MILRINONE

First approved in 1987

Details

Stereochemistry	ACHIRAL
Molecular Formula	C12H9N3O
Molecular Weight	211.2194
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C(C=C(C#N)C(=O)N1)C2=CC=NC=C2

InChI

InChIKey=PZRHRDRVRGEVNW-UHFFFAOYSA-N

InChI=1S/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00235
Curator's Comment: Description was created based on several sources, including https://www.drugs.com/cdi/milrinone.html

Milrinone, a synthetic dimethylxanthine derivative structurally related to theophylline and caffeine, is used in the treatment of peripheral vascular diseases and in the management of cerebrovascular insufficiency, sickle cell disease, and diabetic neuropathy. Milrinone inhibits erythrocyte phosphodiesterase, resulting in an increase in erythrocyte cAMP activity. Subsequently, the erythrocyte membrane becomes more resistant to deformity. Along with erythrocyte activity, Milrinone also decreases blood viscosity by reducing plasma fibrinogen concentrations and increasing fibrinolytic activity. Milrinone is indicated for the treatment of congestive heart failure. Milrinone was marketed under the brand name Primacor.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Phosphodiesterase 3A 7 Target ID: CHEMBL241 Sources: http://www.drugbank.ca/drugs/DB00235	Inhibitor 8297		0.45 µM [IC50]
Phosphodiesterase 3B 8 Target ID: CHEMBL290 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10644042	Inhibitor 8297		1.0 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute decompensated heart failure 3 Sources: https://www.drugs.com/pro/milrinone.html	Primary		Approved 8429	Milrinone Lactate Approved Use Milrinone lactate injection is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Launch Date 2002

C_max

Value	Dose	Co-administered	Analyte	Population
162 μg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3053125	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:		MILRINONE plasma	Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
454 μg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3053125	75 μg/kg bw single, intravenous dose: 75 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:		MILRINONE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1.749 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7728786	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		MILRINONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
439 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7728786	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		MILRINONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
1.92 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7728786	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	MILRINONE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
0.758 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7728786	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	MILRINONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
0.94 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3053125	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	MILRINONE plasma	Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN
1.7 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/3053125	75 μg/kg bw single, intravenous dose: 75 μg/kg bw route of administration: Intravenous experiment type: SINGLE co-administered:	MILRINONE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/17146843/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50693	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50693
MolPort	MolPort-003-666-840	https://www.molport.com/shop/molecule-link/MolPort-003-666-840
MolPort	MolPort-006-138-878	https://www.molport.com/shop/molecule-link/MolPort-006-138-878
Selleck Chemicals	Milrinone(Primacor)	http://www.selleckchem.com/products/Milrinone(Primacor).html
ZINC	ZINC000009224016	http://zinc15.docking.org/substances/ZINC000009224016
eMolecules	591956	https://www.emolecules.com/cgi-bin/more?vid=591956

PubMed

Title	Date	PubMed
Vascular relaxant effects of toborinone on the isolated canine internal mammary artery.	2001	11759883
High calcium and dobutamine positive inotropy in the perfused mouse heart: myofilament calcium responsiveness, energetic economy, and effects of protein kinase C inhibition.	2001	11553322
Possible involvement of cyclic adenosine monophosphate-independent mechanism in the positive chronotropic effect of norepinephrine in the isolated guinea pig right atrium.	2001 Aug	11506118
A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection.	2001 Aug	11494080
Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors: the role of protein kinase A and p38 mitogen-activated protein kinase.	2001 Aug 7	11489779
The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension.	2001 Dec	11726420
Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway.	2001 Dec	11709398
Milrinone echocardiographic viability test: a pilot study.	2001 Jul	11447411
The effects of alpha-human atrial natriuretic peptide and milrinone on pial vessels during blood-brain barrier disruption in rabbits.	2001 Jul	11429361
Inotropes and beta-blockers: is there a need for new guidelines?	2001 Jun	11605160
Dose response to nitric oxide in adult cardiac surgery patients.	2001 Jun	11435053
Comparison of the hemodynamic effects of milrinone with dobutamine in patients after cardiac surgery.	2001 Jun	11426360
A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure.	2001 Jun	11420762
Modulation of thapsigargin-induced calcium mobilisation by cyclic AMP-elevating agents in human lymphocytes is insensitive to the action of the protein kinase A inhibitor H-89.	2001 Jun	11384843
Inhibition of phosphodiesterase type III before aortic cross-clamping preserves intramyocardial cyclic adenosine monophosphate during cardiopulmonary bypass.	2001 Jun	11375808
Local anesthetic toxicity and milrinone.	2001 May	11394526
Combined phosphodiesterase inhibition and beta-blockade in the GI104313, decreases ischemia-induced arrhythmias in the rat.	2001 May	11394520
Sildenafil (viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device.	2001 May	11377161
Improved survival with simendan after experimental myocardial infarction in rats.	2001 May 11	11426847
The role of cGMP hydrolysing phosphodiesterases 1 and 5 in cerebral artery dilatation.	2001 May 18	11412839
Discriminative stimulus effects of the type-4 phosphodiesterase inhibitor rolipram in rats.	2001 Nov	11713620
Cell-based assay for high-throughput quantitative screening of CFTR chloride transport agonists.	2001 Nov	11600438
The evolving management of acute right-sided heart failure in cardiac transplant recipients.	2001 Oct	11583860
Assessment of cardiovascular dynamics by pressure-area relations in pediatric patients with congenital heart disease.	2001 Sep	11547307
Carvedilol titration in patients with congestive heart failure receiving inotropic therapy.	2001 Sep	11526366
Positive inotropic drug infusions for patients with heart failure: current controversies and best practice.	2002 Apr	11984193
Differential effects of specific phosphodiesterase isoenzyme inhibitors on bovine oocyte meiotic maturation.	2002 Apr 15	11944932
The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure-a meta-regression analysis.	2002 Aug	12167393
Phosphodiesterase 3 inhibitors selectively block the spontaneous resumption of meiosis by macaque oocytes in vitro.	2002 Aug	12151440
Acute renal failure secondary to milrinone in a patient with cardiac amyloidosis.	2002 Aug	12148128
Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa.	2002 Aug	12135876
Nitric oxide signalling by selective beta(2)-adrenoceptor stimulation prevents ACh-induced inhibition of beta(2)-stimulated Ca(2+) current in cat atrial myocytes.	2002 Aug 1	12154173
[Reversible cardiomyopathy secondary to interferon-alpha in chronic myelogenous leukemia].	2002 Feb	11865642
Involvement of phosphodiesterase isozymes in osteoblastic differentiation.	2002 Feb	11811555
Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics.	2002 Jan	11773907
Effects of phosphodiesterase III inhibition on length-dependent regulation of myocardial function in coronary surgery patients.	2002 Jun	12173193
22nd International Symposium on Intensive Care and Emergency Medicine, Brussels, Belgium, 19-22 March 2002.	2002 Jun	12133191
Recently published papers: topical issues in pharmacology.	2002 Jun	12133177
Effects of milrinone on hemodynamics and regional blood flow in the hypoxic dog.	2002 Jun	12130834
Treatment of acute heart failure: out with the old, in with the new.	2002 Mar 27	11911762
Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial.	2002 Mar 27	11911756
A potential role for AMP-activated protein kinase in meiotic induction in mouse oocytes.	2002 May 1	11969266
Relaxation induced by milrinone and rolipram in human penile arteries and veins.	2002 May 24	12191588
New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation.	2002 Oct	12352320
Lipopolysaccharide-induced acute renal failure in conscious rats: effects of specific phosphodiesterase type 3 and 4 inhibition.	2002 Oct	12235272
Megadose of milrinone as an alternative to extracorporeal membrane oxygenation for treatment of graft failure early after cardiac transplantation.	2002 Sep	12202888
Potentiation of slow component of delayed rectifier K(+) current by cGMP via two distinct mechanisms: inhibition of phosphodiesterase 3 and activation of protein kinase G.	2002 Sep	12183338
Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis.	2002 Sep	12181427
Exhaled nitric oxide: a marker of pulmonary hemodynamics in heart failure.	2002 Sep 18	12354437
Subtype-specific roles of cAMP phosphodiesterases in regulation of atrial natriuretic peptide release.	2002 Sep 20	12242091

Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Congestive Heart Failure Loading dose: 50 mcg/kg IV over 10 minutes. Maintenance infusion: 0.375 to 0.75 mcg/kg/min.

Route of Administration: Intravenous

In Vitro Use Guide

Milrinone caused the human thoracic artery samples to relax at 10⁻⁴ M concentrations by 44%, when the external Ca²⁺ corresponded to the physiological standard.

Name

Type

Language

MILRINONE

Official Name

English

Milrinone [WHO-DD]

Common Name

English

MILRILA

Brand Name

English

MILRINONE [USP-RS]

Common Name

English

WIN 47,203-2

Code

English

MILRINONE [USAN]

Common Name

English

MILRINONE [JAN]

Common Name

English

WIN-47203-2

Code

English

MILRINONE [USP MONOGRAPH]

Common Name

English

MILRINONE [MI]

Common Name

English

milrinone [INN]

Common Name

English

MILRINONE [VANDF]

Common Name

English

NSC-760072

Code

English

MILRINONE [MART.]

Common Name

English

(3,4'-BIPYRIDINE)-5-CARBONITRILE, 1,6-DIHYDRO-2-METHYL-6-OXO-

Systematic Name

English

1,6-DIHYDRO-2-METHYL-6-OXO(3,4'-BIPYRIDINE)-5-CARBONITRILE

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000175598