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Critical Care (London, England) Mar 2023Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its' optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock.
METHODS
In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days.
RESULTS
Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59-83] vs 94 h [IQR 74-141]; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration.
CONCLUSION
In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.
Topics: Humans; Shock, Septic; Methylene Blue; Vasoconstrictor Agents; Sepsis
PubMed: 36915146
DOI: 10.1186/s13054-023-04397-7 -
Cells Dec 2021Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining,... (Review)
Review
Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increaseding oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. This review summarizes the recent studies on the applications of MB in treating age-related conditions, including neurodegeneration, memory loss, skin aging, and a premature aging disease, progeria.
Topics: Aging; Animals; Brain; Humans; Methylene Blue; Models, Biological; Skin Aging
PubMed: 34943887
DOI: 10.3390/cells10123379 -
Molecular Neurobiology Jun 2018Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used... (Review)
Review
Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used classically for the treatment of malaria, methemoglobinemia, and carbon monoxide poisoning, as well as a histological dye. Its role in the mitochondria, however, has elicited much of its renewed interest in recent years. MB can reroute electrons in the mitochondrial electron transfer chain directly from NADH to cytochrome c, increasing the activity of complex IV and effectively promoting mitochondrial activity while mitigating oxidative stress. In addition to its beneficial effect on mitochondrial protection, MB is also known to have robust effects in mitigating neuroinflammation. Mitochondrial dysfunction has been identified as a seemingly unifying pathological phenomenon across a wide range of neurodegenerative disorders, which thus positions methylene blue as a promising therapeutic. In both in vitro and in vivo studies, MB has shown impressive efficacy in mitigating neurodegeneration and the accompanying behavioral phenotypes in animal models for such conditions as stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review summarizes recent work establishing MB as a promising candidate for neuroprotection, with particular emphasis on the contribution of mitochondrial function to neural health. Furthermore, this review will briefly examine the link between MB, neurogenesis, and improved cognition in respect to age-related cognitive decline.
Topics: Animals; Cognition; Humans; Methylene Blue; Mitochondria; Nerve Degeneration; Neurogenesis; Neuroprotection
PubMed: 28840449
DOI: 10.1007/s12035-017-0712-2 -
Autophagy Feb 2019Cells challenged by photosensitized oxidations face strong redox stresses and rely on autophagy to either survive or die. However, the use of macroautophagy/autophagy to...
Cells challenged by photosensitized oxidations face strong redox stresses and rely on autophagy to either survive or die. However, the use of macroautophagy/autophagy to improve the efficiency of photosensitizers, in terms of inducing cell death, remains unexplored. Here, we addressed the concept that a parallel damage in the membranes of mitochondria and lysosomes leads to a scenario of autophagy malfunction that can greatly improve the efficiency of the photosensitizer to cause cell death. Specific damage to these organelles was induced by irradiation of cells pretreated with 2 phenothiazinium salts, methylene blue (MB) and 1,9-dimethyl methylene blue (DMMB). At a low concentration level (10 nM), only DMMB could induce mitochondrial damage, leading to mitophagy activation, which did not progress to completion because of the parallel damage in lysosome, triggering cell death. MB-induced photodamage was perceived almost instantaneously after irradiation, in response to a massive and nonspecific oxidative stress at a higher concentration range (2 µM). We showed that the parallel damage in mitochondria and lysosomes activates and inhibits mitophagy, leading to a late and more efficient cell death, offering significant advantage (2 orders of magnitude) over photosensitizers that cause unspecific oxidative stress. We are confident that this concept can be used to develop better light-activated drugs. ΔΨm: mitochondrial transmembrane inner potential; AAU: autophagy arbitrary units; ATG5, autophagy related 5; ATG7: autophagy related 7; BAF: bafilomycin A; BSA: bovine serum albumin; CASP3: caspase 3; CF: carboxyfluorescein; CTSB: cathepsin B; CVS: crystal violet staining; DCF: dichlorofluorescein; DCFH: 2',7'-dichlorodihydrofluorescein; DMMB: 1,9-dimethyl methylene blue; ER: endoplasmic reticulum; HaCaT: non-malignant immortal keratinocyte cell line from adult human skin; HP: hydrogen peroxide; LC3B-II: microtubule associated protein 1 light chain 3 beta-II; LMP: lysosomal membrane permeabilization; LTG: LysoTracker™ Green DND-26; LTR: LysoTracker™ Red DND-99; 3-MA: 3-methyladenine; MB: methylene blue; mtDNA: mitochondrial DNA; MitoSOX™: red mitochondrial superoxide probe; MTDR: MitoTracker™ Deep Red FM; MTO: MitoTracker™ Orange CMTMRos; MT-ND1: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; MTT: methylthiazolyldiphenyl-tetrazolium bromide; O: singlet oxygen; OH hydroxil radical; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PBS: phosphate-buffered saline; PI: propidium iodide; PDT: photodynamic therapy; PS: photosensitizer; QPCR: gene-specific quantitative PCR-based; Rh123: rhodamine 123; ROS: reactive oxygen species RTN: rotenone; SQSTM1/p62: sequestosome 1; SUVs: small unilamellar vesicles; TBS: Tris-buffered saline.
Topics: Autophagy; Cell Death; Cell Line; Cell Survival; Humans; Light; Lysosomes; Methylene Blue; Mitochondria; Models, Biological
PubMed: 30176156
DOI: 10.1080/15548627.2018.1515609 -
Brazilian Journal of Cardiovascular... Feb 2021
Topics: COVID-19; Humans; Methylene Blue; SARS-CoV-2
PubMed: 33355812
DOI: 10.21470/1678-9741-2020-0462 -
Nature Communications Sep 2023Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to...
Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.
Topics: Humans; Methylene Blue; Alzheimer Disease; Amyloidogenic Proteins; Cytoskeleton; Phase Transition
PubMed: 37673952
DOI: 10.1038/s41467-023-41241-6 -
BMC Medicine Apr 2018Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has... (Review)
Review
BACKGROUND
Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum. MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria.
METHODS
This systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017.
RESULTS
Out of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction.
CONCLUSIONS
More studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs.
SYSTEMATIC REVIEW REGISTRATION
This study is registered at PROSPERO (registration number CRD42017062349 ).
Topics: Enzyme Inhibitors; Female; Humans; Malaria, Falciparum; Male; Methylene Blue
PubMed: 29690878
DOI: 10.1186/s12916-018-1045-3 -
Biosensors Jul 2022We report a methylene blue (MB)-modified electrochemical aptamer (E-AB) sensor for determining microcystin-LR (MC-LR). The signal transduction of the sensor was based on...
We report a methylene blue (MB)-modified electrochemical aptamer (E-AB) sensor for determining microcystin-LR (MC-LR). The signal transduction of the sensor was based on changes in conformation and position of MB induced by the binding between MC-LR and the modified aptamer probe. In the absence of MC-LR, an aptamer probe was considered partially folded. After combining aptamer and MC-LR, the configuration of the aptamer probe changed and facilitated the electron transfer between MB and the electrode surface. As a result, an increased current response was observed. We optimized the parameters and evaluated the electrochemical performance of the sensor using square wave voltammetry (SWV). MC-LR was measured from 1.0 to 750.0 ng/L with a detection limit of 0.53 ng/L. The reliability of the method was verified by the determination of MC-LR in environmental real samples, such as pond water and tap water. Moreover, we demonstrated that this reagent-less biosensor could be regenerated and reused after rinsing with deionized water with good accuracy and reproducibility. As a reusable and regenerable E-AB sensor, this rapid, reagent-free, and sensitive sensing platform will facilitate routine monitoring of MC-LR in actual samples.
Topics: Aptamers, Nucleotide; Biosensing Techniques; Electrochemical Techniques; Indicators and Reagents; Limit of Detection; Marine Toxins; Methylene Blue; Microcystins; Reproducibility of Results; Water
PubMed: 35892453
DOI: 10.3390/bios12080556 -
The FEBS Journal Aug 2021Indoleamine 2,3-dioxygenases (IDOs) catalyze the oxidative cleavage of L-tryptophan (Trp) to N-formylkynurenine. Two IDOs, IDO1 and IDO2, are present in vertebrates....
Indoleamine 2,3-dioxygenases (IDOs) catalyze the oxidative cleavage of L-tryptophan (Trp) to N-formylkynurenine. Two IDOs, IDO1 and IDO2, are present in vertebrates. IDO1 is a high-affinity Trp-degrading enzyme involved in several physiological processes. By comparison, IDO2 generally has been reported to have low affinity (high K -value) for Trp, and the enzyme's in vivo function remains unclear. Using IDOs from different species, we show that compared with ferrous-oxy (Fe -O ) IDO1, Fe -O IDO2 is substantially more stable and engages in multiple turnovers of the reaction in the absence of a reductant. Without reductant, Fe -O IDO2 showed K -values in the range of 80-356 μM, that is, values substantially lower than reported previously and close to the physiological concentrations of Trp. Methylene blue and ascorbate (Asc), used commonly as the reducing system for IDO activity determination, significantly affected the enzymatic activity of IDO2: In combination, the two reductants increased the apparent K - and k -values 8- to 117-fold and 2-fold, respectively. Asc alone both activated and inhibited IDO2 by acting as a source of electrons and as a weak competitive inhibitor, respectively. In addition, ferric (Fe ) IDO1 and IDO2 exhibited weak dioxygenase activity, similar to tryptophan 2,3-dioxygenase. Our results shed new light in the enzymatic activity of IDO2, and they support the view that this isoform of IDO also participates in the metabolism of Trp in vivo.
Topics: Biocatalysis; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kinetics; Kynurenine; Methylene Blue; Oxidation-Reduction; Tryptophan
PubMed: 33686747
DOI: 10.1111/febs.15806 -
Contemporary Clinical Trials Aug 2018Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their...
Methylene blue-MMX® tablets are proposed as an aid for detection and visualisation of adenomas and carcinomas in patients undergoing colonoscopy, by improving their detection rate and highlighting the presence of the intestinal dysplastic lesions. Single total doses of 100 and 200 mg were administered to healthy volunteers undergoing a bowel cleansing preparation and a full colonoscopy to investigate the colonic staining. The pharmacokinetics of methylene blue and the safety after exposure to the tablets were also investigated. With 200 mg, the best staining, assessed as the sum of acceptable and good staining, was achieved in the ascending colon and rectosigmoid (75% subjects each), the transverse and the descending colon (approximately 63% each). Absence of staining or overstaining were reported for no colonic region of interest in any subject. Similar results were observed in the 100 mg dose group. Methylene blue blood concentrations reached a peak (C) in a median time (T) of 12 h with 100 mg and 16 h with 200 mg. AUC was 10.7 ± 6.7 μg/mLxh after 100 mg and 25.2 ± 7.4 μg/mLxh after 200 mg. Half-life ranged between 9 and 22 h after the lower dose and between 6 and 26 h after the higher dose. The cumulative urinary excretion was about 28% after 100 mg and about 39% after 200 mg up to 60 h post-dose. The overall frequency of adverse events after single dose of the test product administered along with a bowel cleansing preparation was 39%, but only one was related to the test product: abnormal transaminases. The most frequent adverse event was a transient polyuria (17%). One serious adverse event (gastrointestinal haemorrhage) led the subject to study discontinuation and hospitalisation and another subject withdrew the study due to one adverse event (haematemesis). Either event was not related to methylene blue.
Topics: Administration, Oral; Adult; Biological Availability; Cathartics; Colon; Colonic Neoplasms; Colonoscopy; Coloring Agents; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Image Enhancement; Male; Methylene Blue; Middle Aged; Outcome Assessment, Health Care; Quality Improvement; Renal Elimination; Staining and Labeling
PubMed: 29864547
DOI: 10.1016/j.cct.2018.06.001