Details of the Drug Combination

General Information of Drug Combination (ID: DC00C8V)

• Drug Combination Name: Milrinone + Dobutamine
• Indication: Shock, Cardiogenic; Status: Phase 4 [1]
• Component Drugs:
  Milrinone (DM8TUPF): Small molecular drug
  Dobutamine (DMD1B8Z): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Milrinone

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Cardiomyopathy	BC43	Investigative	[3]

Milrinone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 3 (PDE3)	TTZCG4L	NOUNIPROTAC	Modulator	[5]

Milrinone Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[6]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[7]

Indication(s) of Dobutamine

Disease Entry	ICD 11	Status	REF
Heart failure	BD10-BD13	Approved	[4]

Dobutamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[9]

Dobutamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[10]

Dobutamine Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[11]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Affects Response To Substance	[12]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[13]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[15]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[16]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[15]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Secretion	[17]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[18]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[19]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Affects Response To Substance	[8]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Affects Response To Substance	[20]
Kallikrein-1 (KLK1)	OTFGP3UR	KLK1_HUMAN	Affects Response To Substance	[21]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Affects Response To Substance	[22]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[23]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[24]
Cardiac phospholamban (PLN)	OTT3RRJN	PPLA_HUMAN	Affects Response To Substance	[25]

References

• [1] ClinicalTrials.gov (NCT05267886) CAPITAL DOREMI 2: Inotrope Versus Placebo Therapy for Cardiogenic Shock
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5225).
• [3] Milrinone FDA Label
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 535).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] The efficacy of preemptive Milrinone or Amrinone therapy in patients undergoing coronary artery bypass grafting. Anesth Analg. 2002 Jan;94(1):22-30, table of contents. doi: 10.1097/00000539-200201000-00005.
• [7] Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):410-8. doi: 10.1165/rcmb.2002-0247OC. Epub 2003 Apr 24.
• [8] Gene therapy in cardiac surgery: intramyocardial injection of naked plasmid DNA for chronic myocardial ischemia. Eur J Cardiothorac Surg. 2003 Nov;24(5):785-93. doi: 10.1016/s1010-7940(03)00455-x.
• [9] Beta-adrenoceptor alterations coupled with secretory response and experimental periodontitis in rat submandibular glands. Arch Oral Biol. 2008 Jun;53(6):509-16.
• [10] Catechol-O-methyltransferase: substrate-specificity and stereoselectivity for beta-adrenoceptor agents. Xenobiotica. 1986 Jan;16(1):47-52.
• [11] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
• [12] The Arg389Gly 1-adrenoceptor gene polymorphism influences the acute effects of -adrenoceptor blockade on contractility in the human heart. Clin Res Cardiol. 2011 Aug;100(8):641-7. doi: 10.1007/s00392-011-0288-1. Epub 2011 Feb 11.
• [13] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [14] Beta-adrenoceptor activation-induced placental prorenin secretion is mediated by increased renin messenger RNA and protein synthesis. Mol Pharmacol. 1997 Feb;51(2):201-8. doi: 10.1124/mol.51.2.201.
• [15] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [16] Myocardial ischemia induces interleukin-6 and tissue factor production in patients with coronary artery disease: a dobutamine stress echocardiography study. Circulation. 2005 Nov 22;112(21):3272-9. doi: 10.1161/CIRCULATIONAHA.104.532259. Epub 2005 Nov 14.
• [17] Catecholamines suppress leptin release from in vitro differentiated subcutaneous human adipocytes in primary culture via beta1- and beta2-adrenergic receptors. Eur J Endocrinol. 2000 Sep;143(3):439-45. doi: 10.1530/eje.0.1430439.
• [18] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [19] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.
• [20] Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther. 2006 Jan;13(1):8-19. doi: 10.1038/sj.gt.3302589.
• [21] Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. Hypertension. 2002 Nov;40(5):653-9. doi: 10.1161/01.hyp.0000036035.41122.99.
• [22] Left ventricular contractile effects of inducible nitric oxide synthase in the human allograft. Circulation. 1997 Nov 18;96(10):3436-42. doi: 10.1161/01.cir.96.10.3436.
• [23] Effect of 393T>C polymorphism of GNAS1 gene on dobutamine response in Chinese healthy subjects. J Clin Pharmacol. 2009 Aug;49(8):929-36. doi: 10.1177/0091270009337945. Epub 2009 Jun 19.
• [24] A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures. Pac Symp Biocomput. 2006:572-83.
• [25] Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats. J Clin Invest. 2004 Mar;113(5):727-36. doi: 10.1172/JCI18716.