Milrinone

Milrinone is a selective inhibitor of phosphodiesterase 3 (PDE-3) with a IC50 value of 56±12nM [1]

Milrinone has been noted to inhibit both members of the PDE3 family, PDE3A, which is prominent in heart, vascular smooth muscle, and platelets, as well as PDE3B, which is prominent in fat, liver, and pancreatic islets. Milrinone has shown the effect of concentration-dependent inhibition of PDE3 on the photolabelling with a IC50 value of 56±12nM. In addition, Milrinone has been reported to increase the accumulation of [3H]cAMP with a EC50 value of 5329±970nM in platelets. Apart from these, Milrinone has been revealed to have positive inotropic and vasodilatiry activities and thus used in clinical practice for short-trem treatment of patients who have the acute decompensated heart failure [1, 2].

References:
[1] Tang KM1, Jang EK, Haslam RJ. Photoaffinity labelling of cyclic GMP-inhibited phosphodiesterase (PDE III) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors. Eur J Pharmacol. 1994 Jun 15;268(1):105-14.
[2] Cheung P1, Yang G, Boden G. Milrinone, a selective phosphodiesterase 3 inhibitor, stimulates lipolysis, endogenous glucose production, and insulin secretion. Metabolism. 2003 Nov;52(11):1496-500.

Effect of Milrinone Infusion on Pulmonary Vasculature and Stroke Work Indices: A Single-Center Retrospective Analysis in 69 Patients Awaiting Cardiac Transplantation.[Pubmed:28353026]

Am J Cardiovasc Drugs. 2017 Aug;17(4):335-342.

BACKGROUND: Although Milrinone infusion is reported to benefit left ventricular function in chronic left heart failure, few insights exist regarding its effects on pulmonary circulation and right ventricular function. METHODS: We retrospectively reviewed right heart catheterization data at baseline and during continuous infusion of Milrinone in 69 patients with advanced heart failure and analyzed the effects on ventricular stroke work indices, pulmonary vascular resistance and pulmonary arterial compliance. RESULTS: Compared to baseline, Milrinone infusion after a mean 58 +/- 61 days improved mean left ventricular stroke work index (1540 +/- 656 vs. 2079 +/- 919 mmHg.mL/m(2), p = 0.0007) to a much greater extent than right ventricular stroke work index (616 +/- 346 vs. 654 +/- 332, p = 0.053); however, patients with below median stroke work indices experienced a significant improvement in both left and right ventricular stroke work performance. Overall, Milrinone reduced left and right ventricular filling pressures and pulmonary and systemic vascular resistance by approximately 20%. Despite an increase in pulmonary artery capacitance (2.3 +/- 1.6 to 3.0 +/- 2.0, p = 0.013) and a reduction in pulmonary vascular resistance (3.8 +/- 2.3 to 3.0 +/- 1.7 Wood units), Milrinone did not reduce the transpulmonary gradient (13 +/- 7 vs. 12 +/- 6 mmHg, p = 0.252), the pulmonary artery pulse pressure (25 +/- 10 vs. 24 +/- 10, p = 0.64) or the pulmonary artery diastolic to pulmonary capillary wedge gradient (2.0 +/- 6.5 vs. 2.4 +/- 6.0, p = 0.353). CONCLUSION: Milrinone improved left ventricular stroke work indices to a greater extent than right ventricular stroke work indices and had beneficial effects on right ventricular net input impedance, predominantly via augmentation of left ventricular stroke volume and passive unloading of the pulmonary circuit. Patients who had the worst biventricular performance benefited the most from chronic Milrinone infusion.

Effect of intrathecal milrinone injection via lumbar catheter on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.[Pubmed:28298035]

J Neurosurg. 2018 Mar;128(3):717-722.

OBJECTIVE Delayed cerebral ischemia (DCI) is an important complication after aneurysmal subarachnoid hemorrhage (aSAH). Although intrathecal Milrinone injection via lumbar catheter to prevent DCI has been previously reported to be safe and feasible, its effectiveness remains unknown. The goal of this study was to evaluate whether intrathecal Milrinone injection treatment after aSAH significantly reduced the incidence of DCI. METHODS The prospectively maintained aSAH database was used to identify patients treated between January 2010 and December 2015. The cohort included 274 patients, with group assignment based on treatment with intrathecal Milrinone injection or not. A propensity score model was generated for each patient group, incorporating relevant patient variables. RESULTS After propensity score matching, 99 patients treated with intrathecal Milrinone injection and 99 without treatment were matched on the basis of similarities in their demographic and clinical characteristics. There were significantly fewer DCI events (4% vs 14%, p = 0.024) in patients treated with intrathecal Milrinone injection compared with those treated without it. However, there were no significant differences between the 2 groups with respect to their 90-day functional outcomes (46% vs 36%, p = 0.31). The likelihood of chronic secondary hydrocephalus, meningitis, and congestive heart failure as complications of intrathecal Milrinone injection therapy was also similar between the groups. CONCLUSIONS In propensity score-matched groups, the intrathecal administration of Milrinone via lumbar catheter showed significant reduction of DCI following aSAH, without an associated increase in complications.

Continuous Intravenous Milrinone Therapy in Pediatric Outpatients.[Pubmed:28248808]

J Infus Nurs. 2017 Mar/Apr;40(2):92-96.

Milrinone is a phosphodiesterase 3 inhibitor with both positive inotropic and vasodilator properties. Administered as a continuous infusion, Milrinone is indicated for the short-term treatment of patients with acute decompensated heart failure. Despite limited data supporting long-term Milrinone therapy in adults with congestive heart failure, children managed as outpatients may benefit from continuous Milrinone as a treatment for cardiac dysfunction, as a destination therapy for cardiac transplant, or as palliative therapy for cardiomyopathy. The aim of this article is to review the medical literature and describe a home infusion company's experience with pediatric outpatient Milrinone therapy.

Photoaffinity labelling of cyclic GMP-inhibited phosphodiesterase (PDE III) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors.[Pubmed:7925608]

Eur J Pharmacol. 1994 Jun 15;268(1):105-14.

Ultraviolet irradiation of human platelet cytosol in the presence of 32P-labelled cyclic GMP (cGMP) can specifically label 110, 80, 55, 49 and 38 kDa proteins; the 110 kDa species is the subunit of cGMP-inhibited phosphodiesterase (PDE III) and the 80 kDa species that of cGMP-dependent protein kinase (Tang et al., 1993, Biochem. J. 294, 329). We have now shown that although photolabelling of platelet PDE III was inhibited by unlabelled cGMP, 8-bromo-cGMP and cyclic AMP (cAMP), it was not affected by phosphorothioate analogues of these cyclic nucleotides. Specific concentration-dependent inhibitions of the photolabelling of PDE III were observed with the following PDE inhibitors: trequinsin (IC50 = 13 +/- 2 nM), lixazinone (IC50 = 22 +/- 4 nM), Milrinone (IC50 = 56 +/- 12 nM), cilostamide (IC50 = 70 +/- 9 nM), siguazodan (IC50 = 117 +/- 29 nM) and 3-isobutyl 1-methylxanthine (IBMX) (IC50 = 3950 +/- 22 nM). Thus, measurements of the inhibitory effects of compounds on the photolabelling of platelet PDE III provide a simple quantitative means of investigating their actions at a molecular level that avoids the need to purify the enzyme. Photolabelling of rat platelet lysate or rat heart homogenate by [32P]cGMP showed that the 110 kDa PDE III present in human material was replaced by a 115 kDa protein, labelling of which was also blocked by PDE III inhibitors. Heart and other rat tissues contained much less of this putative 115 kDa PDE III than rat platelets. In contrast, the 80 kDa protein was labelled much less in platelets than in many other rat tissue homogenates (e.g., heart, aorta, uterus and lung). Thus, comparison of the relative amounts of specific photolabelled proteins in different cells may provide an indication of different patterns of cyclic nucleotide action. We compared the abilities of phosphodiesterase inhibitors to block the photolabelling of PDE III in human platelet cytosol and to increase the iloprost-stimulated accumulation of cAMP in intact platelets. Whereas trequinsin (EC50 = 19 +/- 3 nM), lixazinone (EC50 = 122 +/- 8 nM), Milrinone (EC50 = 5320 +/- 970 nM) and siguazodan (EC50 = 18880 +/- 3110 nM) all increased platelet cAMP to the same maximum extent, cilostamide and IBMX increased cAMP further, indicating that they inhibited a PDE isozyme in addition to PDE III.

The presence of five cyclic nucleotide phosphodiesterase isoenzyme activities in bovine tracheal smooth muscle and the functional effects of selective inhibitors.[Pubmed:1665737]

Br J Pharmacol. 1991 Oct;104(2):471-7.

1. The profile of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and the relaxant effects of isoenzyme selective inhibitors were examined in bovine tracheal smooth muscle. The compounds examined were the non-selective inhibitor 3-isobutyl-1-methylxanthine (IBMX), zaprinast (PDE V selective), Milrinone and Org 9935 (4,5-dihydro-6-(5,6-dimethoxy-benzo[b]thien-2-yl)-5-methyl-1 (2H)-pyridazinone; both PDE III selective), rolipram (PDE IV selective) and Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]-thiophene-2-carboximidamide HCl a dual PDE III/IV inhibitor). 2. Ion exchange chromatography showed three main peaks of PDE activity. The first peak was stimulated by Ca2+/calmodulin (PDE I), the adenosine 3':5'-cyclic monophosphate (cyclic AMP) hydrolytic activity of the second peak was stimulated by guanosine 3':5'-cyclic monophosphate (cyclic GMP) (PDE II) whilst that of the third peak was not significantly modified by any regulator (PDE IV). Calmodulin affinity chromatography revealed the additional presence of cyclic GMP-specific PDE (PDE V) in the first peak. A clearly distinct peak of cyclic GMP-inhibited PDE (PDE III) was not observed. However, Org 9935 inhibited the third activity peak more effectively in the presence, than in the absence, of rolipram (3 mumol l-1), indicating the presence of PDE III activity. 3. Rolipram was the most potent inhibitor of PDE IV. The mean -log50 IC50 values for rolipram, IBMX, Milrinone, Org 30029, Org 9935 and zaprinast were 5.9 +/- 0.1, 4.9 +/- 0.1, 4.7 +/- 0.1, 4.6 +/- 0.1 and 4.6 +/- 0.1, respectively. 4. Rolipram was a potent relaxant of both histamine (1 pumol -') and methacholine (0.03 pmol -') precontracted preparations; (pD2 values; histamine 7.1 +/- 0.1, methacholine 6.8 /-+ 0.2 and 4.5 +/- 0.1, biphasic relaxation). IBMX also relaxed all preparations (pD2 values; histamine 5.6 +/- 0.1, methacholine 5.6 +/- 0.1) whilst zaprinast (pD2 values; histamine 5.2 +/- 0.1, methacholine 4.4 +/- 0.3), Milrinone (pD2 values; histamine 5.2 + 0.1, methacholine 4.3 + 0.3) and Org 9935 (pD2 values; histamine 4.1 + 0.1, methacholine 4.1 +/- 0.2) did not completely relax preparations at concentrations up to 100 pImol I-. Org 30029 (pD2 values; histamine 6.2 +/- 0.1, methacholine 5.4 +/- 0.1) was a more effective relaxant than can be explained on the basis of PDE IV inhibition alone.5. We conclude that bovine tracheal smooth muscle contains five distinct PDE isoenzymes. PDE IV appears to be more important in the modulation of tissue function than PDE III and PDE V.

Characterization of the cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissues from several animal species.[Pubmed:6195468]

J Cardiovasc Pharmacol. 1983 Sep-Oct;5(5):804-11.

The cardiotonic activity of Milrinone (Win 47203), a potent analogue of amrinone, was demonstrated in isolated guinea pig, cat, rabbit, rat, and hamster atria and papillary muscles. Milrinone, in concentrations of 0.1-300 micrograms/ml, caused concentration-dependent increases in guinea pig papillary muscle and atrial developed tension with minimal increases in atrial rate. Compared with the in vitro inotropic activity of amrinone, Milrinone was approximately 30 times more potent. The inotropic and chronotropic effects of Milrinone do not appear to be mediated by the release of endogenous norepinephrine, by the direct stimulation of beta-adrenergic or histaminergic receptors, or through the stimulation of prostaglandin synthesis. The inotropic response of the guinea pig papillary muscles to isoproterenol was potentiated when isoproterenol was given at the peak effect of a minimally effective concentration of Milrinone or after prolonged incubation with Milrinone. No potentiation was observed when isoproterenol was administered at the peak effect of a high concentration of Milrinone, which suggests that the positive inotropic action of Milrinone may not be solely attributable to cyclic AMP phosphodiesterase inhibition.