Details of the Drug

General Information of Drug (ID: DMJAPE7)

• Drug Name: Methylene blue
• Synonyms: methylene blue; 61-73-4; Methylthioninium chloride; Swiss Blue; Chromosmon; Methylene Blue N; Methylenium ceruleum; Urolene blue; Methylene Blue chloride; Solvent blue 8; Bleu de methylene; Methylene Blue G; Methylene Blue A; External Blue 1; Methylene Blue D; Methylene Blue B; Methylene Blue anhydrous; CI Basic Blue 9; Methylene Blue ZF; Methylene Blue SP; Methylene Blue NZ; Methylene Blue BX; Methylene Blue BD; Methylene Blue SG; Tetramethylene Blue; Methylene Blue ZX; Methylene Blue FZ; Methylene Blue BP; Calcozine; 3,7-Bis-dimethylamino-phenothiazin-5-ylium

Indication

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[1]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[2]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight; 319.9
  Logarithm of the Partition Coefficient; Not Available
  Rotatable Bond Count; 1
  Hydrogen Bond Donor Count; 0
  Hydrogen Bond Acceptor Count; 4
• ADMET Property:
  Clearance: The clearance of drug is 3.0? +/- ?0.7 L/min []
  Half-life: The concentration or amount of drug in body reduced by one-half in 5 C 6.5 hours [3]

Adverse Drug Reaction (ADR)

ADR Term	Variation	Related DOT	DOT ID	REF
Mucosal findings abnormal	Not Available	TNF	OT4IE164	[4]

• Chemical Identifiers:
  Formula: C16H18ClN3S
  IUPAC Name: [7-(dimethylamino)phenothiazin-3-ylidene]-dimethylazanium;chloride
  Canonical SMILES: CN(C)C1=CC2=C(C=C1)N=C3C=CC(=[N+](C)C)C=C3S2.[Cl-]
  InChI: InChI=1S/C16H18N3S.ClH/c1-18(2)11-5-7-13-15(9-11)20-16-10-12(19(3)4)6-8-14(16)17-13;/h5-10H,1-4H3;1H/q+1;/p-1
  InChIKey: CXKWCBBOMKCUKX-UHFFFAOYSA-M
• Cross-matching ID:
  PubChem CID: 6099
  ChEBI ID: CHEBI:6872
  CAS Number: 61-73-4
  DrugBank ID: DB09241
  TTD ID: D09NYS

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[5]
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	Not Available	[6]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Gene/Protein Processing	[7]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Gene/Protein Processing	[8]
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Gene/Protein Processing	[9]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Gene/Protein Processing	[10]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Gene/Protein Processing	[7]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Gene/Protein Processing	[11]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Drug Response	[4]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Methylene blue (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Levalbuterol	DM5YBO1	Moderate	Additive hypertensive effects by the combination of Methylene blue and Levalbuterol.	Asthma [CA23]	[12]
Esketamine	DMVU687	Major	Additive hypertensive effects by the combination of Methylene blue and Esketamine.	Depression [6A70-6A7Z]	[13]
Deutetrabenazine	DMUPFLI	Major	Additive hypertensive effects by the combination of Methylene blue and Deutetrabenazine.	Dystonic disorder [8A02]	[14]
Lasmiditan	DMXLVDT	Major	Additive serotonergic effects by the combination of Methylene blue and Lasmiditan.	Migraine [8A80]	[15]
Ozanimod	DMT6AM2	Major	Decreased metabolism of Methylene blue caused by Ozanimod mediated inhibition of non-CYP450 enzyme.	Multiple sclerosis [8A40]	[16]

References

• [1] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [2] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [5] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [6] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [7] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [8] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
• [9] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [10] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [11] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [12] Boakes AJ, Laurence DR, Teoh PC, Barar FS, Benedikter LT, Prichard BN "Interactions between sympathomimetic amines and antidepressant agents in man." Br Med J 1 (1973): 311-5. [PMID: 4685619]
• [13] Cerner Multum, Inc. "Australian Product Information.".
• [14] Product Information. Austedo (deutetrabenazine). Teva Pharmaceuticals USA, North Wales, PA.
• [15] Boyer EW, Shannon M "The serotonin syndrome." N Engl J Med 352 (2005): 1112-20. [PMID: 15784664]
• [16] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.