ANP levels in the pulmonary artery rapidly decrease when atrial pressure is reduced. These data suggest that atrial pressure is the major determinant for release of ir-ANP in man and that the ability to respond quickly to changes in cardiac filling pressures is maintained in patients with severe CHF. Plasma ir-ANP levels may also become useful as an index of the degree of heart failure and serve as a tool in monitoring response to drug therapy.
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PMID:Atrial natriuretic peptide during acute treatment of congestive heart failure. 296 29

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

The present study was designed to evaluate the regional vascular profile of milrinone in the setting of experimental heart failure. Utilizing the rat model of myocardial infarction and failure (average infarct size 28%), we measured cardiac output (CO), arterial pressure (MAP), LVEDP, heart rate and systemic vascular resistance, as well as regional blood flow (radioactive microspheres 15 +/- 5 microns) before and after milrinone i.v. (20 microns/kg bolus, 3 micrograms/kg/min infusion) in the conscious state (LVEDP 22 mm Hg versus 10 mm Hg in the sham-operated group, p less than 0.01). Similarly, central hemodynamics and regional blood flow were determined before and after dobutamine or captopril, administering equipotent doses. Milrinone reduced LVEDP more than dobutamine, both more than captopril; MAP was decreased by captopril only. Although all three drugs reduced SVR to a similar extent and increased CO, a quite different blood flow distribution occurred. Improvement in flow to skeletal muscle and splanchnic circulatory bed was exerted by milrinone only. Thus, milrinone attenuated the vasoconstriction in those circulations known to be impaired in heart failure. In contrast to captopril, the effects of milrinone on renal perfusion were modest. These results demonstrate the potent vasodilator activity of milrinone, which is independent of its direct-positive inotropic effects, being most prominent in the splanchnic, coronary and skeletal muscle circulation. The latter might have clinical relevance since improved muscular flow during exercise is likely to improve exercise capacity in heart failure after long-term treatment.
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PMID:[Central and regional vascular hemodynamics of milrinone in experimental heart failure: comparison with captopril and dobutamine]. 331 15

Milrinone is a new bipyridine inotrope that has shown promise in initial clinical testing when administered intravenously or orally. The present multicenter study was designed to evaluate the clinical effectiveness and safety of sustained (48 hour) intravenous infusions of different doses of milrinone, as would be used clinically, in a controlled fashion using invasive hemodynamic monitoring. Entry was limited to adult patients with chronic heart failure of functional class III or IV, with a cardiac index less than or equal to 2.5 liters/min per m2 or a pulmonary capillary wedge pressure greater than or equal to 15 mm Hg, or both. After stable baseline hemodynamic recordings were obtained, milrinone was given as loading (microgram/kg per 10 min) and maintenance infusions (microgram/kg per min) to 189 patients in one of four loading/maintenance dosage regimens: 37.5/0.375 (low dose, n = 26), 50/0.50 (intermediate dose, n = 95), 75/0.75 (high dose, n = 15) and 50/0.25 (lowest dose, n = 53). The lowest dose was shown to be ineffective for maintenance therapy. Effective individual patient responses were defined as greater than or equal to 20% increase in cardiac index or decrease in pulmonary capillary wedge pressure, or both. During early therapy (less than or equal to 3 hour), 99% of patients showed an effective maximal response, and 90% an effective mean response. An effective mean response was observed during days 1 and 2 in 80% of patients, with a positive dose-response trend (69% response, low dose; 80%, intermediate dose; 93%, high dose; day 1). Each loading regimen was effective, with maximal mean response occurring at 15 minutes. Cardiac index initially increased by an average of 24 to 42% for all patients in the three groups, whereas pulmonary capillary wedge pressure decreased by 24 to 33%. Initial decreases in systemic vascular resistance averaged 15 to 31%. Initial changes in heart rate (+4 to +13%) and mean arterial pressure (-2 to -13%) were modest. Significant mean hemodynamic responses were maintained over the 48 hours. Increases in cardiac index for days 1 and 2 averaged 38 and 39% for those completing constant low dose drug, 34 and 37% for intermediate dose and 73 and 44% for high dose. Decreases in pulmonary capillary wedge pressure for all patients averaged 18 to 32% on days 1 and 2, with little dose response. Heart rate changes were modest and variable, averaging -9 to 9%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Efficacy and safety of sustained (48 hour) intravenous infusions of milrinone in patients with severe congestive heart failure: a multicenter study. 354 37

A number of small and largely uncontrolled trials have studied the use of vasodilators and inotropic agents in patients with chronic heart failure over the last 15 years. These trials have been of short duration and primarily designed to answer questions about dosages, mechanisms, and toxicity, and therefore they have not been particularly useful in addressing the issue of survival. Despite this drawback, these small clinical trials have been important in providing data about drugs that might be used in large-scale controlled clinical trials designed to test the survival hypothesis--that specific therapy may prolong life in patients with congestive heart failure. Nitrates, hydralazine, and the converting-enzyme inhibitors have emerged as the vasodilators that are most promising in our quest to prolong survival in patients with chronic heart failure. Milrinone has been perhaps the most extensively studied inotropic-vasodilator drug, but there are no data so far to suggest that it may prolong survival. The principal questions that need to be addressed are: Do vasodilators that improve symptoms also improve survival? Which vasodilator drug regimen is most effective in prolonging survival? Should inotropic agents be considered for survival trials? What dose of vasodilator should be used? When in the natural course of the disease should therapy be initiated? Answers are now available to some of these questions, but large-scale clinical trials will be necessary to clarify all of the answers.
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PMID:Physiologic determinants of survival in congestive heart failure. The survival hypothesis: how small uncontrolled studies should influence the design of large-scale clinical trials. 356 19

The cardiac and coronary vasodilator effects of milrinone and amrinone were compared in isolated, blood-perfused papillary muscle and sinoatrial (SA) node and atrioventricular (AV) node preparations of dogs. Milrinone (0.3-100 nmol) and amrinone (0.01-3 mumol) were administered intra-arterially. Both drugs increased the force of contraction of paced and unpaced papillary muscles and the rate of automaticity of the latter; they increased sinus rate and accelerated AV nodal conduction. However, both drugs were not homogeneously effective on cardiac variables but affected them in the following order: The force of contraction of the ventricular muscle greater than SA nodal automaticity divided by AV nodal conduction greater than ventricular automaticity. In producing these cardiac effects, milrinone was 30-60 times more potent than amrinone. Both drugs increased (coronary) blood flow in all preparations. In this respect milrinone was about ten times more potent than amrinone. As a result, milrinone can be characterized as having almost equal cardiotonic and coronary vasodilatory effects, whereas amrinone is more coronary vasodilatory than cardiotonic. These differences in cardiovascular profile may contribute to their differential salutary mechanisms in the treatment of heart failure. Both drugs induced neither AV nodal tachycardia nor ventricular arrhythmia.
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PMID:Comparative study of cardiovascular profiles of milrinone and amrinone by use of isolated, blood-perfused dog heart preparations. 357 Nov 4

Recent studies suggest that, in the presence of heart failure, the capability of skeletal muscle to utilize delivered flow may be impaired due to maldistribution of blood flow within working muscle. Similarly, this mechanism could explain the failure of drugs to improve maximal oxygen consumption (VO2max) immediately. Accordingly, we assessed muscular blood flow distribution (ml/min/g, radioactive microspheres, 15 +/- 5 micron) among and within working muscle, VO2max, and arterial lactate in a rat preparation of myocardial infarction and heart failure (infarct size 36.0 +/- 3.3% of the left ventricle, n = 9), and in sham-operated animals (n = 11). Data were obtained at maximal treadmill exercise during alternate infusions of milrinone and saline. Total skeletal muscle blood flow during exercise was significantly lower in the infarction group (p less than .05 vs sham); reduced blood flow was primarily attributed to decreased flow to oxidative working muscle such as soleus and the red portion of gastrocnemius, whereas blood flow to glycolytic muscle portions (e.g., gastrocnemius white, vastus lateralis white) was similar in the infarction and sham-operated groups. Milrinone increased flow to the glycolytic working muscle portions in sham-operated animals (e.g., vastus lateralis white, 0.23 vs 0.29, p less than .05); by contrast, blood flow to the oxidative muscle fibers was increased in the infarction group (e.g., gastrocnemius red, 1.45 vs 1.87, p less than .05). Arterial lactate levels at similar workloads during exercise were higher in the infarction group (p less than .05). Neither lactate nor VO2max were significantly altered with milrinone in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blood flow distribution within skeletal muscle during exercise in the presence of chronic heart failure: effect of milrinone. 367 57

The cardiac drugs ouabain and milrinone are positive inotropic agents. Since ouabain has inhibitory effects on ion transport in the gastrointestinal tract associated with vasoconstriction and hypoxia, milrinone needed to be tested also. This report indicates that therapeutic levels of milrinone on either side of the isolated stomach wall of the guinea pig has no significant effects on active chloride ion transport or the electrical parameters of the tissue. To verify that milrinone was active in the heart at these same levels, contractility of the isolated heart of the guinea pig was measured. Milrinone significantly increased ventricular pressure and pressure development. Thus milrinone may be expected to exert its inotropic stimulation of the heart during heart failure without compromising gastrointestinal functions.
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PMID:Milrinone produces a positive inotropy but is not inhibitory to gastric ion transport. 374 31

This study examines the acute hemodynamic response to intravenous and oral milrinone in 12 patients with moderate to moderately severe heart failure. The patients received milrinone or placebo at random in an 8-week double-blind trial. Dosing level and schedule were determined by the hemodynamic results. Acute and chronic plasma samples for milrinone concentration were drawn from patients throughout the study. Milrinone was administered intravenously in successive doses of 25, 50, and 75 micrograms/kg. This resulted in a 16.5%, 12.5%, and 28.4% peak increase in cardiac index, with a concomitant 24%, 29%, and 38% decrease in pulmonary capillary wedge pressure. There were no significant relationships between any of the mean maximal hemodynamic values and milrinone plasma concentration. Six patients received milrinone and six patients received placebo; only five patients completed the blinded phase. There was no significant difference between the groups in exercise capacity, but the conditions of five of the six patients who received placebo deteriorated. In two of the patients who received milrinone the aerobic capacity improved greater than 2 cc/min/kg over baseline, and an additional two patients reported a marked subjective improvement. The results of this study indicate that oral milrinone in the management of patients with chronic cardiac failure would justify larger controlled studies.
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PMID:Milrinone in the treatment of chronic cardiac failure: a controlled trial. 390 73


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