METHYLENE BLUE CATION

First marketed in 1921

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H18N3S
Molecular Weight	284.399
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	1

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)C1=CC2=[S+]C3=C(C=CC(=C3)N(C)C)N=C2C=C1

InChI

InChIKey=RBTBFTRPCNLSDE-UHFFFAOYSA-N

InChI=1S/C16H18N3S/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/q+1

HIDE SMILES / InChI

Description
Sources: https://www.drugs.com/monograph/methylene-blue.html
Curator's Comment: http://www.mdpoison.com/media/SOP/mdpoisoncom/healthcareprofessionals/antidote-facts/Methylene%20Blue%20Antidote%20Facts.pdf | https://clinicaltrials.gov/ct2/show/NCT01797978 | https://www.pharmgkb.org/pathway/PA165980834

Methylene blue, also known as methylthioninium chloride, is a medication from WHO's list of essential medicines. Upon administration, methylene blue is converted to leukomethylene blue by erythrocyte methemoblobin reductase in the presence of NADPH. Leukomethylene blue than reduces methemoglobin to oxyhemoglobin, thus restoring oxygen carrying capacity of the blood. Methylene blue is also used as a dye for various diagnostic procedures, for treatment of ifosfamide toxicity and for in vitro staining. Historically, it was used as a photosensitizer for photodynamic therapy for topical treatment of dermatologic or mucocutaneous infections, as an antidote for cyanide poisoning, but these applications are no longer approved. Methylene blue is investigated in clinical trials for treatment of septic shock and Alzheimer's disease.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
NADH-cytochrome b5 reductase 3 6 Target ID: P00387\|\|\|Q9UL55 Gene ID: 1727.0 Gene Symbol: CYB5R3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/7396878	Substrate 661
Nitric oxide synthase (inducible and endothelial) 9 Target ID: CHEMBL2111350 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7679577	Inhibitor 8504		5.3 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Methemoglobinemia 6 Sources: https://www.drugs.com/monograph/methylene-blue.html	Primary	Approved 8583	METHYLENE BLUE Approved Use Used for methemoglobinemia associated with certain drugs (e.g., dapsone, benzocaine, lidocaine), occupational or other exposures to toxic chemicals (e.g., hydrazine, amine-substituted benzenes, nitro-substituted benzenes, nitrates, nitrites), or substance abuse (e.g., inhalation or ingestion of volatile nitrites).
Ifosfamide-induced encelophaty 6 Sources: https://www.drugs.com/monograph/methylene-blue.html	Primary	Approved 8583	METHYLENE BLUE Approved Use Management of ifosfamide-induced encephalopathy
Cancer 609 Sources: https://www.drugs.com/monograph/methylene-blue.html	Diagnostic	Approved 8583	METHYLENE BLUE Approved Use Has been used as diagnostic (visualizing) dye in a variety of procedures, including sentinel lymph node biopsy in cancer patients (e.g., breast cancer patients), endoscopic evaluation of lesions in patients with GERD or Barrett's esophagus, urologic evaluation in patients with ureteral or renal pelvis injury, and thoroscopic procedures in patients with pulmonary nodules.
Dermatologic infections 6 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25048768	Primary	Approved 8583	METHYLENE BLUE Approved Use Has been used as a photosensitizer for photodynamic therapy for topical treatment of dermatologic or mucocutaneous infections (e.g., herpes labialis, eczema herpeticum, oral candidiasis, cutaneous leishmaniasis, chromoblastomycosis) or chronic dermatologic or mucocutaneous conditions (e.g., plaque psoriasis, oral lichen planus).
Septic shock 21 Sources: https://clinicaltrials.gov/ct2/show/NCT01797978	Primary	Phase III 665	Unknown Approved Use Unknown
Alzheimer’s disease 278 Sources: https://clinicaltrials.gov/ct2/show/NCT02380573	Preventing	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
8 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952480/	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2917 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204630s006lbl.pdf	2 mg/kg single, intravenous dose: 2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
134 μM × min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952480/	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
13977 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204630s006lbl.pdf	2 mg/kg single, intravenous dose: 2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10952480/	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
24 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204630s006lbl.pdf	2 mg/kg single, intravenous dose: 2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
6% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204630s006lbl.pdf	2 mg/kg single, intravenous dose: 2 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		METHYLENE BLUE plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
72 mg/kg 4 times / day multiple, intravenous Highest studied dose Dose: 72 mg/kg, 4 times / day Route: intravenous Route: multiple Dose: 72 mg/kg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17026773	unhealthy, 0.5-4.9 Health Status: unhealthy Age Group: 0.5-4.9 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/17026773	Other AEs: Anemia... Other AEs: Anemia (0.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/17026773
1 g single, intravenous Overdose Dose: 1 g Route: intravenous Route: single Dose: 1 g Sources: https://pubmed.ncbi.nlm.nih.gov/973698	healthy, 3 Health Status: healthy Age Group: 3 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/973698	Disc. AE: Tachycardia, Cyanosis... AEs leading to discontinuation/dose reduction: Tachycardia Cyanosis Sources: https://pubmed.ncbi.nlm.nih.gov/973698

AEs

AE	Significance	Dose	Population
Anemia	0.8%	72 mg/kg 4 times / day multiple, intravenous Highest studied dose Dose: 72 mg/kg, 4 times / day Route: intravenous Route: multiple Dose: 72 mg/kg, 4 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17026773	unhealthy, 0.5-4.9 Health Status: unhealthy Age Group: 0.5-4.9 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/17026773
Cyanosis	Disc. AE	1 g single, intravenous Overdose Dose: 1 g Route: intravenous Route: single Dose: 1 g Sources: https://pubmed.ncbi.nlm.nih.gov/973698	healthy, 3 Health Status: healthy Age Group: 3 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/973698
Tachycardia	Disc. AE	1 g single, intravenous Overdose Dose: 1 g Route: intravenous Route: single Dose: 1 g Sources: https://pubmed.ncbi.nlm.nih.gov/973698	healthy, 3 Health Status: healthy Age Group: 3 Sex: M Sources: https://pubmed.ncbi.nlm.nih.gov/973698

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P000KBE
1PlusChem LLC	1P0035Q5
1PlusChem LLC	1P00IKXL
A2B Chem	AI66137
AA Blocks	AA00IKE5
AAA Chemistry	AR-1K4257
ABI Chem	AC1L1HI1
ABI Chem	AC1Q4UZ6
AbovChem LLC	HY-14536
Acros Organics	12675
Acros Organics	22980
Acros Organics	41424
Acros Organics	41425
AK Scientific	6335AF
AK Scientific	6336AF
AK Scientific	6337AF
AK Scientific	6338AF
Alfa Chemistry	42771
Alfa Chemistry	A18174
Alfa Chemistry	ACM61734
Alfa Chemistry	ACM7220793
Alfa Chemistry	J60823
Alinda	IBS-E0000554
Ambinter	Amb19654466	http://www.ambinter.com/reference/19654466
Ambinter	Amb21855833	http://www.ambinter.com/reference/21855833
Angene	AGN-PC-0O0J7Q
Angene	AGN-PC-0OH2YS
Apollo Scientific	BIA4084
Aronis	M04821
AstaTech	43008
Aurora Fine Chemicals LLC	A12.866.455	http://online.aurorafinechemicals.com/info?ID=A12.866.455
BioSynth	M-3598
BLD Pharm	BD139888
BLD Pharm	BD305948
BLD Pharm	BD338910
BOC Sciences	122965-43-9
BOC Sciences	26283-09-0
BOC Sciences	37247-10-2
BOC Sciences	61-73-4
BOC Sciences	7220-79-3
Bosche Scientific	M2940
Bosche Scientific	M2943
Capot Chemical	35596
Chem-Impex International	210
Chem-Impex International	22930
Chem Scene	CS-0013101
Chem Scene	CS-2959
ChemDiv	0083-0118
ChemShuttle	141809
Chemspace	CSSS00160696622	https://chem-space.com/CSSS00160696622
Compound Cloud	104827
Compound Cloud	16211647
Compound Cloud	4139
Compound Cloud	6099
DC Chemicals	DC11091	http://www.dcchemicals.com/product_show-DC11091.html
eMolecules	207322640
eMolecules	271447134
eMolecules	28206441
eMolecules	56968286
eMolecules	66729975
Enamine	EN300-6504462
eNovation Chemicals	D329417
eNovation Chemicals	D394566
Fluorochem	468422
Fluorochem	492385
Hairui	HR144947
Hangzhou APIChem Technology	AC-15225
Hangzhou APIChem Technology	AC-8349
Hangzhou Yuhao Chemical Technology	HL3337
Hangzhou Yuhao Chemical Technology	JZ4569
Hangzhou Yuhao Chemical Technology	LT7437
Hangzhou Yuhao Chemical Technology	XJ6809
Hangzhou Yuhao Chemical Technology	YH15655
KeyOrganics	AS-35256
Lab Network	33
Lab Network	LN00193772
Lab Network	LN00194290
Lab Network	LN00237724
Lab Network	LN02135350
mcule	MCULE-6490213141	https://mcule.com/MCULE-6490213141/
MedChem Express	HY-14536
MedChem Express	HY-B1359
Molnova	M15760
Molnova	M18906
MolPort	MolPort-001-494-481
MolPort	MolPort-003-666-690
MolPort	MolPort-004-963-308
MolPort	MolPort-006-110-157
MolPort	MolPort-039-063-118
MuseChem	A000087
MuseChem	M057779
MuseChem	M060342
MuseChem	R037152
MuseChem	R045681
NCI Plated 2007	215213
NCI Plated 2007	3089
NCI Plated 2007	617593
Ryan Scientific	Diolane
Scientific Exchange	R-079267
Selleck Chemicals	S4535
Sigma Aldrich	66725
Sigma Aldrich	M1800900
Sigma Aldrich	M44907
Sigma Aldrich	M9140\|SIAL
Sigma Aldrich	MB1
Smolecule	S564122	https://www.smolecule.com/products/s564122
TargetMol	T0006
TargetMol	T6888
Tetrahedron	TS78351
Tetrahedron	TS80135
TimTec	SBB060907
TimTec	ST093058
TimTec	ST50406156
TimTec	ST50406802
TimTec	ST50411628
Tocris	3213
Vitas-M Laboratory	STL483851	http://www.request.vitasmlab.com/index.php?option=com_search_stk&Itemid=22&stk=STL483851&?utm_source=pubchem&utm_medium=p_search_link&utm_campaign=pubchem_search&utm_content=pubchem_slink
W&J PharmaChem	50C912420
Yuhao Chemical	LT7437	http://www.chemyuhao.com/61-73-4.html
ZINC	ZINC000012414057	http://zinc15.docking.org/substances/ZINC000012414057

PubMed

Title	Date	PubMed
Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine.	1982 Feb	7075467
Neurotoxicity in conscious rats following intraventricular SNAP, a nitric oxide donor.	1994 Jul	7969812
Toxic oil stimulates collagen synthesis acting at a pretranslational level in cultured fat-storing cells.	1994 Mar	8119541
[Treatment of ifosfamide induced encephalopathy with methylene-blue].	1995 Jul	7549123
Methylene blue for ifosfamide-associated encephalopathy.	1995 May 4	7700329
Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy.	1996	8803513
[Successful treatment with methylene blue of ifosfamide-induced central nervous system effects].	1996 Apr 26	8620831
Ifosfamide encephalopathy and methylene-blue: a case report.	1996 Aug	8879383
Alternative approaches to the management of priapism.	1998 Mar	9542685
Dual action of phenylarsine oxide on the glucose transport activity of GLUT1.	2009 Dec 10	19686715
Superoxide signaling in pain is independent of nitric oxide signaling.	2009 Oct 28	19794317
Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors.	2011 Aug	21554916
The specific interaction of the photosensitizer methylene blue with acetylcholinesterase provides a model system for studying the molecular consequences of photodynamic therapy.	2013 Mar 25	23159732
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903

Patents

Sample Use Guides

In Vivo Use Guide

Main route of adminitration is intravenous, 1-2 mg/kg by slow IV injection. Inject slowly over several minutes (usually 3–10 minutes). Historically was also administered orally, but oral preparations are no longer commercially available in US. As a photosensitizer is administered topically. For a diagnostic purposes is administered by local instillation or injection.

Route of Administration: Other

In Vitro Use Guide

Suspension of erytrocytes from acid/citrate/dextrose-treated blood were incubabed on air with 0.5M M-sodium nitrite solution in isoosmotic saline. The erytrocytes were separated by centrifugation, washed, and incubated at pH 7.4 and 37°C with 10 mM glucose and 10 uM Methylene Blue. Samples were taken at defined intervals and hemolysed with 10 vol of ice-cold water, after that the content of mehtemoglobin, hemoglobins intermediate and oxyhemoglobin was estimated.

Name

Type

Language

METHYLTHIONINIUM

Preferred Name

English

METHYLENE BLUE CATION

Common Name

English

Methylthioninium [WHO-DD]

Common Name

English

PHENOTHIAZIN-5-IUM, 3,7-BIS(DIMETHYLAMINO)-

Systematic Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/10/807