Details of the Drug Combination

General Information of Drug Combination (ID: DCA8ICG)

• Drug Combination Name: Miconazole + Dantrolene
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Miconazole (DMPMYE8): Small molecular drug
  Dantrolene (DM1D8XY): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 18.45
  Bliss Independence Score: 18.45
  Loewe Additivity Score: 20.7
  LHighest Single Agent (HSA) Score: 20.7

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Miconazole

Disease Entry	ICD 11	Status	REF
Cutaneous candidiasis	1F23.14	Approved	[2]
Fungal infection	1F29-1F2F	Approved	[3]
Mycoses	1F2Z	Approved	[2]
Onychomycosis	EE12.1	Approved	[2]
Tinea corporis	1F28.Y	Approved	[2]
Tinea cruris	1F28.3	Approved	[2]
Tinea versicolor	1F2D.0	Approved	[2]
Tinea pedis	1F28.2	Investigative	[2]

Miconazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[5]

Miconazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]

Miconazole Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[7]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[8]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Decreases Expression	[10]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Decreases Expression	[10]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[10]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[11]
Adenylate cyclase type 9 (ADCY9)	OT1IZT5K	ADCY9_HUMAN	Increases Activity	[12]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Decreases Activity	[13]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[14]
Interleukin-5 (IL5)	OTAFPSCO	IL5_HUMAN	Decreases Expression	[14]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Increases Expression	[15]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[15]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[15]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[17]

Indication(s) of Dantrolene

Disease Entry	ICD 11	Status	REF
Hyperthermia	MG26	Approved	[4]

Dantrolene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Ryanodine receptor (RYR)	TT9YXM1	NOUNIPROTAC	Modulator	[5]

Dantrolene Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]

Dantrolene Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Insulin-like growth factor II (IGF2)	OTJ4O6MW	IGF2_HUMAN	Decreases Response To Substance	[19]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Decreases Response To Substance	[19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[20]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[21]

References

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• [2] Miconazole FDA Label
• [3] 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: 2449).
• [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: 4172).
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
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• [8] The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
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• [10] Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor. Mol Pharmacol. 2006 Jul;70(1):329-39.
• [11] In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450. Toxicol In Vitro. 2011 Jun;25(4):890-6.
• [12] Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):497-504. doi: 10.1007/s00210-018-01610-1. Epub 2019 Jan 3.
• [13] The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
• [14] Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis. J Invest Dermatol. 2001 Dec;117(6):1635-46. doi: 10.1046/j.0022-202x.2001.01566.x.
• [15] Miconazole induces protective autophagy in bladder cancer cells. Environ Toxicol. 2021 Feb;36(2):185-193. doi: 10.1002/tox.23024. Epub 2020 Sep 27.
• [16] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [17] Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.
• [18] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [19] Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model. World J Surg. 2006 Mar;30(3):333-45. doi: 10.1007/s00268-005-0339-8.
• [20] 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.
• [21] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.