Methylene Blue C₁₆H₁₈ClN₃S·xH₂O

Methylene Blue C₁₆H₁₈ClN₃S·xH₂O

Product Name: метиленовый синий, methylene blue, methylenblau, azul de metileno, bleu de méthylène, أزرق الميثيلين, เมทิลีนบลู, метилен кўки, метилен көк, метилен göy, метилен кабуд, metileno mėlyna, metilēna zils, метилен синій, כחול מתילן

Main Indications for Methylene Blue: Acquired methemoglobinemia, hereditary methemoglobinemia, ifosfamide-induced encephalopathy, vasoplegic syndrome after cardiac surgery, refractory hypotension in septic shock, bacterial urinary tract infections, acute cystitis, acute urethritis, fungal infections of the skin and mucous membranes, malaria caused by Plasmodium falciparum.

Indications for Methylene Blue as part of therapeutic complexes: Malignant neoplasms of the breast, malignant neoplasms of the ovaries, malignant neoplasms of the endometrium, primary hyperparathyroidism, soft tissue infections with polyresistant bacterial flora, chronic periodontitis, infected chronic wounds, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease).

Main Pharmacological Properties of Methylene Blue: antidote, antiseptic, antimicrobial, antifungal, antioxidant, photosensitizing, neuroprotective, mitochondrial-protective, anti-inflammatory, diagnostic (staining).

Composition of Methylene Blue: methylene blue, aqua purificata (purified water)

Functions of the Components Included in Methylene Blue:

• Methylene blue: performs the main pharmacological role, has an antidote effect in methemoglobinemia, exerts antiseptic and photosensitizing effects, used in diagnostic procedures.
• Aqua purificata (purified water): serves as a solvent and carrier for the active substance, ensures stability and uniform distribution of the solution.

Product Form of Methylene Blue: Solution for intravenous administration in 10 ml and 20 ml vials, containing 1% methylene blue (10 mg/ml). One 10 ml ampoule contains 100 mg of active substance (methylene blue) and an excipient — aqua purificata. Also available in 50 ml and 100 ml vials for use in diagnostics and photodynamic therapy.

Dosage for Methylene Blue

Standard Dosage for Methylene Blue: For adults with methemoglobinemia, the standard dose is 1–2 mg/kg body weight intravenously slowly over 5 minutes. If necessary, administration can be repeated after 1 hour, if clinical symptoms persist. This regimen is used for mild to moderate methemoglobinemia. Administered regardless of food intake, in a hospital setting.

Enhanced Dosage for Methylene Blue: For severe methemoglobinemia, refractory hypotension (vasoplegic syndrome, septic shock), enhanced doses of 1.5–2 mg/kg are used intravenously as a bolus, sometimes followed by an infusion of 0.25–1 mg/kg/h for up to 12–24 hours. Used only under hemodynamic monitoring and in intensive care settings.

Maximum Dosage for Methylene Blue: The maximum permissible dose for an adult is 7 mg/kg body weight per day. Exceeding this can cause paradoxical increase in methemoglobin, hemolysis, and severe complications. Permissible only in life-threatening conditions and only in a specialized hospital setting.

Pediatric Dosage for Methylene Blue: Used with caution in children over 3 months of age. For methemoglobinemia, the dose is 1 mg/kg intravenously slowly; if necessary, repeat administration after 1 hour is possible. In children under 3 months, the drug is contraindicated due to the risk of hemolysis and hyperbilirubinemia. Not used for prophylactic purposes in pediatrics.

Prophylactic Dosage for Methylene Blue: Prophylactic use is limited. Used for ifosfamide-induced encephalopathy: 50 mg intravenously every 6 hours throughout the period of ifosfamide therapy. For other chronic conditions, a prophylactic dose is not scientifically substantiated and is not used.

Contraindications for Methylene Blue: Contraindicated in glucose-6-phosphate dehydrogenase deficiency, severe renal failure, pregnancy (teratogenic effect registered in experiments), during lactation (penetrates into breast milk), in newborns under 3 months (high risk of hemolysis). Data on contraindications in elderly patients without comorbidities have not been registered.

Side Effects of Methylene Blue: Overdose may lead to paradoxical methemoglobinemia, hemolysis, tachycardia, hypertension, chest pain, staining of skin, mucous membranes, and urine blue or green. Headache, nausea, phlebitis at the injection site have also been described.

Adjustment Based on Patient Body Weight: For patients with body weight below 60 kg, it is recommended to calculate the dose strictly based on mg/kg and not exceed 1 mg/kg for standard conditions. For patients with body weight above 60 kg — the dose is also calculated based on body weight, but should not exceed 7 mg/kg/day.

Storage Conditions for Methylene Blue: Store the solution in a light-protected place at a temperature of +4...+25 °C. After opening the ampoule or vial, use the solution immediately; dispose of leftovers. Shielding from direct sunlight is mandatory. Protection from electromagnetic radiation does not require special conditions. Shelf life of hermetically sealed ampoules and vials — up to 24 months.

Precaution before using Methylene Blue: Before starting therapy, it is necessary to undergo clinical and laboratory tests to exclude contraindications and assess treatment safety. Mandatory tests include complete blood count with determination of hemoglobin level and reticulocyte count, biochemical blood test with assessment of liver and kidney function, study of glucose-6-phosphate dehydrogenase enzyme activity to exclude G6PD deficiency, coagulogram, determination of methemoglobin level in the blood. If concomitant therapy with serotonergic drugs is present, a doctor's consultation is recommended to exclude the risk of serotonin syndrome.

Toxicity and Biosafety — Methylene Blue

Based on experimental research data, methylene blue (Methyleni coerulei chloridum) is classified as a substance with moderate toxicity. In animal experiments, acute toxicity values were established: LD₅₀ for oral administration in mice is about 1200 mg/kg body weight, for intravenous administration — about 180 mg/kg body weight, in rats for oral administration — about 1180 mg/kg body weight. In cellular models, methylene blue exhibits moderate cytotoxic effects at concentrations exceeding the therapeutic range.

The cumulative toxicity of the drug is determined mainly by the active component — methylene blue. Excipients (purified water in solutions) do not add toxicity. Thus, the final toxicity of the solution corresponds to the toxicity of the active substance and is assessed as moderately hazardous when clinical doses are exceeded.

When therapeutic dosages are observed, the drug is considered safe; however, administration of doses above 7 mg/kg in humans may lead to paradoxical methemoglobinemia, hemolysis, and pronounced hemodynamic disturbances.

Synergy — Methylene Blue

Methylene blue (Methyleni coerulei chloridum) is a monomolecular drug, but its pharmacological effectiveness in many cases increases when combined with other pharmacological agents and biologically active substances. In vitro and in vivo experiments have shown that methylene blue exhibits pronounced synergy with antioxidants such as curcumin, quercetin, and green tea polyphenols, due to additive and potentiating effects on the suppression of reactive oxygen species and stabilization of mitochondrial membranes. This interaction is predominantly tissue-specific, manifesting in neuronal and cardiomyocyte cell populations.

Pharmacological synergy is also noted when combined with immunostimulating agents of plant origin, for example extracts of Tinospora cordifolia and Spirulina platensis. These combinations exhibit modulating and protective effects at the cellular level, enhancing leukocyte resistance to oxidative stress and improving their functional activity. The nature of this interaction can be characterized as potentiating, aimed at complementing antioxidant and immunomodulatory mechanisms.

Methylene blue in combination with plant or synthetic photosensitizers demonstrates pronounced photodynamic synergy. Under the action of light of the appropriate wavelength, an additive and in some cases potentiating effect on the generation of singlet oxygen and other reactive species is observed, which enhances antimicrobial and cytotoxic action. This type of interaction belongs to the systemic and tissue-specific levels and is realized through the activation of similar cascades of photochemical reactions.

Synergy of methylene blue with nitrate reductase enzymes has also been noted, through which the reduction of hemoglobin and stabilization of oxidoreductase processes are enhanced. This interaction can be classified as protective, as it ensures a reduction in the toxicity of nitroso compounds.

Thus, methylene blue exhibits a wide spectrum of pharmacological synergy: antioxidant, photodynamic, immunomodulatory, and metabolic. The nature of the interaction varies from additive to potentiating and modulating, covering both systemic and cellular levels of action.

References: PubMed, PMC, Semantic Scholar, ScienceDirect, SpringerLink, Wiley.

Pharmacodynamics of Methylene Blue

The pharmacodynamics of methylene blue are related to its chemical structure — a phenothiazine core capable of reversible redox transformations. At the systemic level, it exhibits antioxidant, antiseptic, photosensitizing, and neuroprotective effects. Inside cells, it acts as an electron acceptor and donor, involved in the mitochondrial respiratory chain and stabilizing adenosine triphosphate production, which defines its mitochondrial-protective properties.

The drug modulates the activity of reductase cascade enzymes, particularly methemoglobin reductase, reducing hemoglobin iron from the ferric to the ferrous state. This ensures the maintenance of tissue oxygenation at the systemic level. At the immunological level, methylene blue exerts a modulating effect, reducing the production of pro-inflammatory cytokines and stabilizing cell membranes.

Photodynamic activity is due to the ability of the molecule to transition to an excited state under light exposure and generate reactive oxygen species. These processes are realized at the local level in tissues and cells, enhancing the antimicrobial and antifungal effect.

On the nervous system, the drug exerts a neuroprotective effect, partly by suppressing protein aggregation processes and reducing oxidative damage to neurons. This action is systemic and cellular in nature, reflecting the influence on mitochondrial processes and redox homeostasis.

Thus, the pharmacodynamics of methylene blue are determined by a complex of antidote, antimicrobial, antioxidant, photosensitizing, and modulating effects, realized at the cellular, tissue, and systemic levels.

References: PubMed, PMC, Semantic Scholar, ScienceDirect, SpringerLink, Wiley.

Pharmacokinetics of Methylene Blue

After oral administration, methylene blue is well absorbed in the gastrointestinal tract, undergoing partial metabolism in the liver. Biotransformation includes reduction to leucomethylene blue, which has pharmacological activity and can participate in reversible redox reactions. In the intestine, it interacts with microflora, which affects the rate of reduction and circulation of metabolites.

With intravenous administration, the absorption phase is absent, and the drug is rapidly distributed in tissues. The highest concentration is noted in the liver, spleen, kidneys, and adrenal glands. Accumulation occurs in erythrocytes, where it acts as an electron acceptor for the reduction of methemoglobin. It is found to a lesser extent in muscles and the central nervous system.

With topical and transdermal application, limited penetration through intact epithelium is noted; however, bioavailability increases significantly with skin and mucous membrane damage. The inhalation route is not primary, but in experimental use, the drug can penetrate the systemic circulation through the alveolar barrier.

Metabolism occurs predominantly in the liver with the participation of redox system enzymes. Excretion is carried out by the kidneys in the form of colored metabolites and partly unchanged, leading to characteristic blue or green coloration of urine. Some metabolites are excreted in bile, and with prolonged use, deposition in tissues is possible. A small amount of the drug may be excreted through sweat glands and mucous membranes.

Thus, the pharmacokinetics of methylene blue are characterized by good systemic absorption, rapid distribution to organs with high metabolic activity, biotransformation in the liver, and predominantly renal excretion with staining of biological fluids.

References: PubMed, PMC, ScienceDirect, SpringerLink, Wiley.

Mechanisms of Action and Scientific Rationale: Methylene Blue

Liver and Gastrointestinal Tract. Methylene blue participates in redox processes in hepatocytes, supporting the antioxidant status and reducing the level of reactive oxygen species. At the cellular level, it exhibits membrane-stabilizing and lipotropic effects, protecting cell membranes from lipid peroxidation. At the systemic level, this manifests in the modulation of liver enzyme systems, including cytochromes and redox cascades.
Reference: https://pubmed.ncbi.nlm.nih.go...

Immune System. Methylene blue exerts a modulating effect on the activity of macrophages and neutrophils, reducing the production of pro-inflammatory cytokines and reactive oxygen species. At the level of signaling cascades, an influence on NF-κB and JAK/STAT is noted, leading to a decrease in the expression of pro-inflammatory mediators. The nature of the interaction can be characterized as protective and modulating.
Reference: https://pubmed.ncbi.nlm.nih.go...

Nervous System. In neurons, methylene blue serves as an electron acceptor and donor, supporting the function of the mitochondrial respiratory chain and reducing the likelihood of apoptosis. It has antioxidant and neuroprotective effects, preventing protein aggregation and reducing energy metabolism. Influence on MAPK cascades and inhibition of processes related to excessive formation of free radicals provides a potentiating protective effect.
Reference: https://pubmed.ncbi.nlm.nih.go...

Endocrine and Metabolic Regulation. Methylene blue regulates the activity of enzymes involved in redox processes and nitrogen compound metabolism. It can reduce the pathological activity of nitric oxide synthase, thereby modulating the level of vasoactive mediators. This interaction has an additive character and manifests at the cellular and tissue levels, including in the vascular endothelium.
Reference: https://pubmed.ncbi.nlm.nih.go...

Thus, the mechanisms of action of methylene blue cover systemic, tissue, and cellular levels, manifesting through antioxidant, anti-inflammatory, membrane-stabilizing, and modulating effects. They are realized through influence on enzyme systems, inflammatory mediators, and signaling cascades, which ensures the multifaceted pharmacological action of the drug.
References: PubMed, PMC, ScienceDirect, SpringerLink, Wiley.

Overview of the Drug Methylene Blue (C₁₆H₁₈ClN₃S)

Methylene blue (lat. Methylenum coeruleum; N, N, N′, N′-tetramethylthioninium chloride trihydrate, 3,7-bis(dimethylamino)phenothiazin-5-ium chloride) — an organic compound from the group of thiazine dyes with the chemical formula C₁₆H₁₈ClN₃S·H₂O. The substance appears as dark green crystals with a bronze luster, readily soluble in water. In analytical chemistry, it is used as an indicator and dye, and in medicine — as a pharmacological drug with a wide range of applications.

Methylene blue exhibits properties of an antidote against certain toxins, acts as a photosensitizer and redox agent. It is used in the treatment of methemoglobinemia, carbon monoxide poisoning, urinary tract infections, malaria therapy, and as an adjuvant in septic conditions. In recent years, its antiviral potential has been actively researched.

In photodynamic therapy conditions, methylene blue demonstrates pronounced photosensitizing activity: under light exposure with a wavelength of about 665 nm, its effectiveness in destroying pathogenic cells increases several times. This effect is used to destroy microorganisms, viruses, and altered cells in experimental and clinical practice.

Special attention has been drawn to research conducted in Russia and abroad during the COVID-19 pandemic. Studies from Sechenov University and University Clinical Hospital No. 1 showed that methylene blue in combination with photodynamic irradiation possesses pronounced antiviral activity. Volunteers with a laboratory-confirmed diagnosis received inhalations of a methylene blue solution followed by exposure to red light on the nasopharynx and chest area. After the first sessions, a decrease in body temperature, reduction in symptoms of respiratory failure, and positive dynamics on computed tomography were noted.

International studies (including publications by Chinese and European authors) confirmed that the photodynamic application of methylene blue provides an additional universal mechanism for virus inactivation, including coronaviruses and respiratory pathogens. This effect is associated with the formation of reactive oxygen species and their damaging action on viral capsids and nucleic acids.

Thus, methylene blue is a universal pharmacological agent with proven antidote, antimicrobial, and photosensitizing properties. Modern research confirms its promise not only in classical areas of application (methemoglobinemia, poisoning, infections) but also as a component of innovative therapy methods, including photodynamic effects in viral infections and oncological processes.