Methylene blue

For the pharmaceutical uses of this chemical, see methylthioninium chloride.
Methylene blue
Names
IUPAC names
3,7-bis(Dimethylamino)-
phenothiazin-5-ium chloride
Other names
C.I. 52015
Identifiers
ATC code V03AB17
V04CG05
61-73-4 Yes
ChEBI CHEBI:6872 Yes
ChEMBL ChEMBL405110 Yes
ChemSpider 5874 Yes
Jmol-3D images Image
PubChem 6099
UNII 8NAP7826UB Yes
Properties
C16H18N3SCl
Molar mass 319.85 g/mol
Melting point 100 to 110 °C (212 to 230 °F; 373 to 383 K) (with decomposition)
Boiling point Decomposes
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 Yes verify (what is: Yes/?)
Infobox references

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.[1] 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.

As an experimental pharmaceutical drug, the International Nonproprietary Name (INN) of methylene blue is methylthioninium chloride.[2][3]

Methylene blue was first prepared in 1876 by German chemist Heinrich Caro (1834-1910).[4] It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[5]

Medical uses

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').[6]

Combined with light

Methylene blue combined with light has been used to treat resistant plaque psoriasis,[7] AIDS-related Kaposi's sarcoma,[8] West Nile virus,[9] and to inactivate staphylococcus aureus,[10] HIV-1,[11] Duck hepatitis B,[12] adenovirus vectors,[13] and hepatitis C.[14] Phenothiazine dyes and light have been known to have virucidal properties for over 80 years.[15] In some circumstances, the combination can cause DNA damage that may lead to cancer.[16][17]

Methemoglobinemia

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.[18] At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.[18]

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.[19] Similar use is noted in the treatment of hypotension associated with overwhelming infections (sepsis).[20]

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,[21] although first demonstrated by Bo Sahlin of Lund University, in 1926.[21][22]

Dye or stain

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. Methylene blue is used as an aid to visualisation/orientation in a number of medical devices, including a Surgical sealant film, TissuePatch.

When methylene blue is "polychromed" (oxidized in solution or "ripened" by fungal metabolism,[23] 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.[24] 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).[25]

A traditional application of methylene blue is the intravital or supravital staining of nerve fibers, an effect first described by Paul Ehrlich in 1887.[26] A dilute solution of the dye is either injected into tissue or applied to small freshly removed pieces. The selective blue coloration develops with exposure to air (oxygen) and can be fixed by immersion of the stained specimen in an aqueous solution of ammonium molybdate. Vital methylene blue was formerly much used for examining the innervation of muscle, skin and internal organs.[27][28][29] The mechanism of selective dye uptake is incompletely understood; vital staining of nerve fibers in skin is prevented by ouabain, a drug that inhibits the Na/K-ATPase of cell membranes.[30]

Placebo

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.[31] This same side effect makes methylene blue difficult to test in traditional placebo-controlled clinical studies.[32]

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.[33] 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 up to six doses a day have resulted in improvement of symptoms within 10 minutes to several days.[34] Alternatively, it has been suggested that intravenous methylene blue every six hours for prophylaxis during ifosfamide treatment in patients with history of ifosfamide neuropsychiatric toxicity.[35] Prophylactic administration of methylene blue the day before initiation of ifosfamide, and three times daily during ifosfamide chemotherapy has been recommended to lower the occurrence of ifosfamide neurotoxicity.[36]

Vasoplegic syndrome after cardiac surgery

Some literature has reported the use of methylene blue as an adjunct in the management of patients experiencing vasoplegic syndrome after cardiac surgery.[37][38][39]

History

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 Guttmann 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.[40] 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.[41]

Side effects

Cardiovascular Central Nervous System Dermatologic Gastrointestinal Genito-urinary Hematologic
• Hypertension
• Precordial pain		 • Dizziness
• Mental confusion
• Headache
• Fever		 • Staining of skin
• Injection site necrosis (SC)		 • Fecal discoloration
• Nausea
• Vomiting
• Abdominal pain		 • Discoloration of urine (doses over 80µg)
• Bladder irritation		 • Anemia

[42][43]

Methylene blue is a monoamine oxidase inhibitor (MAOI),[44] 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).[45]

It causes hemolytic anemia in carriers of the G6PD (favism) enzymatic deficiency.

Preparation

This compound may be prepared by treating dimethyl-4-phenylenediamine with hydrogen sulfide dissolved in hydrochloric acid, followed by oxidation with ferric chloride:[46]

Light absorption properties

Absorption spectrum of methylene blue, in terms of the molar extinction coefficient (base 10 logarithm). In this dataset a peak absorbance of 1.7 (i.e. 98% of transmitted light absorbed) was observed with 665 nm light passing through 1 cm of 10 micromolar methylene blue solution.

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:[47]

Species Absorption peak Extinction coefficient (dm3/mole·cm)
MB+ (solution) 664 95000
MBH2+ (solution) 741 76000
(MB+)2 (solution) 605 132000
(MB+)3 (solution) 580 110000
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

Other uses

A volumetric flask of a methylene blue solution

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[48] 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

Further information: MBAS assay

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).

The MBAS assay cannot distinguish between specific surfactants, however. Some examples of anionic surfactants are carboxylates, phosphates, sulfates, and sulfonates.

Methylene Blue Value of Fine Aggregate

Methylene Blue Value reflects the amount of the clay minerals in the aggregate samples.[49] Methylene Blue solution is successively added to fine aggregate which is being agitating in water. The presence of free dye solution can be checked with stain test on a filter paper.[50]

Biology

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 reduced in viable cells leaving them unstained. However dead cells are unable to reduce the oxidized methylene blue and the cells are stained blue. Methylene blue can interfere with 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.

Aquaculture

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 although a combination of malachite green and formaldehyde are far more effective against 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".[51]

Research

Malaria

Methylene blue was identified by Paul Ehrlich about 1891 as a possible treatment for malaria.[52] 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 blue or green, and the sclera (the whites of the eyes) blue. Interest in its use as an anti-malarial has recently been revived,[41] 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.[53]

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.[54] 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.[55] 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[56] 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.
As of June, 2013, the company is soliciting patients to participate in a phase III clinical trial of their product after achieving what the company described as, "remarkable success" in phase II. They have reformulated the drug, creating LMTX™, which has been prioritised ahead of rember® due-to better outcome expected with the newer product.[57]

Methylene blue might also delay senescence as one study has shown that it extended the lifespan of IMR90 fibroblasts by more than 20 population doublings.[58]

The new formula LMTX™, addresses some of the concerns about dose-response which were raised earlier in the study.[59]

Cancer

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.[60] Combined with plant auxin (indole-3-acetic acid), methylene blue is being investigated for the photodynamic treatment of cancer.[61]

See also

References

  1. ↑ http://www.methylene-blue.com/substance.php
  2. ↑ Adams V., Marley J., McCarroll C. (November 2007). "Prilocaine induced methaemoglobinaemia in a medically compromised patient. Was this an inevitable consequence of the dose administered?". Br. Dent. J. 203 (10): 585–7. doi:10.1038/bdj.2007.1045. PMID 18037845.
  3. ↑ Linz A.J., Greenham R.K., Fallon L.F. (May 2006). "Methemoglobinemia: an industrial outbreak among rubber molding workers". J. Occup. Environ. Med. 48 (5): 523–8. doi:10.1097/01.jom.0000201815.32098.99. PMID 16688009.
  4. ↑ Badische Anilin- und Sodafabrik [BASF] (Mannheim, Germany), "Verfahren zur Darstellung blauer Farbstoffe aus Dimethylanilin und anderen tertiaren aromatischen Monaminen" (Method for preparation of blue dyes from dimethylaniline and other tertiary aromatic monoamines), Deutsches Reich Patent no. 1886 (December 15, 1877). Available on-line at: P. Friedlaender, Fortschritte der Theerfarbenfabrikation und verwandter Industriezweige (Progress of the manufacture of coal-tar dyes and related branches of industry), volume 1 (Berlin, Germany: Julius Springer, 1888), pages 247-249.
    See also:
  5. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  6. ↑ http://www.rxlist.com/prosed-ds-drug.htm
  7. ↑ Salah M., Samy N., Fadel M. (January 2009). "Methylene blue mediated photodynamic therapy for resistant plaque psoriasis". J. Drugs Dermatol. 8 (1): 42–9. PMID 19180895.
  8. ↑ Tardivo J.P., Del Giglio A., Paschoal L.H., Baptista M.S. (August 2006). "New photodynamic therapy protocol to treat AIDS-related Kaposi's sarcoma". Photomed Laser Surg 24 (4): 528–31. doi:10.1089/pho.2006.24.528. PMID 16942436.
  9. ↑ Papin J.F., Floyd R.A., Dittmer D.P. (November 2005). "Methylene blue photoinactivation abolishes West Nile virus infectivity in vivo". Antiviral Res. 68 (2): 84–7. doi:10.1016/j.antiviral.2005.07.001. PMID 16118025.
  10. ↑ Zolfaghari P.S., Packer S., Singer M., Nair S.P., Bennett J., Street C., Wilson M. (2009). "In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent". BMC Microbiol. 9: 27. doi:10.1186/1471-2180-9-27. PMC 2642833. PMID 19193212.
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  13. ↑ Schagen F.H., Moor A.C., Cheong S.C., Cramer S.J., van Ormondt H., van der Eb A.J., Dubbelman T.M., Hoeben R.C. (May 1999). "Photodynamic treatment of adenoviral vectors with visible light: an easy and convenient method for viral inactivation". Gene Ther. 6 (5): 873–81. doi:10.1038/sj.gt.3300897. PMID 10505113.
  14. ↑ Müller-Breitkreutz K., Mohr H. (November 1998). "Hepatitis C and human immunodeficiency virus RNA degradation by methylene blue/light treatment of human plasma". J. Med. Virol. 56 (3): 239–45. doi:10.1002/(SICI)1096-9071(199811)56:3<239::AID-JMV11>3.0.CO;2-9. PMID 9783692.
  15. ↑ Wagner S.J., Skripchenko A., Robinette D., Mallory D.A., Hirayama J., Cincotta L., Foley J. (2000). "The use of dimethylmethylene blue for virus photoinactivation of red cell suspensions". Dev. Biol. (Basel) 102: 125–9. PMID 10794099.
  16. ↑ Sturmey R.G., Wild C.P., Hardie L.J. (May 2009). "Removal of red light minimizes methylene blue-stimulated DNA damage in oesophageal cells: implications for chromoendoscopy". Mutagenesis 24 (3): 253–8. doi:10.1093/mutage/gep004. PMID 19218330.
  17. ↑ Olliver J.R., Wild C.P., Sahay P., Dexter S., Hardie L.J. (August 2003). "Chromoendoscopy with methylene blue and associated DNA damage in Barrett's oesophagus". Lancet 362 (9381): 373–4. doi:10.1016/S0140-6736(03)14026-3. PMID 12907012.
  18. ↑ 18.0 18.1 Brent J. (2005). Critical care toxicology: diagnosis and management of the critically poisoned patient. Elsevier Health Sciences.
  19. ↑ http://jtcs.ctsnetjournals.org/cgi/content/abstract/125/6/1426
  20. ↑ http://www.medscape.com/viewarticle/409626
  21. ↑ 21.0 21.1 Matilda Moldenhauer Brooks (1936). "Methylene blue as an antidote for cyanide and carbon monoxide poisoning". The Scientific Monthly 43 (6): 585–586. JSTOR 16280.
  22. ↑ http://jama.jamanetwork.com/article.aspx?articleid=241464
  23. ↑ Dako Education Guide - Special Stains and H & E " second edition Chapter 19: On Chemical Reactions and Staining Mechanisms by John A. Kiernan, Subsection What is Giemsa’s stain and how does it color blood cells, bacteria and chromosomes? p172
  24. ↑ J Exp Med. 1907 Nov 1;9(6):645-70. ON THE CHEMISTRY AND STAINING PROPERTIES OF CERTAIN DERIVATIVES OF THE METHYLENE BLUE GROUP WHEN COMBINED WITH EOSIN. Wilson TM.
  25. ↑ Dacie and Lewis Practical Haematology 10th ed, p61
  26. ↑ Ehrlich,P. (1887) Biol. Centralblatt 6: 214, cited from Baker JR (1958) Principles of Biological Microtechnique (Reprinted 1970, with corrections). Methuen, London.
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  28. ↑ Schabadasch A (1930) Untersuchungen zur Methodik der Methylenblaufarbung des vegetativen Nervensystems. Zeitschrift fur Zellforschung 10: 221-243.
  29. ↑ Zacks Zacks SI (1973) The Motor Endplate, 2nd ed. Huntington, NY: Krieger
  30. ↑ Kiernan JA (1974) Effects of metabolic inhibitors on vital staining with methylene blue. Histochemistry 40: 51-57.
  31. ↑ Novella Steve. "The ethics of deception in medicine". Science Based Medicine. Retrieved 2008-01-24.
  32. ↑ "Methylene blue for cognitive dysfunction in bipolar disorder". United States National Library of Medicine. September 20, 2005. Retrieved 2009-02-15.
  33. ↑ Alici-Evcimen Y., Breitbart W.S. (October 2007). "Ifosfamide neuropsychiatric toxicity in patients with cancer". Psychooncology 16 (10): 956–960. doi:10.1002/pon.1161. PMID 17278152.
  34. ↑ Patel P.N. (2006). "Methylene blue for management of ifosfamide induced encephalopathy". Annals of Pharmacotherapy 40 (2): 266–303. doi:10.1345/aph.1G114. PMID 16391008.
  35. ↑ Dufour C.; Grill J.; Sabouraud P. et al. (February 2006). "Ifosfamide induced encephalopathy: 15 observations". Arch. Pediatr. (in French) 13 (2): 140–145. doi:10.1016/j.arcped.2005.10.021. PMID 16364615.
  36. ↑ Aeschlimann T.; Cerny, T; Küpfer, A (1996). "Inhibition of (mono)amine oxidase activity and prevention of ifosfamide encephalopathy by methylene blue". Drug. Metab. Dispos. 24 (12): 1336–1339. PMID 8971139.
  37. ↑ Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ (February 2004). "Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery.". Ann Thorac Surg 77 (2): 496–9. doi:10.1016/S0003-4975(03)01510-8. PMID 14759425.
  38. ↑ "BestBets: Is Methylene Blue of benefit in treating adult patients who develop vasoplegic syndrome during Cardiac Surgery".
  39. ↑ Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH (May 2008). "Methylene blue and vasoplegia: who, when, and how?". Mini Rev Med Chem 8 (5): 472–90. doi:10.2174/138955708784223477. PMID 18473936.
  40. ↑ http://www.plosone.org/article/info:doi/10.1371/journal.pone.0005318
  41. ↑ 41.0 41.1 Schirmer H.; Coulibaly B.; Stich A. et al. (2003). "Methylene blue as an antimalarial agent—past and future". Redox Rep 8 (5): 272–276. doi:10.1179/135100003225002899. PMID 14962363.
  42. ↑ Mokhlesi B., Leikin J.B., Murray P., Corbridge T.C. (March 2003). "Adult toxicology in critical care: Part II: specific poisonings". Chest 123 (3): 897–922. doi:10.1378/chest.123.3.897. PMID 12628894.
  43. ↑ Harvey J.W., Keitt A.S. (May 1983). "Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia". Br. J. Haematol. 54 (1): 29–41. doi:10.1111/j.1365-2141.1983.tb02064.x. PMID 6849836.
  44. ↑ Ramsay RR; Dunford, C.; Gillman, C.K. (August 2007). "Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction.". Br J Pharmacol 152 (6): 946–951. doi:10.1038/sj.bjp.0707430. PMC 2078225. PMID 17721552.
  45. ↑ Gillman P.K. (October 2006). "Methylene blue implicated in potentially fatal serotonin toxicity". Anaesthesia 61 (10): 1013–4. doi:10.1111/j.1365-2044.2006.04808.x. PMID 16978328.
  46. ↑ L. Michaelis; M. P. Schubert; S. Granick (1940). "Semiquinone Radicals of the Thiazines". J. Am. Chem. Soc. 62 (1): 204–211. doi:10.1021/ja01858a060.
  47. ↑ J. Cenens and R. A. Schoonheydt (1988). "VISIBLE SPECTROSCOPY OF METHYLENE BLUE ON HECTORITE, LAPONITE B, AND BARASYM IN AQUEOUS SUSPENSION" (PDF). Clay and Clay Minerals 36 (3): 214–224.
  48. ↑ Spectroquant 114779 Sulfide Test. Method: photometric 0.020 - 1.50 mg/l S2−
  49. ↑ Standard Test Method for Rapid Determination of the Methylene Blue Value for Fine Aggregate or Mineral Filler Using a Colorimeter
  50. ↑ Construction Standard CS3:2013 – Aggregates for Concrete
  51. ↑ Aquarium Chemical Treatments
  52. ↑ Guttmann, P. and Ehrlich. P. (1891) "Über die Wirkung des Methylenblau bei Malaria" (On the effect of methylene blue on malaria), Berliner Klinische Wochenschrift, 28 : 953-956.
  53. ↑ Meissner P.E.; Mandi G.; Coulibaly B. et al. (2006). "Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine". Malaria Journal 5: 84. doi:10.1186/1475-2875-5-84. PMC 1617109. PMID 17026773.
  54. ↑ "Alzheimer's drug 'halts' decline". BBC News. 2008-07-30. Retrieved 2008-07-30.
  55. ↑ "Slowing disease's mental ravages". Chicago Tribune. 2008-07-30.
  56. ↑ Medina DX, C. A., Oddo S (2011). "Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity." Brain Pathology 21(2): 140-149.
  57. ↑ "Phase III".
  58. ↑ Atamna H., Nguyen A., Schultz C., Boyle K., Newberry J., Kato H., Ames B.N. (March 2008). "Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways". FASEB J. 22 (3): 703–712. doi:10.1096/fj.07-9610com. PMID 17928358.
  59. ↑ "Concerns".
  60. ↑ NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis. Wondrak GT. Free Radic Biol Med. 2007 Jul 15;43(2):178-90
  61. ↑ http://cancerres.aacrjournals.org/cgi/content/full/63/4/776

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