Proveblue Mechanism of Action

Pharmacotherapeutic group: All other therapeutic products, antidotes. ATC code: V03AB17.
Pharmacology: Pharmacodynamics: In vivo, in low concentration, methylthioninium chloride speeds up the conversion of methaemoglobin to haemoglobin.
Methylene blue also possesses weak antiseptic and bacteriological staining properties and is reported to inhibit amine oxidase in tissues. The drug appears to bind irreversibly to viral nucleic acid and cause disruption of the virus molecule upon exposure to light.
The use of methylene blue as a diagnostic aid is based on its ability to stain tissue. Any skin discolouration can be removed with hypochlorite solution. Its use in parathyroid surgery has induced adverse CNS effects when administered concomitantly with serotonergic medicinal products (see Interactions).
Paediatric population: The efficacy of methylthioninium chloride for the treatment of methaemoglobinaemia in peadiatric population was demonstrated in two retrospective studies and one open randomised clinical trial. Case reports of efficacy are also available in literature.
Please refer to Precautions for important safety information.
Pharmacokinetics: After intravenous administration Proveblue is rapidly taken up by the tissues. It is also well absorbed by the oral route. The majority of the dose is excreted in the urine, usually in the form of leucomethylthioninium chloride.
The mean (SD) terminal half-life of methylthioninium chloride after intravenous administration is 24.7 (7.2) h. About 75% of an oral dose of methylene blue is excreted in the urine, a small proportion of which is the unchanged drug, while some is excreted via the bile.
After a single 1 mg/kg intravenous dose of methylthioninium chloride, AUC_0-96h increased by 52%, 116%, and 192% in subjects with mild (estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m²), moderate (eGFR 30-59 mL/min/1.73 m²), and severe (eGFR 15-29 mL/min/1.73 m²) renal impairment, respectively. C_max increased by 42%, 34%, and 15% in subjects with mild, moderate, and severe renal impairment respectively. The half-life was unchanged in patients with mild to moderate renal impairment.
The AUC_0-96h of Azure B after a single 1 mg/kg intravenous dose increased by 29%, 94%, and 339% in subjects with mild (estimated glomerular filtration rate (eGFR) 60-89 mL/min/1.73 m²), moderate (eGFR 30-59 mL/min/1.73 m²), and severe (eGFR 15-29 mL/min/1.73 m²) renal impairment, respectively. C_max increased by 23%, 13%, and 65% in subjects with mild, moderate, and severe renal impairment respectively.
Proveblue is an in vitro inhibitor of P-gp.
Proveblue is not an in vitro substrate for BCRP or OCT2 and is not an in vitro inhibitor of BCRP, OAT1 or OAT3.
Toxicology: Preclinical Safety Data: Repeated dose toxicity: One-month repeated dose toxicity in dogs showed no macroscopic toxic effects.
Adverse reactions, seen at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were moderate regenerative anaemia associated with increased mean platelet count and fibrinogen levels, a minimal increase in mean total bilirubin blood values and an increased incidence of moderate urine bilirubin levels.
Genotoxicity: Methylthioninium chloride was mutagenic in gene mutation assays in bacteria and mouse lymphoma cells but not in vivo mouse micronucleus assay when administered intravenously at 62 mg/kg.
Carcinogenicity: Some evidence of carcinogenic activity of methylthioninium chloride has been shown in male mice and male rats. An equivocal evidence of carcinogenic activity was observed in female mice. No evidence of carcinogenic activity was observed in female rats.
Reproductive Toxicology: In vitro, methylthioninium chloride has been shown to reduce motility of human sperm in a dose dependent manner. It has also been shown to inhibit the growth of cultured two-cell mouse embryos and the production of progesterone in cultured human luteal cells.
In rats and rabbits, teratogenic effects have been reported, with foetal and maternal toxicity. In rats, increased resorption rates have been observed.