Methylene blue
Overview
 
Methylene blue is a heterocyclic aromatic
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 with the molecular formula C
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

16H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

18N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

3S
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

Cl
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...

. It has many uses in a range of different fields, such as biology
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...

 and chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in water. The hydrated form has 3 molecules of water per molecule of methylene blue. Methylene blue should not be confused with methyl blue
Methyl blue
Methyl blue, also known as Cotton blue, Helvetia blue, Acid blue 93, or C.I. 42780, is a chemical compound with the molecular formula C37H27N3Na2O9S3. It is used as a stain in histology. Methyl blue stains collagen blue in tissue sections. It is soluble in water and slightly soluble in ethanol...

, another histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

 stain, new methylene blue
New methylene blue
New methylene blue is an organic staining agent used in diagnostic cytopathology and histopathology, typically for staining immature red blood cells. It is closely related to methylene blue, an older stain already in wide use....

, nor with the methyl violet
Methyl violet
Methyl violet is a family of organic compounds that are mainly used as dyes. Depending on the amount of attached methyl groups, the color of the dye can be altered. Its main use is as a purple dye for textiles and to give deep violet colors in paint and ink...

s often used as pH indicator
PH indicator
A pH indicator is a halochromic chemical compound that is added in small amounts to a solution so that the pH of the solution can be determined visually. Hence a pH indicator is a chemical detector for hydronium ions or hydrogen ions in the Arrhenius model. Normally, the indicator causes the...

s.

The International Nonproprietary Name
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 (INN) of methylene blue is methylthioninium chloride.
Methylene blue is widely used as a redox indicator
Redox indicator
A redox indicator is an indicator that undergoes a definite color change at a specific electrode potential....

 in analytical chemistry
Analytical chemistry
Analytical chemistry is the study of the separation, identification, and quantification of the chemical components of natural and artificial materials. Qualitative analysis gives an indication of the identity of the chemical species in the sample and quantitative analysis determines the amount of...

.
Encyclopedia
Methylene blue is a heterocyclic aromatic
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...

 chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 with the molecular formula C
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

16H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

18N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

3S
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

Cl
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...

. It has many uses in a range of different fields, such as biology
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...

 and chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in water. The hydrated form has 3 molecules of water per molecule of methylene blue. Methylene blue should not be confused with methyl blue
Methyl blue
Methyl blue, also known as Cotton blue, Helvetia blue, Acid blue 93, or C.I. 42780, is a chemical compound with the molecular formula C37H27N3Na2O9S3. It is used as a stain in histology. Methyl blue stains collagen blue in tissue sections. It is soluble in water and slightly soluble in ethanol...

, another histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...

 stain, new methylene blue
New methylene blue
New methylene blue is an organic staining agent used in diagnostic cytopathology and histopathology, typically for staining immature red blood cells. It is closely related to methylene blue, an older stain already in wide use....

, nor with the methyl violet
Methyl violet
Methyl violet is a family of organic compounds that are mainly used as dyes. Depending on the amount of attached methyl groups, the color of the dye can be altered. Its main use is as a purple dye for textiles and to give deep violet colors in paint and ink...

s often used as pH indicator
PH indicator
A pH indicator is a halochromic chemical compound that is added in small amounts to a solution so that the pH of the solution can be determined visually. Hence a pH indicator is a chemical detector for hydronium ions or hydrogen ions in the Arrhenius model. Normally, the indicator causes the...

s.

The International Nonproprietary Name
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

 (INN) of methylene blue is methylthioninium chloride.

Chemistry

Redox indicator

Methylene blue is widely used as a redox indicator
Redox indicator
A redox indicator is an indicator that undergoes a definite color change at a specific electrode potential....

 in analytical chemistry
Analytical chemistry
Analytical chemistry is the study of the separation, identification, and quantification of the chemical components of natural and artificial materials. Qualitative analysis gives an indication of the identity of the chemical species in the sample and quantitative analysis determines the amount of...

. Solutions of this substance are blue when in an oxidizing environment, but will turn colorless if exposed to a reducing agent. The redox properties can be seen in a classical demonstration of chemical kinetics
Chemical kinetics
Chemical kinetics, also known as reaction kinetics, is the study of rates of chemical processes. Chemical kinetics includes investigations of how different experimental conditions can influence the speed of a chemical reaction and yield information about the reaction's mechanism and transition...

 in general chemistry, the "blue bottle
Blue bottle (chemical reaction)
The blue' bottle reaction is a chemical reaction in which a colorless solution in a closed bottle containing some air turns blue upon shaking and then decolorizes again after a while. After shaking again the blue color returns and this cycle can be repeated several times...

" experiment. Typically, a solution is made of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 (dextrose), methylene blue, and sodium hydroxide. Upon shaking the bottle, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 oxidizes methylene blue, and the solution turns blue. The dextrose will gradually reduce the methylene blue to its colorless, reduced form. Hence, when the dissolved dextrose is entirely consumed, the solution will turn blue again.

Peroxide generator

Methylene blue is also a photosensitizer used to create singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...

 when exposed to both oxygen and light. It is used in this regard to make organic peroxides by a Diels-Alder reaction which is spin forbidden with normal atmospheric triplet oxygen
Triplet oxygen
Triplet oxygen is the ground state of the oxygen molecule. The electron configuration of the molecule has two unpaired electrons occupying two degenerate molecular orbitals...

.

Sulfide analysis

The formation of methylene blue after the reaction of hydrogen sulfide
Hydrogen sulfide
Hydrogen sulfide is the chemical compound with the formula . It is a colorless, very poisonous, flammable gas with the characteristic foul odor of expired eggs perceptible at concentrations as low as 0.00047 parts per million...

 with dimethyl-p-phenylenediamine and iron(III)
Ferric
Ferric refers to iron-containing materials or compounds. In chemistry the term is reserved for iron with an oxidation number of +3, also denoted iron or Fe3+. On the other hand, ferrous refers to iron with oxidation number of +2, denoted iron or Fe2+...

 at pH 0.4 – 0.7 is used to determine by photometric measurements
Ultraviolet-visible spectroscopy
Ultraviolet-visible spectroscopy or ultraviolet-visible spectrophotometry refers to absorption spectroscopy or reflectance spectroscopy in the ultraviolet-visible spectral region. This means it uses light in the visible and adjacent ranges...

 sulfide
Sulfide
A sulfide is an anion of sulfur in its lowest oxidation state of 2-. Sulfide is also a slightly archaic term for thioethers, a common type of organosulfur compound that are well known for their bad odors.- Properties :...

 concentration in the range 0.020 to 1.50 mg/L (20 ppb to 1.5 ppm). The test is very sensitive and the blue coloration developing upon contact of the reagents with dissolved H2S is stable for 60 min. Ready-to-use kits such as the Spectroquant sulfide
Sulfide
A sulfide is an anion of sulfur in its lowest oxidation state of 2-. Sulfide is also a slightly archaic term for thioethers, a common type of organosulfur compound that are well known for their bad odors.- Properties :...

 test facilitate routine analyses. The methylene blue sulfide test is a convenient method often used in soil microbiology to quickly detect in water the metabolic activity of sulfate reducing bacteria (SRB). It should be observed that in this test, methylene blue is a product of reaction and not a reagent.

The addition of a strong reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...

, such as ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...

, to a sulfide-containing solution is sometimes used to prevent sulfide oxidation from atmospheric oxygen. Although it is certainly a sound precaution for the determination of sulfide with an ion selective electrode
Ion selective electrode
An ion-selective electrode , also known as a specific ion electrode , is a transducer that converts the activity of a specific ion dissolved in a solution into an electrical potential, which can be measured by a voltmeter or pH meter. The voltage is theoretically dependent on the logarithm of the...

, it might however hamper the development of the blue color if the freshly formed methylene blue is also reduced, as described here above in the paragraph on redox indicator.

Water testing

A color reaction
Color reaction
In chemistry, a color reaction or colour reaction is a chemical reaction that is used to transform colorless chemical compounds into colored derivatives which can be detected visually or with the aid of a colorimeter....

 in an acidified, aqueous methylene blue solution containing chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...

 can detect anionic surfactants in a water sample. Such a test is known as an MBAS assay
MBAS assay
A methylene blue active substances assay, or MBAS assay, is a colorimetric analysis test method that uses methylene blue to detect the presence of anionic surfactants in a sample of water...

 (methylene blue active substances assay).

The MBAS assay cannot distinguish between specific surfactants, however. Some examples of anionic surfactants are carboxylates, phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

s, sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...

s, and sulfonate
Sulfonate
A sulfonate is a salt or ester of a sulfonic acid. It contains the functional group R-SO2O-.- Sulfonate salts:Anions with the general formula RSO2O− are called sulfonates. They are the conjugate bases of sulfonic acids with formula RSO2OH. As sulfonic acids tend to be strong acids, the...

s.

Biology

In biology methylene blue is used as a dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....

 for a number of different staining procedures, such as Wright's stain
Wright's stain
Wright's stain is a histologic stain that facilitates the differentiation of blood cell types. It is used primarily to stain peripheral blood smears and bone marrow aspirates which are examined under a light microscope...

 and Jenner's stain
Jenner's stain
Jenner's Stain is used in microscopy for staining blood smears....

. Since it is a temporary staining technique, methylene blue can also be used to examine RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 or DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 under the microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...

 or in a gel: as an example, a solution of methylene blue can be used to stain RNA on hybridization membranes in northern blot
Northern blot
The northern blot is a technique used in molecular biology research to study gene expression by detection of RNA in a sample. With northern blotting it is possible to observe cellular control over structure and function by determining the particular gene expression levels during differentiation,...

ting to verify the amount of nucleic acid present. While methylene blue is not as sensitive as ethidium bromide
Ethidium bromide
Ethidium bromide is an intercalating agent commonly used as a fluorescent tag in molecular biology laboratories for techniques such as agarose gel electrophoresis. It is commonly abbreviated as "EtBr", which is also an abbreviation for bromoethane...

, it is less toxic and it does not intercalate
Intercalation (chemistry)
In chemistry, intercalation is the reversible inclusion of a molecule between two other molecules . Examples include DNA intercalation and graphite intercalation compounds.- DNA intercalation :...

 in nucleic acid chains, thus avoiding interference with nucleic acid retention on hybridization membranes or with the hybridization process itself.

It can also be used as an indicator to determine if a cell such as yeast is alive or not. The blue indicator turns colorless indicating living cells. However, if it stays blue it doesn't mean that the cell is dead or there are no cells. Methylene blue can inhibit the respiration of the yeast as it picks up hydrogen ions made during the process and the yeast cell cannot then use those ions to release energy.

In neuroscience, methylene blue can also serve as a non-selective inhibitor of NO synthase.

Medicine

Methylene blue is a monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....

 (MAOI), and if infused intravenously at doses exceeding 5 mg/kg, may precipitate serious serotonin toxicity, serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...

, if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonin reuptake inhibitor (e.g., duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...

, sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...

, venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...

, clomipramine
Clomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...

, imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...

).

Methylene blue is also structurally similar to the chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...

 and the typical antipsychotics. It is the basic compound from which chlorpromazine and many other antipsychotics are made.

Methylene blue is a component of a frequently prescribed urinary analgesic/anti-infective/anti-spasmodic known as "Prosed", which also contains methanamine, hyoscyamine
Hyoscyamine
Hyoscyamine is a tropane alkaloid. It is a secondary metabolite found in certain plants of the Solanaceae family, including henbane , mandrake , jimsonweed , tomato and deadly nightshade...

 sulfate, and salicylate. A similar, more popular combination medication known as "Urised" (and its generic counterparts) was discontinued in 2007, quite possibly because of the way in which methanamine was included into the formulation (and its ease of separation from the other components of the medication), and the fact that methanamine is a precursor to methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...

, making it a target for clandestine use. The new formulation ("Prosed") sequesters the methanamine using a method which makes its separation nearly impossible.

Malaria

Methylene blue was identified by Paul Ehrlich
Paul Ehrlich
Paul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...

 about 1891 as a successful treatment for malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. It disappeared as an anti-malarial during the Pacific War
Pacific War
The Pacific War, also sometimes called the Asia-Pacific War refers broadly to the parts of World War II that took place in the Pacific Ocean, its islands, and in East Asia, then called the Far East...

 in the tropics, since American and Allied soldiers disliked its two prominent, but reversible side effects: turning the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 green, and the sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...

 (the whites of the eyes) blue. Interest in its use as an anti-malarial has recently been revived, especially due to its low price. Several clinical trials are in progress, trying to find a suitable drug combination. Initial attempts to combine methylene blue with chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...

 were disappointing; however, more recent attempts have appeared more promising.

Cancer

Recent research suggests that methylene blue, toluidine blue, and other 3,7-diaminophenothiazinium-based redox cyclers induce selective cancer cell apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

. Combined with plant auxin (indole-3-acetic acid), methylene blue is being investigated for the photodynamic treatment
Photodynamic therapy
Photodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic...

 of cancer.

Combined with light

Methylene blue combined with light has been used to treat resistant plaque psoriasis, AIDS-related Kaposi's sarcoma, West Nile virus, and to inactivate staphylococcus aureus, HIV-1, Duck hepatitis B, adenovirus vectors, and hepatitis C. Phenothiazine dyes and light have been known to have virucidal properties for over 80 years. In some circumstances, the combination can cause DNA damage that may lead to cancer.

Methemoglobinemia

While many texts indicate that methylene blue has oxidizing agent properties, its effects as an oxidizing agent occurs only at very high doses. At pharmacologic doses it has reducing agent properties. It is owing to this reason that methylene blue is employed as a medication for the treatment of methemoglobinemia
Methemoglobinemia
Methemoglobinemia is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood. Methemoglobin is an oxidized form of hemoglobin that has an increased affinity for oxygen, resulting in a reduced ability to release oxygen to tissues. The oxygen–hemoglobin...

. This can arise from ingestion of certain pharmaceuticals, toxins, or broad beans
Vicia faba
This article refers to the Broad Bean plant. For Broadbean the company, see Broadbean, Inc.Vicia faba, the Broad Bean, Fava Bean, Field Bean, Bell Bean or Tic Bean, is a species of bean native to north Africa and southwest Asia, and extensively cultivated elsewhere. A variety is provisionally...

. Through the methemoglobin reductase enzyme (which is NADPH dependent), it is reduced by NADPH allowing it to have an affinity for methylene blue (among other dyes). As a result, methylene blue is reduced to leucomethylene blue, which then acts to reduce the heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...

 group from methemoglobin to hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

. At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.

Methylene blue also blocks accumulation of cyclic guanosine monophosphate (cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...

) by inhibiting the enzyme guanylate cyclase
Guanylate cyclase
-Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:...

: this action results in reduced responsiveness of vessels to cGMP-dependent vasodilators like nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 and carbon monoxide
Carbon monoxide
Carbon monoxide , also called carbonous oxide, is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is highly toxic to humans and animals in higher quantities, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal...

. Cardiac surgical teams have found this very useful in the treatment of extremely low blood pressure (hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

)which may occur during heart surgery requiring cardiac bypass. Similar use is noted in the treatment of hypotension associated with overwhelming infections (sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

).

Cyanide poisoning

Since its reduction potential is similar to that of oxygen and can be reduced by components of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...

, large doses of methylene blue are sometimes used as an antidote to potassium cyanide
Potassium cyanide
Potassium cyanide is an inorganic compound with the formula KCN. This colorless crystalline compound, similar in appearance to sugar, is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications include jewelry for chemical gilding and...

 poisoning, a method first successfully tested in 1933 by Dr. Matilda Moldenhauer Brooks in San Francisco.

Carbon monoxide poisoning

Methylene blue was also used in the mid-twentieth century in the treatment of carbon monoxide poisoning
Carbon monoxide poisoning
Carbon monoxide poisoning occurs after enough inhalation of carbon monoxide . Carbon monoxide is a toxic gas, but, being colorless, odorless, tasteless, and initially non-irritating, it is very difficult for people to detect...

.

Dye

Methylene blue is used in endoscopic
Colonoscopy
Colonoscopy is the endoscopic examination of the large bowel and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It may provide a visual diagnosis and grants the opportunity for biopsy or removal of suspected...

 polypectomy
Polyp (medicine)
A polyp is an abnormal growth of tissue projecting from a mucous membrane. If it is attached to the surface by a narrow elongated stalk, it is said to be pedunculated. If no stalk is present, it is said to be sessile. Polyps are commonly found in the colon, stomach, nose, sinus, urinary bladder...

 as an adjunct to saline
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...

 or epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

, and is used for injection into the submucosa around the polyp to be removed. This allows the submucosal tissue plane to be identified after the polyp is removed, which is useful in determining if more tissue needs to be removed, or if there has been a high risk for perforation. Methylene blue is also used as a dye in chromoendoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...

, and is sprayed onto the mucosa of the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

 in order to identify dysplasia
Dysplasia
Dysplasia , is a term used in pathology to refer to an abnormality of development. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process...

, or pre-cancerous lesions. Intravenously injected methylene blue is readily released into the urine and thus can be used to test the urinary tract for leaks or fistula
Fistula
In medicine, a fistula is an abnormal connection or passageway between two epithelium-lined organs or vessels that normally do not connect. It is generally a disease condition, but a fistula may be surgically created for therapeutic reasons.-Locations:Fistulas can develop in various parts of the...

s.

In surgeries such as sentinel lymph node
Sentinel lymph node
The sentinel lymph node is the hypothetical first lymph node or group of nodes reached by metastasizing cancer cells from a primary tumor.-Physiology:...

 dissections, methylene blue can be used to visually trace the lymphatic drainage of pertinent tissues. Similarly, methylene blue is added to bone cement
Bone cement
Bone cements have been used very successfully to anchor artificial joints for more than half a century. Artificial joints are anchored with bone cement. The bone cement fills the free space between the prosthesis and the bone and plays the important role of an elastic zone...

 in orthopedic operations to provide easy discrimination between native bone and cement. Additionally, methylene blue accelerates the hardening of bone cement, increasing the speed at which bone cement can be effectively applied.

It can also be used to stain lymph nodes.

Placebo

Methylene blue has been used as a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

; physicians would tell their patients to expect their urine to change color and view this as a sign that their condition had improved. This same side effect makes methylene blue difficult to test in traditional placebo-controlled clinical studies.

Ifosfamide neurotoxicity

Another, less well-known use of methylene blue is its utility for treating ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...

 neurotoxicity. Methylene blue was first reported for treatment and prophylaxis of ifosfamide neuropsychiatric toxicity in 1994. A toxic metabolite of ifosfamide, chloroacetaldehyde
Chloroacetaldehyde
Chloroacetaldehyde is the organic compound with the formula ClCH2CHO. Like some related compounds, it is highly electrophilic reagent and a potentially dangerous alkylating agent. The compound is not normally encountered in the anhydrous form, but rather as the hydrate , ClCH2CH2. ...

 (CAA), disrupts the mitochondrial respiratory chain, leading to an accumulation of nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 hydrogen (NADH). Methylene blue acts as an alternative electron acceptor, and reverses the NADH inhibition of hepatic gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

 while also inhibiting the transformation of chloroethylamine into chloroacetaldehyde, and inhibits multiple amine oxidase activities, preventing the formation of CAA. The dosing of methylene blue for treatment of ifosfamide neurotoxicity varies, depending upon its use simultaneously as an adjuvant in ifosfamide infusion, versus its use to reverse psychiatric symptoms that manifest after completion of an ifosfamide infusion. Reports suggest that methylene blue at 50–60 mg up to six doses a day have resulted in improvement of symptoms within 10 minutes to several days. Alternatively, it has been suggested that intravenous methylene blue 50 mg every six hours for prophylaxis during ifosfamide treatment in patients with history of ifosfamide neuropsychiatric toxicity. Prophylactic administration of 50 mg of methylene blue the day before initiation of ifosfamide, and 50 mg three times daily during ifosfamide chemotherapy has been recommended to lower the occurrence of ifosfamide neurotoxicity.

Clinical trials

TauRx Therapeutics
TauRx Therapeutics
TauRx Therapeutics Ltd is a startup pharmaceutical company that is based in Singapore.The company was founded in 2002 by the late gynecologist, surgeon and venture capitalist K. M...

 has reported that methylene blue (methylthioninium chloride), under the tradename Rember
Rember
Methylthioninium chloride is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation. The drug is of potential interest for the treatment of patients with Alzheimer's...

, may provide a way of halting or slowing the progression of Alzheimer's dementia. However, the formulation used was different from that commonly available as a medicine and caution has been expressed about use of methylene blue as a treatment for Alzheimer's. TauRx Therapeutics has suggested that the mechanism by which methylene blue might delay or reverse neurodegeneration in Alzheimer's disease is as an inhibitor of Tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...

 aggregation. While methylene blue arguably has an effect on Tau aggregation, it also has an effect on mitochondrial function which is likely to play an important role. In vitro studies suggest that methylene blue might be an effective remedy for both Alzheimer's and Parkinson's disease by enhancing key mitochondrial biochemical pathways. It can disinhibit and increase complex IV, whose inhibition correlates with Alzheimer's disease.

Methylene blue might also delay senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...

 as one study has shown that it extended the lifespan of IMR90 fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s by more than 20 population doublings.

These findings are highly controversial, and a clear dosage response curve has not been found.

Aquaculture

Methylene blue is used in aquaculture
Aquaculture
Aquaculture, also known as aquafarming, is the farming of aquatic organisms such as fish, crustaceans, molluscs and aquatic plants. Aquaculture involves cultivating freshwater and saltwater populations under controlled conditions, and can be contrasted with commercial fishing, which is the...

 and by tropical fish hobbyists as a treatment for fungal infections. It can also be effective in treating fish infected with ich, the parasitic protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...

 Ichthyophthirius multifiliis. It is usually used to protect newly laid fish eggs from being infected by fungus or bacteria. This is useful when the hobbyist wants to artificially hatch the fish eggs.
Methylene Blue is also very effective when used as part of a "medicated fish bath" for treatment of ammonia, nitrite, and cyanide poisoning as well as for topical and internal treatment of injured or sick fish as a "first response".

As a prank

It is, or was at one time, a common prank among college students in biomedical fields to spike someone's drink with methylene blue, thus creating amusement at the victim's expense when he reacts with alarm to his urine turning blue. With concern over date rape drugs, spiking someone's drink is considered far more serious than it used to be, and the prank has somewhat gone out of fashion.

As a plot device

An episode of M*A*S*H, "Sons and Bowlers", showed Major Winchester using a dose of methylene blue to take down a rival camp's bowling
Bowling
Bowling Bowling Bowling (1375–1425; late Middle English bowle, variant of boule Bowling (1375–1425; late Middle English bowle, variant of boule...

 champion—who had been a high-ranked professional bowler in civilian life—during a contest. The champ panics when his urine turns blue, and listens to Winchester's advice to refrain from all exercise – including bowling, which allows the 4077th to win.

In the 1946 film noir, Decoy
Decoy (film)
Decoy is a 1946 American film noir. Directed by Jack Bernhard, the film stars Jean Gillie, Edward Norris, Robert Armstrong, Herbert Rudley, Sheldon Leonard and Marjorie Woodworth...

,
the chemical is portrayed in an entirely different manner - as having resuscitation qualities – in that it is used successfully to bring a criminal back to life after execution by hydrocyanic gas.

Adverse reactions

Cardiovascular Central Nervous System Dermatologic Gastrointestinal Genito-urinary Hematologic
Hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...


• Precordial pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

Dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....


• Mental confusion
Headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...


Fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

• Staining of skin
• Injection site necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 (SC)
• Fecal discoloration
Nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...


Vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...


• Abdominal pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

• Discoloration of urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...


Bladder
Bladder
Bladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...

 irritation
Anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...



Causes hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...

 in carriers of the G6PD (favism) enzymatic deficiency.

See also

  • New methylene blue
    New methylene blue
    New methylene blue is an organic staining agent used in diagnostic cytopathology and histopathology, typically for staining immature red blood cells. It is closely related to methylene blue, an older stain already in wide use....

  • Phenothiazine
    Phenothiazine
    Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...

     structure
  • Rember
    Rember
    Methylthioninium chloride is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation. The drug is of potential interest for the treatment of patients with Alzheimer's...

    , investigational drug for Alzheimer's disease containing methylene blue

External links

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