Methylene Blue is one of the first synthetic pharmaceuticals used in medicine. First discovered over one hundred years ago, it has most recently been studied to treat respiratory disease for patients severely affected by COVID-19-related medical protocols.
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What is Methylene Blue?
Methylene blue has historic uses as a dye for medical procedures in addition to treatment for methemoglobinemia, cyanide poisoning, ifosfamide toxicity, and shock. Most recently it has undergone clinical trials as a treatment for COVID-19-related respiratory disease and is on the World Health Organization’s List of Essential Medicines.
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Methylene Blue History
First prepared by German chemist Heinrich Caro in 1876, Methylene blue is referred to as “the first fully synthetic drug used in medicine.” Initially used to treat malaria, it was followed by administration for the treatment of carbon monoxide and cyanide poisoning in 1933 by Matilda Brooks.
Methylene Blue Uses
Methylene blue has a wide range of medical applications in addition to its use as a dye in various procedures. Some conditions treated by methylene blue include:
Methemoglobinemia
Methylene blue is used to treat methemoglobinemia caused by ingesting specific pharmaceuticals, toxic substances, or broad beans. Its mechanism of action is through the NADH or NADPH-dependent methemoglobin reductase enzymes that reduce methemoglobin back to hemoglobin.
When injected intravenously, methylene blue is reduced to leucomethylene blue, lowering the heme group to hemoglobin from methemoglobin. While methylene blue can reduce the half-life of methemoglobin from hours to minutes, large amounts can result in methemoglobinemia.
Cyanide poisoning
Large doses of methylene blue were used to treat potassium cyanide poisoning. Since the reduction potential of methylene blue is similar to that of oxygen, it can also be reduced by specific components of the electron transport chain.
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Dye or stain
When used as an adjunct to saline or epinephrine, methylene blue is used in endoscopic polypectomy when injected into submucosa to remove polyps. Since methylene blue enables practitioners to identify submucosal tissue planes, it is useful to determine if more tissue needs to be removed or there is perforation risk.
Methylene blue is also used to identify dysplasia or precancerous lesions as a dye in chromoendoscopy. In addition, methylene blue can be injected into urine to test the urinary tract for fistulas or leaks.
Other uses of methylene blue include:
- Sentinel lymph node dissections
- Addition to bone cement in orthopedic operations
- Visualisation aid for medical devices
- Excision of fistulas and pilonidal sinuses
- Gastrointestinal surgeries: bowel resection, gastric bypass
- Redox indicator
- Peroxide generator
- Biological staining
- Water testing
- Sulfide analysis
- Aquaculture
Ifosfamide toxicity
Methylene blue is used to treat ifosfamide neurotoxicity. First reported in 1994, methylene blue was administered for the treatment and prophylaxis of ifosfamide neuropsychiatric toxicity. Chloroacetaldehyde, a toxic metabolite of ifosfamide, disrupts the mitochondrial respiratory chain and results in the accumulation of nicotinamide adenine dinucleotide hydrogen.
Methylene blue reverses the NADH inhibition of hepatic gluconeogenesis and acts as an alternative electron acceptor. It also prevents chloroethylamine’s transformation into chloroacetaldehyde and inhibits multiple amine oxidase activities, preventing the formation of chloroacetaldehyde.
Shock
Methylene blue is used to treat septic shock and anaphylaxis. For people with vasoplegic syndrome (redistributive shock), methylene blue consistently increases blood pressure, however has not been shown to improve oxygen delivery or decrease in mortality.
Methylene Blue Treatment for COVID-19
Currently, there is no pharmacological intervention to treat hypoxemia and respiratory distress in COVID-19 patients. Methylene Blue is presently being studied as a protocol to improve oxygen saturation (SpO2) and respiratory rate (RR). Early results have shown that adding methylene blue to treatment protocols significantly improves SpO2 and the signs of respiratory distress in patients affected by COVID-19, resulting in decreased hospital stay and mortality.
Methylene Blue Structure
Methylene blue is a formal derivative of phenothiazine. When in a hydrated form, it has three water molecules per unit of methylene blue with a pH of 6 in water (at 10g/l) at a temperature of 25°C (77 °F).
Methylene Blue Mechanism of Action
Methylene Blue converts the ferric iron in hemoglobin to ferrous iron, a process where the iron atom loses two electrons to form Fe+2.
Methylene Blue Studies
Current research trials for methylene blue include:
- Methylene Blue For Treatment of Hospitalized COVID-19 patients: A randomized, controlled, open-label clinical trial. https://pubmed.ncbi.nlm.nih.gov/34019535/
- Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. https://pubmed.ncbi.nlm.nih.gov/24101169/
- Methylene blue fluorescence of the ureter during colorectal surgery. https://pubmed.ncbi.nlm.nih.gov/29785456/
- Methylene blue reduces incidence of early postoperative cognitive disorders in elderly patients undergoing major non-cardiac surgery: An open-label randomized controlled clinical trial. https://pubmed.ncbi.nlm.nih.gov/33091706/
- Modified methylene blue injection improves lymph node harvest in rectal cancer. https://pubmed.ncbi.nlm.nih.gov/25331064/
- Methylene blue vs. methyl aminolevulinate photodynamic therapy in the treatment of mild-to-moderate toenail onychomycosis: Short- and medium-term effects. https://pubmed.ncbi.nlm.nih.gov/32890444/
- Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. https://pubmed.ncbi.nlm.nih.gov/27284082/
- Intradiskal methylene blue treatment for diskogenic low back pain. https://pubmed.ncbi.nlm.nih.gov/24780850/
Methylene Blue Side Effects
Side effects of methylene blue range widely and can include:
- Cardiovascular: hypertension, precordial pain
- Central Nervous System: fever, headache, mental confusion, dizziness
- Dermatologic: skin staining, necrosis at the injection site
- Hematologic: anemia
- Gastrointestinal: nausea, vomiting, abdominal pain, fecal discoloration
- Genito-urinary: urine discoloration, bladder irritation
Methylene Blue Price
Prices for methylene blue can vary significantly according to manufacturer and country of origin. Click here to receive a quote for GMP-certified methylene blue.
Methylene Blue FAQ
Methylene blue has a half-life of 5 to 24 hours, depending on the amount administered.
Side effects of methylene blue include hypertension, precordial pain, fever, headache, mental confusion, dizziness, skin staining, necrosis at the injection site, anemia, nausea, vomiting, abdominal pain, fecal discoloration, urine discoloration, and bladder irritation.
Side effects of methylene blue vary according to the type of treatment and dosage. Typically, the half-life of methylene blue is 5-24 hours, where its amount decreases by half during each successive time period.
Prices vary according to manufacturer and country of origin. Click here to obtain a quote for GMP-certified methylene blue.
