|Jmol-3D images||Image 1|
|Molar mass||319.85 g/mol|
100-110 °C (with decomposition)
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Methylene blue (CI 52015) is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. 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, another histology stain, new methylene blue, nor with the methyl violets often used as pH indicators.
Light absorption properties 
Methylene blue is a potent cationic dye with maximum absorption of light around 670 nm. The specifics of absorption depend on a number of factors, including protonation, adsorption to other materials, and metachromasy - the formation of dimers and higher-order aggregates depending on concentration and other interactions:
|Species||Absorption peak||Extinction coefficient (dm3/mole·cm)|
|MB+ (adsorbed on clay)||673||116000|
|MBH2+ (adsorbed on clay)||763||86000|
|(MB+)2 (adsorbed on clay)||596||80000|
|(MB+)3 (adsorbed on clay)||570||114000|
Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses of the micro-gram level there have been shown to be improvements in memory consolidation, and there is a neuroprotective effect as well. It also has been shown that in low doses methylene blue protects the brain from disease by acting as an antioxidant in the mitochondria, it also acts as an artificial electron donor to complex I, complex II, complex III, and complex IV of the mitochondria. However, methylene blue can take electrons away from the electron transport chain complexes, at higher doses. Methylene blue is capable of autoxidizing in vivo at low concentrations, in the reduced colorless form (leukomethylene blue). At these concentrations methylene blue and leukomethylene blue are at an equilibrium, and form a reversible reduction-oxidation system. This autoxidazing property provides a mechanism for electron transfer to oxygen. This may be responsible for the various dose related responses at the physiological, behaviorial and biochemical levels. Doses of 60 ug have been indicated for nootropic use.
Redox indicator 
Methylene blue is widely used as a redox indicator in analytical chemistry. 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 in general chemistry, the "blue bottle" experiment. Typically, a solution is made of glucose (dextrose), methylene blue, and sodium hydroxide. Upon shaking the bottle, oxygen 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 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.
Sulfide analysis 
The formation of methylene blue after the reaction of hydrogen sulfide with dimethyl-p-phenylenediamine and iron(III) at pH 0.4 – 0.7 is used to determine by photometric measurements sulfide 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 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, such as ascorbic acid, 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, 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 in an acidified, aqueous methylene blue solution containing chloroform can detect anionic surfactants in a water sample. Such a test is known as an MBAS assay (methylene blue active substances assay).
In biology methylene blue is used as a dye for a number of different staining procedures, such as Wright's stain and Jenner's stain. Since it is a temporary staining technique, methylene blue can also be used to examine RNA or DNA under the microscope or in a gel: as an example, a solution of methylene blue can be used to stain RNA on hybridization membranes in northern blotting to verify the amount of nucleic acid present. While methylene blue is not as sensitive as ethidium bromide, it is less toxic and it does not intercalate 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 eukaryotic cells such as yeast are alive or not. The methylene blue is unable to penetrate viable cells leaving them unstained. However dead cells are unable to keep the methylene blue from penetrating the cell membrane, staining the cells blue. 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.
Medical uses 
Methylene blue is a monoamine oxidase inhibitor (MAOI), and if infused intravenously at doses exceeding 5 mg/kg, may precipitate serious serotonin toxicity, serotonin syndrome, if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonin reuptake inhibitor (e.g., duloxetine, sibutramine, venlafaxine, clomipramine, imipramine).
Methylene blue is a component of a frequently prescribed urinary analgesic/anti-infective/anti-spasmodic known as "Prosed", a combination of drugs which also contains phenyl salicylate, benzoic acid, hyoscyamine sulfate, and methenamine (aka hexamethylenetetramine and not to be confused with 'methanamine').
Methylene blue was identified by Paul Ehrlich about 1891 as a successful treatment for malaria. It disappeared as an anti-malarial during the Pacific War in the tropics, since American and Allied soldiers disliked its two prominent, but reversible side effects: turning the urine green, and the sclera (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 were disappointing; however, more recent attempts have appeared more promising.
Recent research suggests that methylene blue, toluidine blue, and other 3,7-diaminophenothiazinium-based redox cyclers induce selective cancer cell apoptosis by NAD(P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Combined with plant auxin (indole-3-acetic acid), methylene blue is being investigated for the photodynamic treatment 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.
While many texts indicate that methylene blue has oxidizing agent properties, its effects as an oxidizing agent occur 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. This can arise from ingestion of certain pharmaceuticals, toxins, or broad beans.. Normally, through the NADH or NADPH dependent methemoglobin reductase enzymes, methemoglobin is reduced back to hemoglobin. When large amounts of methemoglobin occur secondary to toxins, methemoglobin reductases are overwhelmed. Methylene blue, when injected intravenously as an antidote, is itself first reduced to leucomethylene blue, which then reduces the heme group from methemoglobin to hemoglobin. Methylene blue can reduce the half life of methemoglobin from hours to minutes. At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.
Methylene blue also blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase: this action results in reduced responsiveness of vessels to cGMP-dependent vasodilators like nitric oxide and carbon monoxide. Cardiac surgical teams have found this very useful in the treatment of extremely low blood pressure (hypotension)which may occur during heart surgery requiring cardiac bypass. Similar use is noted in the treatment of hypotension associated with overwhelming infections (sepsis).
Cyanide poisoning 
Since its reduction potential is similar to that of oxygen and can be reduced by components of the electron transport chain, large doses of methylene blue are sometimes used as an antidote to potassium cyanide poisoning, a method first successfully tested in 1933 by Dr. Matilda Moldenhauer Brooks in San Francisco.
Carbon monoxide poisoning 
Methylene blue is used in endoscopic polypectomy as an adjunct to saline or epinephrine, 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, and is sprayed onto the mucosa of the gastrointestinal tract in order to identify dysplasia, 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 fistulas.
In surgeries such as sentinel lymph node dissections, methylene blue can be used to visually trace the lymphatic drainage of pertinent tissues. Similarly, methylene blue is added to bone cement 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.
When methylene blue is "polychromed" (Oxidized in solution or "ripened" by fungal metabolism, as originally noted in the thesis of Dr D L Romanowsky in 1890's), it gets serially demethylated and forms all the tri, di, mono and non methyl intermediates - which are Azure B, Azure A, Azure C and thionine respectively. This is the basis of the basophilic part of the spectrum of Romanowski-Giemsa effect. If only synthetic Azure B and Eosin Y is used, it may serve as a standardized Giemsa stain; but, without methylene blue, the normal neutrophilic granules tend to overstain and look like toxic granules. On the other hand, if methylene blue is used it might help to give the normal look of neutrophil granules and may additionally also enhances the staining of nucleoli and polychromatophilic RBCs (reticulocytes).
Methylene blue has been used as a placebo; 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 neurotoxicity. Methylene blue was first reported for treatment and prophylaxis of ifosfamide neuropsychiatric toxicity in 1994. A toxic metabolite of ifosfamide, chloroacetaldehyde (CAA), disrupts the mitochondrial respiratory chain, leading to an accumulation of nicotinamide adenine dinucleotide hydrogen (NADH). Methylene blue acts as an alternative electron acceptor, and reverses the NADH inhibition of hepatic gluconeogenesis 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 has reported that methylene blue (methylthioninium chloride), under the tradename Rember, 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 aggregation. While methylene blue arguably has an effect on Tau aggregation, it has been shown to have a great effect in dissociation of amyloids and also has an effect on mitochondrial function which are both likely targets that result in its therapeutic effect. 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.
These findings are highly controversial, and a clear dosage response curve has not been found.
Methylene blue is used in aquaculture 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 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".
Methylene blue has been described as "the first fully synthetic drug used in medicine." Its use in the treatment of malaria was pioneered by Paul Guttman and Paul Ehrlich in 1891. During this period before the first World War, researchers like Ehrlich believed that drugs and dyes worked in the same way, by preferentially staining pathogens and possibly harming them. Methylene blue continued to be used in the second World War, where it was not well liked by soldiers, who observed, "Even at the loo, we see, we pee, navy blue." Antimalarial use of the drug has recently been revived. The blue urine was used to monitor psychiatric patients' compliance with medication regimes. This led to interest - from the 1890s to the present day - in the drug's antidepressant and other psychotropic effects. It became the lead compound in research leading to the discovery of chlorpromazine.
In popular culture 
In the 1946 film noir, Decoy, the chemical is portrayed in an entirely different manner - as having resuscitative qualities – in that it is used successfully to bring a criminal back to life after execution by hydrocyanic gas.
A 1982 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 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.
Adverse reactions 
|Cardiovascular||Central Nervous System||Dermatologic||Gastrointestinal||Genito-urinary||Hematologic|
• Precordial pain
• Mental confusion
|• Staining of skin
• Injection site necrosis (SC)
|• Fecal discoloration
• Abdominal pain
|• Discoloration of urine
• Bladder irritation
See also 
- New methylene blue
- Phenothiazine structure
- Rember, investigational drug for Alzheimer's disease containing methylene blue
- Romanowsky stain
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