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: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aortic regurgitation (AR) was induced in rabbits by aortic valve puncture. Two years later, echocardiography [two-dimensional (2-D) and M-mode; Doppler] was used to monitor acute left ventricular (LV) effects of milrinone. At that time, two of eight AR survivors had hindlimb edema and/or ascites. Baseline LV diameter and wall thickness of AR rabbits was 125-145% for that of sham-operated subjects; mean stroke volume and total LV output (TLVO) were approximately 2.5 x normal; regurgitant fraction was 0.57; and effective (forward) cardiac output (CO) was normal. Basal LV fractional shortening (FS) and mean circumferential fiber shortening velocity (Vcf) were not significantly depressed. Milrinone (10 micrograms/kg/min. i.v.) decreased mean LV stroke volume and TLVO by 25-33% (p less than 0.05). However, forward CO was maintained as regurgitant stroke volume fell an average of 52%. Milrinone significantly reduced aortic mean reverse/mean forward blood flow velocity ratio (-16%) and LV end-diastolic (ED) chamber diameter (-7%), consistent with reduced regurgitation. Mean Vcf was 39% greater than that seen after saline infusion (p less than 0.05). Thus, milrinone promoted Vcf and maintained forward CO in rabbits with chronic compensated AR while appreciably reducing LV regurgitation, chamber size, and total output. These beneficial effects may reflect vasodilating and positive inotropic activities confirmed in normal rabbits.
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PMID:Beneficial hemodynamic effects of milrinone in conscious rabbits with chronic aortic regurgitation. 247 82

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

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Milrinone. A preliminary review of its pharmacological properties and therapeutic use. 305 25

Milrinone and dobutamine are positive inotropic agents with beneficial hemodynamic effects in patients with congestive heart failure. This study was undertaken to compare the effects of intravenous milrinone and dobutamine in patients with stable New York Heart Association class III or IV congestive heart failure and to test the hypothesis that intravenous milrinone is at least as beneficial as dobutamine in this setting. Seventy-nine patients were randomized to either dobutamine therapy at incremental doses of 2.5, 5, 7.5, 10, 12.5 and 15 micrograms/kg/min, or milrinone as a bolus of 50 or 75 micrograms/kg followed by an infusion of 0.5 to 1.0 micrograms/kg/min. Both agents significantly increased heart rate, cardiac index and stroke volume index and decreased pulmonary artery wedge pressure and systemic vascular resistance compared with baseline levels (p less than 0.01). During sustained infusion for 48 hours, no difference in hemodynamic effects was observed between the 2 drugs. Ventricular tachycardia occurred in 5 patients (3 taking milrinone, 2 taking dobutamine); 1 patient taking milrinone had ventricular fibrillation. Milrinone and dobutamine elicited similar beneficial hemodynamic results with relatively few adverse effects.
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PMID:Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy. 359 89

Milrinone is a potent positive inotropic and vascular smooth muscle-relaxing agent in vitro, and therefore, it is not known to what extent each of these actions contributes to the drug's hemodynamic effects in patients with heart failure. In 11 patients with New York Heart Association class III or IV congestive heart failure, incremental intravenous doses of milrinone were administered to determine the dose-response relationships for heart rate, systemic vascular resistance, and inotropic state, the latter measured by peak positive left ventricular derivative of pressure with respect to time (dP/dt). To clarify further the role of a positive inotropic action, the relative effects of milrinone and nitroprusside on left ventricular stroke work and dP/dt were compared in each patient at doses matched to cause equivalent reductions in mean arterial pressure or systemic vascular resistance, indices of left ventricular afterload. Milrinone caused heart rate, stroke volume, and dP/dt to increase, and systemic vascular resistance to decrease in a concentration-related manner. At the two lowest milrinone doses resulting in serum concentrations of 63 +/- 4 and 156 +/- 5 ng/ml, respectively, milrinone caused significant increases in stroke volume and dP/dt, but no changes in systemic vascular resistance or heart rate. At the maximum milrinone dose administered (mean serum concentration, 427 +/- 11 ng/ml), heart rate increased from 92 +/- 4 to 99 +/- 4 bpm (P less than 0.01), mean aortic pressure fell from 82 +/- 3 to 71 +/- 3 mmHg (P less than 0.01), right atrial pressure fell from 15 +/- 2 to 7 +/- 1 mmHg (P less than 0.005), left ventricular end-diastolic pressure fell from 26 +/- 3 to 18 +/- 3 (P less than 0.005), stroke volume index increased from 20 +/- 2 to 30 +/- 2 ml/m2 (P less than 0.005), stroke work index increased from 14 +/- 2 to 21 +/- 2 g X m/m2 (P less than 0.01), and dP/dt increased from 858 +/- 54 to 1,130 +/- 108 mmHg/s (P less than 0.005). When compared with nitroprusside for a matched reduction in mean aortic pressure or systemic vascular resistance, milrinone caused a significantly greater increase in stroke work index at the same or lower left ventricular end-diastolic pressure. Milrinone caused a concentration-related increase in dP/dt (32% increase at maximum milrinone dose), whereas nitroprusside had no effect. These data in patients with severe heart failure indicate that in addition to a vasodilating effect, milrinone exerts a concentration-related positive inotropic action that contributes significantly to the drug's overall hemodynamic effects. The positive inotropic action occurs at drug levels that do not exert significant chronotropic or vasodilator effects.
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PMID:Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. 397 22

Milrinone, a new bipyridine compound related to amrinone, is a potent non-adrenergic inotrope in experimental preparations and also shows vasodilator activity. In the present study the haemodynamic and metabolic effects of milrinone were evaluated in 12 patients with congestive heart failure. Milrinone 5 mg given orally produced a sharp reduction in left ventricular end diastolic pressure without significantly affecting stroke volume. The improvement in left ventricular function was due to a combination of vasodilation and positive inotropism. Thus small reductions in blood pressure and systemic vascular resistance were associated with increments in the isovolumic indices of left ventricular function. The relation between left ventricular end systolic pressure and dimension was displaced leftwards and downwards. Only reductions in left ventricular cavity dimension were statistically significant, however. Though myocardial oxygen consumption did not change significantly, it tended to increase whereas lactate consumption tended to decrease. This trend towards oxygen imbalance suggests the need for caution in the use of milrinone in patients with severe coronary artery disease.
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PMID:Milrinone in heart failure. Acute effects on left ventricular systolic function and myocardial metabolism. 401 14

Glucagon has been reported to be one of the most effective treatments for severe beta-blocker poisoning. Recently, amrinone was suggested as an alternative therapeutic choice for beta-blocker poisoning. Milrinone, a derivative of amrinone, acts independently of beta-adrenoceptors and increases cyclic AMP. Therefore milrinone may also be effective in the treatment of beta-blocker poisoning. In the present study, we compared the effect of glucagon and milrinone in treating severe beta-blocker poisoning. Following the administration of 10 mg/kg propranolol i.v. over 10 min, heart rate, cardiac output, mean arterial pressure, stroke volume, and end tidal CO2 were depressed, while central venous pressure, and pulmonary capillary wedge pressure increased significantly (p < 0.05). Following the administration of saline (Group S, N = 3), glucagon 20 micrograms/kg (Group G, N = 5), and milrinone 300 micrograms/kg (Group M, N = 5), hemodynamic parameters were observed for 30 min. In group M, mean arterial pressure, cardiac output and stroke volume recovered to their baseline values, while central venous pressure and pulmonary capillary wedge pressure decreased. Although there were no significant differences between groups G and M, the heart rate, central venous pressure and pulmonary capillary wedge pressure, mean arterial pressure and stroke volume did not return to baseline values in group G. Milrinone administration produced a significant hemodynamic improvement without increasing the heart rate in the canine model of severe heart failure caused by propranolol. In the glucagon treatment group, central venous pressure and pulmonary capillary wedge pressure improved less than the milrinone group. Although more data are needed before a clinical recommendation, milrinone might be an effective drug to treat beta-blocker poisoning.
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PMID:Milrinone versus glucagon: comparative hemodynamic effects in canine propranolol poisoning. 800 35

To evaluate the inotropic efficacy of phosphodiesterase inhibition in hearts with and without ischemic injury, 27 sheep were evaluated sonomicrometrically during incremental volume loading on right heart bypass. Contractility was assessed with the preload recruitable stroke work relationship. Active relaxation rate was estimated using the time constant of isovolumic pressure decay (tau). For nonischemic assessment, groups 1 and 2 (n = 6 each) underwent 45 minutes of vented perfusion after which milrinone was administered to group 1; group 2 served as nonischemic controls. There was no detectable increase in preload recruitable stroke work or decrement in tau after milrinone administration. Groups 3 and 4 underwent 15 minutes of 37 degrees C ischemia (aortic cross-clamping) followed by 30 minutes of vented reperfusion. Milrinone was then administered to group 3 (n = 7); group 4 (n = 8) served as ischemically injured controls. Inotropic and lusitropic effects were present (group 3 preload recruitable stroke work: 35.4 +/- 5.8 mJ.beat-1.100 g-1.mL-1 before milrinone to 49.5 +/- 4.4 mJ.beat-1.100 g-1.mL-1 after milrinone [p < 0.05]; group 3 tau: 51.8 +/- 5.5 ms before milrinone to 32.2 +/- 2.5 ms after milrinone [p < 0.02]). Although milrinone restored contractility and increased the rate of active relaxation in the postischemic hearts, there was no detectable inotropic effect in nonischemic hearts. In this model, milrinone augments contractility and relaxation in postischemic myocardium but offers little inotropic benefit in non-ischemically injured hearts.
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PMID:Ischemia-dependent efficacy of phosphodiesterase inhibition. 814 19

ACh exerted a biphasic effect in the in vitro working heart of Rana esculenta. High concentrations (10(-7) M) of ACh depressed stroke volume (SV) and stroke work (SW) by approximately 30% with a shorter systolic phase and reduced peak pressure. Doses from 10(-10) M induced a positive response peaking at 10(-8) M (SV: +8.6%; SW: +6. 5%) and a prolonged systolic phase without affecting peak pressure. Atropine and pirenzepine blocked both the positive and the negative effects of ACh. Pretreatment with Triton X-100 (0.1 ml, 0.05%) or with nitric oxide (NO)-cGMP pathway antagonists (NG-nitro-L-arginine, NG-nitro-L-arginine methyl ester, NG-monomethyl-L-arginine, and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one) abolished the positive and negative cholinergic effects. Infusion of 8-bromoguanosine 3', 5'-cyclic monophosphate reverted the positive effect of ACh to a negative effect. Milrinone blocked the positive inotropism but did not change the negative cholinergic response. The NO donor 3-morpholinosydnonimine generated a biphasic dose-response curve with a maximum positive effect at 10(-8) M (SV: +8%; SW: +5.6%; systolic phase: +28 ms) and a negative effect at 5 x 10(-8) M (SV and SW: about -12%; systolic phase: -70 ms; peak pressure: -1.50 mm). We conclude that in the avascular frog heart the endocardial endothelium mediates the inotropic effect of luminal cholinergic stimuli via a NO-cGMP pathway.
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PMID:Endocardial endothelium mediates luminal ACh-NO signaling in isolated frog heart. 995 Aug 65

A randomized, open-label, parallel-group design was used to determine the percentage of patients achieving improvements in predetermined baseline hemodynamic end points (>20% to 30% increase in cardiac index depending on baseline values and >25% decrease in pulmonary capillary wedge pressure), assessed at hour 0 (end of initial dose titration) and 1, 2, 4, 8, and 24 hours after the infusion of milrinone or nitroglycerin. In total, 125 patients (60 milrinone, 65 nitroglycerin) enrolled in this study, and 119 (58 milrinone, 61 nitroglycerin) were evaluable for the efficacy analysis. A significantly greater proportion of milrinone-treated patients reached (45% v 14%, P =.005) and maintained (24% v 6%, P =.026) hemodynamic goals than did nitroglycerin-treated patients; the time to achieve hemodynamic goals was significantly less in milrinone-treated patients (33 +/- 2 v 54 +/- 10 minutes, P <.001). Milrinone was also significantly more effective in decreasing systemic vascular resistance (P =.004), increasing stroke volume (P =.008), and improving global clinical status. Inodilator therapy with milrinone seems more efficacious in attaining sustained hemodynamic improvement than does pure intravenous vasodilator therapy with nitroglycerin in treating patients with decompensated heart failure.
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PMID:A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure. 1142 Jul 62


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