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Medical uses of Methylene Blue (wikipedia 8/2012) Methylene blue is a monoamine oxidase inhibitor (MAOI),[6] 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).[7] Methylene blue is also structurally similar to chlorpromazine and the typical antipsychotics. It is the basic compound from which chlorpromazine and many other antipsychotics are made.[8] 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').[9] [edit] Malaria 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,[10] 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;[11] however, more recent attempts have appeared more promising. [edit] 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.[12] Combined with plant auxin (indole-3-acetic acid), methylene blue is being investigated for the photodynamic treatment of cancer.[13] [edit] Combined with light Methylene blue combined with light has been used to treat resistant plaque psoriasis,[14] AIDS-related Kaposi's sarcoma,[15] West Nile virus,[16] and to inactivate staphylococcus aureus,[17] HIV-1,[18] Duck hepatitis B,[19] adenovirus vectors,[20] and hepatitis C.[21] Phenothiazine dyes and light have been known to have virucidal properties for over 80 years.[22] In some circumstances, the combination can cause DNA damage that may lead to cancer.[23][24] [edit] 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. This can arise from ingestion of certain pharmaceuticals, toxins, or broad beans.[citation needed]. 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, methemoglbin 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. [25] At high doses, however, methylene blue actually induces methemoglobinemia, reversing this pathway.[25] 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.[26] Similar use is noted in the treatment of hypotension associated with overwhelming infections (sepsis).[27] [edit] 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.[28] [edit] Carbon monoxide poisoning Methylene blue was also used in the mid-twentieth century in the treatment of carbon monoxide poisoning.[28] [edit] Dye/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. It can also be used to stain lymph nodes. When methylene blue is "polychromed" (Oxidized in solution or "ripened" by fungal metabolism,[29] 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.[30] 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).[31] [edit]