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ChemInform Abstract: Cellular and Molecular Actions of Methylene Blue in the Nervous System
Abstract
Methylene Blue (MB), following its introduction to biology in the 19th century by Ehrlich, has found uses in various areas of medicine and biology. At present, MB is the first line of treatment in methemoglobinemias, is used frequently in the treatment of ifosfamide-induced encephalopathy, and is routinely employed as a diagnostic tool in surgical procedures. Furthermore, recent studies suggest that MB has beneficial effects in Alzheimer's disease and memory improvement. Although the modulation of the cGMP pathway is considered the most significant effect of MB, mediating its pharmacological actions, recent studies indicate that it has multiple cellular and molecular targets. In the majority of cases, biological effects and clinical applications of MB are dictated by its unique physicochemical properties including its planar structure, redox chemistry, ionic charges, and light spectrum characteristics. In this review article, these physicochemical features and the actions of MB on multiple cellular and molecular targets are discussed with regard to their relevance to the nervous system.
... and demonstrates strong electrophilic activation of oxidizing electron-rich double bonds in biological molecules and macromolecules [9]. Recent studies have suggested that MB has beneficial effects on memory improvement and Alzheimer's disease [10]. Currently, it is used clinically in a wide range of medications that treat conditions such as methemoglobinemia, urinary tract infections, plaque psoriasis, thyroid surgery, cancer chemotherapy, and ifosfamide-induced encephalopathy [10]. ...
... Recent studies have suggested that MB has beneficial effects on memory improvement and Alzheimer's disease [10]. Currently, it is used clinically in a wide range of medications that treat conditions such as methemoglobinemia, urinary tract infections, plaque psoriasis, thyroid surgery, cancer chemotherapy, and ifosfamide-induced encephalopathy [10]. ...
Methylene blue (MB) is a well-established and extensively studied photosensitizer for photodynamic therapy (PDT), since it can generate singlet oxygen with a high quantum yield upon irradiation within the phototherapeutic (600–950 nm) window. However, its activity can decrease due to the formation of dimers or higher aggregates, which can take place in an aqueous solution at relatively high concentrations. The incorporation of this molecule into a matrix can avoid this aggregation and increase its activity relative to PDT. Silica porous nanoparticles are chosen here as a matrix to host MB. The size and pore geometry are tuned in order to decrease MB leaching while maintaining good singlet oxygen generation and colloidal stability for further applications in nanomedicine. In addition, phenyl functions are grafted on the pores of the silica matrix in order to avoid MB aggregation, thereby increasing the activity of the photosensitizer in the singlet oxygen generation. DFT calculations give insight in the structure of the aggregation of the MB units, and the roles of water and organic environments are investigated through time-dependent calculations on UV-vis spectra.
... For more than a century, methylene blue (MB), a tricyclic phenothiazine often referred to as methylthionine hydrochloride, has been used for a variety of medical purposes, including targeting specific cellular targets. MB has been shown to prevent tau aggregation in vitro and has beneficial effects on AD and memory improvement [185]. According to Akour E and colleagues' research, the interaction between the reduction in and oxidation of tau's native cysteine residues forms the basis of the process that inhibits tau aggregation. ...
Alzheimer’s and Parkinson’s are the most common neurodegenerative diseases (NDDs). The development of aberrant protein aggregates and the progressive and permanent loss of neurons are the major characteristic features of these disorders. Although the precise mechanisms causing Alzheimer’s disease (AD) and Parkinson’s disease (PD) are still unknown, there is a wealth of evidence suggesting that misfolded proteins, accumulation of misfolded proteins, dysfunction of neuroreceptors and mitochondria, dysregulation of enzymes, and the release of neurotransmitters significantly influence the pathophysiology of these diseases. There is no effective protective medicine or therapy available even with the availability of numerous medications. There is an urgent need to create new and powerful bioactive compounds since the number of people with NDDs is rising globally. Heterocyclic compounds have consistently played a pivotal role in drug discovery due to their exceptional pharmaceutical properties. Many clinically approved drugs, such as galantamine hydrobromide, donepezil hydrochloride, memantine hydrochloride, and opicapone, feature heterocyclic cores. As these heterocyclic compounds have exceptional therapeutic potential, heterocycles are an intriguing research topic for the development of new effective therapeutic drugs for PD and AD. This review aims to provide current insights into the development and potential use of heterocyclic compounds targeting diverse therapeutic targets to manage and potentially treat patients with AD and PD.
... It is valued for its vibrant blue color which is often deployed in the dyeing of cotton, wool and silk fabrics. Beyond textiles, MB finds use in the paper and leather industries where it serves as a coloring agent [11,12]. Additionally, it plays a crucial role in the chemical industry as a redox indicator in analytical chemistry and as a stain in biological research. ...
Through a statistical physics modeling approach, a detailed theoretical scrutiny was conducted utilizing four distinct models based on the grand canonical ensemble to fit the Methylene Blue adsorption isotherms onto Sodium StyreneSulfonate-co-Dimethylacrylamide (NaSS-DMA) hydrogel surface. Steriographic along with energetic-thermodynamic metrics have been inspected in response to combined effects of temperature and concentration. The uptake process was best described by a bimodal-energy linking monolayer scenario involving two sites and energies ( = 15.73 kJ/mol and = 17.85 kJ/mol) characterized by a multi-molecule adsorption process (n1 = 8.383 and n2 = 2.5967) at T = 295 K. Steriographic discussion revealed that the position of the adsorbate is non-parallel but a larger number of entities can be linked in the same receptor site. The adhesion reaction is exothermic and when the concentration exceeds 95 mg/L, the adsorbed amount decreases significantly in response to incremented heat conditions. More importantly, the investigated linking process is primarily driven by weak van der Waals forces (energies below 45 kJ/mol) while the negative values of Gibbs free energy validated its spontaneity. These outcomes supported the development of a robust mathematical framework that accurately predicts removal efficiencies of Methylene Blue onto NaSS-DMA hydrogel surface providing a deeper understanding of the involved nanoscale surface linking. The findings can be effectively translated into real-world applications for water treatment and environmental detoxification through the use of super-adsorbent hydrogels. By leveraging their optimized steric, energetic and thermodynamic properties, these hydrogels exhibit exceptional adsorption efficiency, enabling the removal of hazardous contaminants like Methylene Blue from polluted water systems. Their high capacity for adsorption, combined with stability and reusability, makes them ideal for large-scale applications in wastewater treatment plants and industrial effluent management. Finally, their compatibility with existing water purification technologies allows seamless integration into current systems, offering a cost-effective, sustainable and scalable solution for addressing water pollution challenges.
... Furthermore, it causes irritation to the eyes, respiratory infections, affects the digestive system, and can cause vomiting and nausea. 28,29 Therefore, methylene blue is a serious threat to living organisms. Its removal from aqueous media is necessary. ...
The rapidly expanding industrialization and global increase in economic activities have drawn attention to the concerning accumulation of waste. The textile industry plays a significant role in environmental pollution, especially in and water pollution. Harmful dyes used during the fabrication process are mixed with water bodies through sewage or wastewater ejected from industrial factories. These toxic dyes are not only applied in textile industries but also used in other industries like pharmaceutical companies and rubber manufacturing. Therefore, scientists have adopted alternative techniques for the degradation of organic dyes because of eliminating the drawbacks from the traditionally used techniques. Catalytic degradation of organic dyes with the help of a safe and easy nanocatalyst is one of the best alternatives. Accordingly, the use of biomaterials or waste materials offers an easy, cost-effective and eco-friendly approach for the synthesis of such nanocatalysts. Several nanocatalysts have been used for the degradation of dyes present in industrial wastewater. The well-known semi-conductor selenium has several important properties, viz., optoelectronic, photovoltaic, thermoconductivity, and anisotropy, and has drawn significant research attention for its catalytic application in dye degradation. Considering all these points, selenium nanoparticles synthesized via green techniques provide the best possible alternative catalyst for the degradation of organic dyes in industrial wastewater. The current review covers various aspects of the biosynthesis of selenium nanoparticles; their application as a catalyst for the degradation of harmful organic dyes, viz., methylene blue, methyl orange, rhodamine B, alizarin S, malachite green, sunset yellow, fuchsin, safranin T, Congo red, and bromothymol blue; and their mechanism for the degradation process. This review will also shed light on the importance of using green chemistry towards the synthesis of selenium nanoparticles and different biosynthesis procedures and explores all aspects of the interesting catalytic activity towards the dye degradation mechanism. Hence this article will be beneficial to both industrialists and acdemicians bridging the gap between industrial and academic sceintists.
... The principle behind the Alamar Blue assay involves a reduction of the non-fluorescent indicator dye resazurin to its highly fluorescent form resorufin in the presence of reducing agents, especially NADH and NADPH ( Supplementary Fig. 1). In line with its reported role as a redox-cycling substrate, MB transforms, in the presence of NADH or NADPH, into leucomethylene blue, which, in turn, is subsequently oxidized back to MB by O 2 17 . This redox-cycling results in the utilization of NADH/NADPH and O 2 17 , leading to an increase in O 2 consumption and a general decline in the availability of NADH and NADPH. ...
Methylene blue (MB) is an antifungal agent widely used during critical stages of zebrafish development. Most guidelines recommend 0.00005% or 0.0001% of MB for embryo/larval rearing. The Organisation for Economic Co-operation and Development zebrafish embryo toxicity test guideline omits MB recommendations, leading to inconsistent MB use in zebrafish research. Because MB affects oxidative energy metabolism in vitro and in vivo, we investigate possible metabolic effects of recommended MB concentrations in developing zebrafish (1–5 days post-fertilization (dpf)). MB increases O2 consumption rate at 1 dpf, followed by an overall reduction in oxidative energy metabolism in post-hatch eleutheroembryos (4–5 dpf). Concomitantly, mitochondrial transcripts decrease in 1 and 4 dpf zebrafish. Our findings show that MB, at recommended husbandry concentrations, affects oxidative metabolism and can thus confound experiments. Since the zebrafish embryo/larval model is gaining traction as a high-throughput New Approach Methodology (NAM) for toxicity assessment, researchers should reconsider MB use.
... As one common azo dye in the printing and dyeing industry and potential in causing serious effects in ecosystem and living beings, MO and MB is an organic, heterocyclic, synthetic and high watersoluble anionic and cationic dyes, respectively. Typically, MB is a toxic dye (Russo et al., 2016), large amount of which (more than 7.0 mg/kg) can cause nausea, high pressure of blood, abdominal pain and mental health issue (Bharagava et al., 2021;Quansah et al., 2020, Oz et al., 2011. The reactive singlet oxygen that is produced by photo-sensibilized of MB by white light it may damage the DNA structures resulting threatening the human health (Albadarin et al., 2017). ...
The produced material was used in this study as an adsorbent to remove the organic pollutants such as methylene blue (MB) and methyl orange (MO) from an aqueous solution. Scanning electron microscopy (SEM), Fourier transform infrared spectra (FTIR), X-ray diffraction (XRD), Particle size analysis (PSA) characterization techniques were used to analyze morphological, chemical structure, nature and size of particles of an adsorbent. The dose study was performed to check optimum dose for removal of cationic dye (CD) and anionic dye (AD) which was 1g/L and 3 g/L, respectively. Different isotherm studies (Langmuir, Freundlich, Temkin, Dubinin-Radushkevich) were performed and confirm that the adsorption process followed Langmuir isotherm which means that adsorption is monolayer it was again confirmed by value of R 2 (0.98 for MB and 0.95 for MO). Kinetics study revealed that Pseudo-second-order (PSO) followed for both MB and MO which confirmed chemisorption. High value of ∆H⁰ was observed for MB confirmed that adsorption process is chemisorption. Negative value of ∆S⁰ revealed that process is spontaneous in nature. High removal percentages of MB and MO were achieved 95.7% and 94%, respectively, revealed that Legerstroemia speciosa biochar (LSB) is very effective adsorbent for the removal of organic pollutants (MB and MO).
... [123,126] Methylene blue Inhibits the chaperone function of the Hsp70 protein by binding with the glucocorticoid receptor. [127,128] Natural Inhibitors ...
Simple Summary
Mortalin is a heat shock protein 70 stress chaperone family member with variable subcellular localization in normal and cancer cells. It is an essential protein with multiple functions that support and promote proliferation, endorsed by its enriched expression in various cancers. Due to its prime involvement in stress adaptation and carcinogenesis, regulating Mortalin expression and function is a viable therapeutic avenue.
Abstract
Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials.
... The awareness that psychotropic drugs have antimicrobial properties goes back to the nineteenth century when Paul Ehrlich observed the bactericidal action of methylene blue, a molecule that led to the synthesis of chlorpromazine, ushering in the development of antipsychotic agents [124]. Moreover, antidepressant drugs can be traced back to the antimicrobial isoniazid which was found to induce euphoria in tuberculosis patients [125,8]. ...
... Different types of cancer can be developed as a consequence of chronic exposure to contaminated water with MB [7]. Animal studies have shown that MB suspended in water interaction effects to the liver [8], kidneys [9] and central nervous system [10]. On the other hand, allergic reactions can manifest skin irritation, itching or respiratory symptoms because of MB exposition [11]. ...
Methylene blue (MB) concentrations in residual water were detected using fractional calculus, the Rössler chaotic attractor and laser systems. A Nd:YVO4 nanosecond pulsed laser at 532 nm, with pulse energies ranging from 2 µJ to 7 µJ, was applied to irradiate different water samples containing MB concentrations from 20 µl to 100 µl. Fractional calculus was employed with the purpose of modeling the temperature distribution in the samples, with the Caputo fractional derivative describing photothermal effects induced by laser irradiation. Different MB concentrations were detected by using the Rössler chaotic attractor, it monitored variation on concentrations, associating attractor shapes with MB concentrations. Lower concentrations showed a weaker attractor response, whereas higher concentrations manifest stronger attractor shapes in magnitude. Raman spectroscopy confirmed the detection of MB in residual water from the Requena dam, located in Tepeji del Río de Ocampo, Hidalgo, Mexico. The application of fractional calculus improved the prediction of heat distribution in the samples, by incorporating numerical simulation. The results suggest that this approach is suitable for real-time monitoring, as it associates MB concentrations with distinct chaotic attractor shapes. This technique shows promise for the detection of other contaminants as well. Future research should focus on refining this method and expanding its application to develop innovative monitoring solutions.
... Methylene blue (MB), crystal violet (CV), and malachite green (MG) present main organic dye pollutants. The removal of these dyes from the wastewater is especially important, as the consumption of water contaminated with MB, CV or MG can lead to major health issues such as excessive sweating, difficulty breathing, confusion, skin rashes, eye irritation, respiratory problems, vomiting, tissue damage, and nausea [7]. However, such a removal should be environmentally friendly to exclude or minimize any additional water contamination. ...
Dyes used in industries such as textile, paper, and leather are known to be harmful to both human health and aquatic ecosystems, which makes critically important the search of effective and sustainable methods for their removal from wastewater in order to mitigate the detrimental pollution effects. Here, we show that titanium nitride nanoparticles (TiN NPs) synthesized by scalable methods of pulsed laser ablation in liquid ambient (water, acetone and acetonitrile) can serve as extremely efficient sorbents for water decontamination from dye molecules (methylene blue, crystal violet, and malachite green). Our tests show that adsorption of TiN NPs is associated with the electrostatic effect due to a strong negative charge of laser-synthesized TiN NPs and the presence of pores in the NPs. Comprehensive characterization using scanning and transmission electron microscopy, along with Raman spectroscopy, evidenced that the appearance of surface charge is related to the formation of under-stoichiometric TiN (TiN1−x), associated with the predominance of nitrogen vacancies. This study identifies an optimal configuration of vacancy defects that maximizes dye adsorption, with TiN NPs synthesized in water exhibiting superior performance, achieving a dye sorption capacity of 136.5 mg g⁻¹ at room temperature for methylene blue, which corresponds to best earlier reported values for nanomaterials. This study not only extends the utility of TiN NPs to environmental remediation but also highlights the critical influence of synthesis conditions on their functional properties, offering a pathway towards the design of more effective materials for pollution control.
... Similar to amyloid tracer [ 13 C] PiB and tau tracer [ 13 C] PBB3, the first identified and the most studied second generation TAIs are derived from a small dye compound methylthioninium chloride (MTC). Also known as methylene blue, the dye was previously applied in the indications of methemoglobinemia, ifosfamide-induced encephalopathy, thyroid surgery etc. [105]. One of MTC's outstanding advantages is its ability to successfully bypass the blood-brain barrier via oral administration [106]. ...
Alzheimer’s disease (AD) is the most common type of human dementia and is responsible for over 60% of diagnosed dementia cases worldwide. Abnormal deposition of β-amyloid and the accumulation of neurofibrillary tangles have been recognised as the two pathological hallmarks targeted by AD diagnostic imaging as well as therapeutics. With the progression of pathological studies, the two hallmarks and their related pathways have remained the focus of researchers who seek for AD diagnostic and therapeutic strategies in the past decades. In this work, we reviewed the development of the AD biomarkers and their corresponding target-specific small molecule drugs for both diagnostic and therapeutic applications, underlining their success, failure, and future possibilities.
... [7] Besides, dyes release harmful effects on the central nervous and reproductive systems. [8] Consequently, serious efforts have been employed to accomplish constructive purification methods to vanish these toxic pollutants. However, their improper purification process led to residual contaminants in water, which is a matter of significant concern for the health and wealth of the ecosystem, as it can cause endocrine disruption. ...
In the present day, photocatalysis has become the primary and most promising technology to generate renewable energy and degrade environmental pollutants. Remarkable efforts have been made to improve photocatalytic efficiency. Among these, introducing an external magnetic field is considered a promising strategy to boost photocatalytic performance. This review explores the dynamic realm of improving photocatalytic efficiency, with a particular emphasis on the strategic integration of external magnetic fields. Examining recent breakthroughs, we reviewed the influence of magnetic fields on diverse catalyst materials, including both magnetic and nonmagnetic variants, 2D materials, and semiconductors. Comprehensive coverage is provided on the mechanisms governing photocatalytic dye degradation, materials utilized for catalysis, and the profound impact of magnetic fields on enhancing reaction kinetics. This review also focuses on recent advances in the application and effect of magnetic fields in the magnetic and nonmagnetic catalysts towards dye degradation. This review provides a forward‐looking view, highlighting the potential of magnetic field‐enhanced photocatalysis to play a central role in sustainable energy and environmental management.
... Subsequently, MB was used in the study of malaria treatment and achieved success, becoming the first synthetic compound used to treat malaria [3]. Afterwards, MB was used to treat methemoglobinemia, cyanide poisoning, neurodegenerative diseases, and so on [4][5][6]. In recent years, MB has attracted increasing attention in the field of water treatment as an effective disinfectant [7]. ...
Methylene blue (MB) is a chemical dye which is used as an alternative drug for malachite green. In this study, based on computational chemistry, a novel hapten (TM) of MB was designed by comparing the conformational and electronic properties of MB. TM was synthesized and further conjugated with bovine serum albumin (BSA) and Ovalbumin (OVA). Then, the polyclonal antibodies were obtained by immunization with the immunogen of TM-BSA. Under optimal conditions, a sensitive indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed for the determination of MB, with an IC50 value of 41.5 μg L−1 and displaying a cross reaction of 78.2~88.9% with three different MB metabolins. The limit of detection (LOD) and the limit of quantitation (LOQ) for MB were validated to be 4.8 µg/kg and 6.0 µg/kg, respectively. Spiking experiments showed recoveries between 82.3% and 84.3%, with a relative standard deviation (RSD) of ≤6%. The results showed the generated polyclonal antibodies from the new hapten TM were reliable and could be used for detecting MB in fishery productions.
... Methylene blue (MB) is an FDA-approved medication that has been widely used in clinical practice for over a century. At the cellular level, MB exhibits a notable ability to traverse the cell membrane, distributing itself across various subcellular compartments such as lysosomes and mitochondria [8][9][10]. MB's affinity for mitochondria appears particularly significant. ...
Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species.
To investigate the effect of long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice.
Although we observed some beneficial effects of MB and MitoQ in vitro, the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 in UM-HET3 mice.
Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.
... This leads to the rapid reduction of MB to its colorless form, leucomethylene blue (LMB), in the absence of oxygen [62]. Oxygen and molecules with high oxidation potential, can then re-oxidize LMB to MB, creating a cyclic electron donor-acceptor pair [59,63,64]. ...
... Moreover, in the same context MB can cause skin and nervous system irritation and inflict significant damage to the liver and digestive system. MB poisoning has been linked to inflammation of leptomeninges, neuronal apoptosis, increased heart rate, and symptoms such as nausea and vomiting [12,13]. Numerous methods have been reported for the removal of MB, including ozonation [14], photodegradation [15], membrane filtration [16], extraction [17], ion exchange [18], irradiation [19], coagulation-flocculation [20], and others. ...
This study assessed the effectiveness of Olive Leaf Biomass (OLB) and Sulfuric Acid-Treated Olive Leaf Biomass (SATOLB) in removing Methylene Blue (MB) from water. Sulfuric acid was used to activate SATOLB, resulting in improved adsorp-tion effectiveness. The optimal removal of MB for both materials was observed at pH 6. SATOLB demonstrated an improved efficiency compared to OLB by achieving a 75% removal of MB within a timeframe of 8 min, surpassing OLB's 36% removal rate. The pseudo-second-order model accurately characterizes the adsorption kinetics, suggesting chemisorption. The SATOLB and OLB phenomena can be accurately characterized by the Langmuir and Freundlich isotherms, respectively. These isotherms provide insights into the adsorption processes, indicating whether monolayer or multilayer adsorption is occurring. The process exhibited endothermicity and spontaneity, which were influenced by intraparticle diffusion, chemical interactions, and external mass transfer. The study suggests that SATOLB shows promise as an eco-friendly candidate for wastewater treatment.
... The Type II mechanism proceeds through singlet oxygen and mainly leads to the breakages of nucleic acids. [34] Therefore, it is essential to balance the need for efficient electron transfer with the potential for light-induced toxicity. ...
Electron shuttles are pivotal in enhancing the conversion efficiency at the biotic‐abiotic interface within microbial photoelectrochemical systems. Nevertheless, the potentially toxic effects of electron shuttles on microbial cells and their instability when exposed to light are often overlooked. This concept highlights the attention paid to electron shuttles in microbial photoelectrochemical systems, such as the cytotoxicity, the photoexcited state, and the photostability. Furthermore, it offers theoretical guidance for selecting electron shuttles to optimize sustainable energy production and environmental remediation.
... MB has been reported to accumulate within mitochondria, improve mitochondrial respiration, and inhibit superoxide production. [34] Thus, MB was also expected to inhibit mitochondrial ROS in this study. We explored the mitochondrial ROS scavenging capability of BP-MB using a MitoSox kit in which the fluorescence intensity represents mitochondrial ROS accumulation. ...
The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction and reactive oxygen species overproduction. However, the treatment of AD remains challenging owning to the hindrance caused by the blood–brain barrier (BBB) and the complex pathology of AD. Nasal delivery represents an effective means of circumventing the BBB and delivering drugs to the brain. In this study, black phosphorus (BP) is used as a drug carrier, as well as an antioxidant, and loaded with a tau aggregation inhibitor, methylene blue (MB), to obtain BP‐MB. For intranasal (IN) delivery, a thermosensitive hydrogel is fabricated by cross‐linking carboxymethyl chitosan and aldehyde Pluronic F127 (F127‐CHO) micelles. The BP‐MB nanocomposite is incorporated into the hydrogel to obtain BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention and controlled drug release. After IN administration, BP‐MB is continuously released and delivered to the brain, exerting synergistic therapeutic effects by suppressing tau neuropathology, restoring mitochondrial function, and alleviating neuroinflammation, thus inducing cognitive improvements in mouse models of AD. These findings highlight a potential strategy for brain‐targeted drug delivery in the management of the complex pathologies of AD.
... It was first synthesized by Heinrich Caro in 1876. This compound can be prepared by treating dimethyl-4phenylenediamine with hydrogen sulfide dissolved in hydrochloric acid and then oxidizing it with chloride ferric [2]. It is not highly dangerous but has a harmful effect on living organisms [3] and waters [4]. ...
Nous avons mis au point une membrane en utilisant un support polymère mixte composé de polyfluorure de vinylidène (PVDF), de polyvinylpyrrolidone (PVP) et de la molécule amphiphile Tween 20 (TW20) comme agent extractif (AE). Pour évaluer les performances de la membrane élaborée, nous avons déterminé des paramètres à l'échelle macroscopique tels que le flux initial J0 et la perméabilité P, ainsi que des paramètres à l'échelle microscopique comme la constante d'association Kass et le coefficient de diffusion apparent D*. Ensuite, nous avons calculé les paramètres d'activation tels que l'énergie d'activation (Ea), l'enthalpie (ΔH#ass) et l'entropie (ΔS#). Enfin, nous avons examiné l'impact du charbon activé sur l'évolution des processus effectués et sur les performances de la membrane, notant une amélioration significative. Les résultats obtenus suggèrent que la membrane développée pour les processus étudiés présente un potentiel réel dans les techniques de séparation et de pré-concentration.
... Because MB is toxic, carcinogenic, and non-biodegradable, it possesses a great risk to human health and damaging impacts on the environment [21]. Multiple health hazards form due to the MB, including respiratory distress, metabolic and psychological issues, vision loss, and abdominal disfunctions [22]. Additionally, it results in vomiting, diarrhoea, cyanosis, indigestion, jaundice, methemoglobinemia, shock, necrotic tissues, and tachycardia, which kills premature cells in tissues and irritates the skin and eyes [23]. ...
In this work, crystalline copper-zinc ferrite nanoparticles were synthesized by a simple co-precipitation method. Morphological characterization of produced samples was done using a scanning electron microscope (SEM). A transmission electron microscope (TEM) was utilised for further identification and confirmation of the particle morphology and size. Moreover, Fourier transformation infrared (FTIR) spectroscopy and X-ray diffraction (XRD) was employed to examine crystalline structure, chemical structure, and surface area respectively. Optical properties were examined by UV–Vis spectroscopy. The results indicate that the Zn0.5Cu0.5Fe2O4 nanoparticles’ crystallite size was 28.5 nm. The experiments focused on the impact of various factors, such as pH levels, initial MB concentration, and nanocatalyst dosage, on the observed photocatalytic efficiency. The photocatalytic performance of Zn0.5Cu0.5Fe2O4 nanoparticles under UV light was evaluated by decolorization of Methylene Blue (MB) azo dye. Photocatalysis degradation of 10 ppm of MB adding 15 mg of Zn0.5Cu0.5Fe2O4 nanoparticles was 94% after 135 min at room temperature and pH value of 9. Further interpretation was carried out and a proposed mechanism for the MB photodegradation by Zn0.5Cu0.5Fe2O4 nanoparticles was suggested.
... Various studies have reported the pathogenetic effect of exogenously applying F. oxysporum spores to the plants. 35 In the present study, Fusarium exposure exhibited more yellowing and wilting in DPA in contrast to WT. The severity of wilting occurred due to blockage of xylem vessels with progressive growth of F. oxysporum in leaves and shoots and reduction of Chl contents, which eventually leads to death. ...
Wheat (Triticum aestivum) employs various strategies to defend against Fusarium oxysporum, a soil-borne vascular fungal pathogen that disrupts structural integrity and metabolism. The purpose of this research was to ascertain the alterations of anatomical and biochemical responses in wild-type (WT) and DPA-treated wheat (T. aestivum) seedlings exposed to F. oxysporum. The WT and DPA-treated seedlings showed disorganization of parenchyma cells, sclerenchyma cells, vascular bundles (VBs), and lower numbers of xylem (Xy) and phloem (Ph) cells, and reduced thickness of the cuticle layer (C) at the epidermal layer of shoots. The content of chlorophyll (Chl), carbohydrate, and nucleic acid was reduced in WT and DPA-treated seedlings during infection. Enhanced defense responses through peroxidase (POD), and polyphenol oxidase (PPO) was observed to be high in WT as compared to DPA-treated seedlings under stress condition. In addition, the content of salicylic acid (SA) and phenolics was increased in WT than DPA under stress condition. However, the DPA-treated seedlings showed enhanced growth of fungal mycelia compared to WT during stress condition. Hence, the anatomical and biochemical aspects of DPA-treated seedlings decreased as compared to WT when exposed to F. oxysporum.
... Methylene blue dye (MD) exists as a well-known chemical substance that require electrochemical and optical characteristics have been scientifically investigated and frequently utilized in biological science [7,8], drugs [9][10][11][12], and chemical science [13,14] over several generations [15]. MD, that can often be purchased in the form of salts, derives its most significant features from the cationic compounds heteroaromatic molecule 3, 7-bis(dimethylamino)-phenothiazin-5-ium, which provides the reason for the bright blue color it exhibits in aqueous solutions [15]. ...
Doping crystalline materials with chemical dyes impacts their optical, mechanical, and electrical behavior significantly as well. Nontoxic, water-soluble, and highly photosensitive methylene blue (C16H18ClN3S) dye had been doped into the optically active glycine magnesium chloride semi-organic compound. Thus, the vapour diffusion approach was used for nucleation of the methylene blue doped glycine magnesium chloride crystal (MDGMC). The single crystal X-ray diffraction (SCXRD) tool was adopted to evaluate a newly formed MDGMC crystal exhibiting trigonal in structure,P31 space group lattice parameters such as a=b≠c and with V=234.93 ų. PXRD analyses have confirmed the existence of hybrid compositions with dye and the crystallite dimensions of the chemical substances. The electronic shift was observed at 210 nm cutoff wavelength, exhibiting an optical bandgap about 5.1356 eV, and its vibrations were investigated through spectroscopic instruments such as UV–NIR and FTIR. The outermost layer of the developed crystal material was analyzed using X-rays and scanning electron microscope, along with energy dispersive X-ray analysis (EDAX) for chemical collaboration. The practical and theoretical perspectives of our research were combined with the help of the Gaussian 09W software and its basic set DFT/B3LYP. In connection with this, we computed the molecular electrostatic surface potential (MESP) to evaluate the electrostatic potentials of MDGMC in the range of -8.733e-2to+8.733e-2a.u. the materials interacted in their optimum molecular structure. Reactivity indices and energy surface aptitudes generated HOMO–LUMO via frontiers orbitals of molecules. The Mulliken charge analysis (MCA) was used to approximate atomic values in molecules derived using DFT computations. Experimental and theoretical studies show MDGMC complex compound crystals offer superior optical and electronic activity, making them ideal for photonic equipment design due to their light sensitivity.
... Given its effectiveness as both a preventive and rescue therapy, inhibiting both constitutive and inducible nitric oxide synthase, as well as guanylate cyclase, it is considered the treatment of choice. However, methylene blue can precipitate serotonin syndrome if associated with serotonergic antidepressants since it is a potent inhibitor of monoamine oxidase [31]. Our patient, although they had a history of major depressive syndrome, was not under more medical treatment for 20 years. ...
Background:
Vasoplegic shock syndrome (VSS) after an off-pump coronary artery bypass graft (OPCABG) is an extremely rare condition. Inotropic support is usually the first-line therapy, though it can precipitate several complications or be ineffective. We report the first case of severe refractory VSS after OPCABG successfully treated with hydroxycobalamin.
Methods:
A 77-year-old gentleman underwent OPCABG for three vessels coronary artery disease. Preoperative LV ejection fraction was 28%, and the patient before surgery started sacubitril/valsartan titrated, then, at the highest dose. Surgery was uneventful and, by the end of the procedure, TEE showed improved biventricular contractility.
Results:
The patient was transferred to the ICU without inotropic support, but soon developed hypotension. TEE ruled out pericardial tamponade and confirmed fair contractility. Norepinephrine was titrated to a medium-high dose, vasopressin was started and a Swan-Ganz catheter was placed. SVR was 480 dyn·s·cm-5. Despite aggressive pharmacologic treatment (including methylprednisolone and methylene blue), no improvements were noticed. Ten grams of hydroxycobalamin were administered. One hour later, hemodynamic status re-assessment showed SVR > 800 dyn·s·cm-5. Afterward, vasopressors were gradually reduced.
Conclusions:
Our case demonstrated the importance of adequate early treatment in VSS after OPCABG. This case report shows, for the first time, that hydroxycobalamin was effectively used to restore homeostasis.
... The recalcitrant nature of MB makes it difficult to remove from wastewater by conventional treatment processes [41]. It is constituted by atoms of functional groups containing nitrogen, aromatic rings, and conjugated double bonds (responsible for the intense blue color), which gives it a complex, very resistant, and chemically stable conformation that hinders its decomposition into less harmful or innocuous simple compounds when exposed to photolysis or conventional water treatment under typical environmental conditions. ...
Wastewater-containing dyes are an environmental problem. The prime source of dye pollutants is the textile industry, such as paper manufacturing, food processing, leather, pigments, etc. Dye removal from wastewater using nanotechnology has received attention in recent decades thanks to efficient nanomaterials improving traditional technologies. In recent years, multiple research reports on carbon nanotubes for dye removal and photocatalytic dye degradation provided substantial insight into the comprehension of nanotechnology and remediation. This work presents a review and bibliometric analysis of carbon nanotubes for dye removal and photocatalytic dye degradation, which have an environmental impact today. The bibliometric study showed that the current research tendency on carbon nanotubes applied in dye removal and photocatalysis is still growing. According to research, this work observed that carbon nanotubes for dye removal exhibit high removal and efficient photocatalysis activity, indicating the functionality of nanotechnology for environmental remediation. The analysis of the parameters involved in the removal studies, such as temperature and pH, showed adsorption behavior. The photodegradation of methylene blue demonstrated the photocatalytic activity of carbon nanotubes attributed to the sp2 lattice of graphitic configuration.
... Research carried out in 1993 was the pioneering study to make use of artificial soluble redox mediators as a strategy for harnessing the antioxidant potential of viable bacteria [42]. Methylene blue, a redox dye created by German chemist Heinrich Caro in 1876 [43], was one of the first mediators to be employed. According to Arup [44], Neisser and Wechsberg made the initial suggestion that methylene blue could be a valuable tool for determining the bacterial load in milk in 1900. ...
Extracellular electron transfer (EET) is a biological mechanism that plays a crucial role in various bioelectrochemical systems (BESs) and has substantial implications for renewable energy production. By utilizing the metabolic capacities of exoelectrogens, BESs offer a viable and environmentally friendly approach to electricity generation and chemical production; however, the diminished effectiveness of EET remains a hindrance to their optimal application in practical contexts. This paper examines the various strategies that have the potential to be employed to enhance the efficiency of EET systems and explores the potential for the integration of BESs technology with contemporary technologies, resulting in the development of an enhanced and sustainable system. It also examines how quorum sensing, electrode modifications, electron shuttles, and mediators can aid in improving EET performance. Many technological innovations, such as additive manufacturing, the science of nanotechnology, the technique of genetic engineering, computational intelligence, and other combinations of technologies that can be used to augment the efficacy of BESs are also discussed. Our findings will help readers understand how BESs, though an evolving technology, can play an important role in addressing our environmental concerns. Technical constraints are identified, and future directions in the field of EET are suggested.
The work solves the problem of obtaining adsorbents from cheap and available feedstock able for the removal of low-molecular-weight toxic organic substances from aqueous solutions. It is proposed to obtain an adsorbent from the wastes of such biodegradable polymer as polylactic acid (PLA), for example, from used packaging. The polymer was heated up to the melting point, cooled and ground. The thermally treated PLA sample contained end carboxyl and hydroxyl groups, which were identified with Fourier-IR spectroscopy, and the ion-exchange activity of the polymer was found. These groups provide a surface charge density of 0.02−0.12 C m-2 in the pH range of 4−10, ξ-potential reaches 30 mV in an alkaline media. Adsorption of such cationic dye as methylene blue (MB) was studied under static and dynamic conditions. The Temkin and Freundlich models were applied to the adsorption isotherms, an increase in the adsorption capacity of the polymer was found with an increase in pH from 4 to 10, while the surface became more energetically heterogeneous. The capacity of PLA is 16−30 mg g-1 in the absence of a supporting electrolyte, and 10−28 mg g-1, when adsorption occurs from a two-component solution containing also NaCl. According to the results of the study of MB adsorption, and the data of electronic spectroscopy for suspension of the polymer, it was established that the dye removal from the solution occurs mainly due to electrostatic attraction to the negatively charged PLA surface. The adsorbent was proposed to be employed for the removal of the residual colour of wastewater after its treatment, for example, with reverse osmosis or nanofiltration.
Through a statistical physics modeling approach, a detailed theoretical scrutiny was conducted utilizing four distinct models based on the grand canonical ensemble to fit the Methylene Blue adsorption isotherms onto NaSS-DMA hydrogel surface. Steriographic along with energetic-thermodynamic metrics have been inspected in response to combined effects of temperature and concentration. The uptake process was best described by a bimodal-energy linking monolayer scenario involving two sites and energies (𝜀 1 = 15.73 kJ/mol and 𝜀 2 = 17.85 kJ/mol) characterized by a multi-molecule adsorption process (n 1 = 8.383 and n 2 = 2.5967) at T = 295 K. Steriographic discussion revealed that the position of the adsorbate is non-parallel but a larger number of entities can be anchored in the same receptor site. The docking reaction is exothermic and when the concentration exceeds 95 mg/L, the adsorbed amount decreases significantly in response to incremented heat conditions. More importantly, the investigated linking process is primarily driven by weak van der Waals forces (energies below 45 kJ/mol) while the negative values of Gibbs free energy validated its spontaneity. These outcomes supported the development of a robust mathematical framework that accurately predicts removal efficiencies of Methylene Blue onto NaSS-DMA hydrogel surface providing a deeper understanding of the involved nanoscale surface linking.
A mesoporous SBA-15-immobilized L-proline-Cu(I) complex [L-proline-CuI-SBA-15] was prepared via immobilization of commercially readily available (4-(chloromethyl)phenyl)trimethoxysilane onto SBA-15, followed by reaction with N-Boc-trans-4-hydroxy-L-proline, and then the deprotection and coordination with CuI....
Chronic obstructive pulmonary disease (COPD) is a major cause of worldwide mortality
and disability. COPD is responsible for early mortality, high mortality, and significant costs to
health systems. It affects millions of people worldwide and causes significant morbidity and
mortality.The projection for 2020 indicates that COPD will be the 3rd leading cause of death
worldwide (from 6th in 1990) and lost through early mortality or disability (Disability-Adjusted
Life Years) (12th in 1990) the 5th major reason for years. Active smoking remains the main risk
factor, but other factors are becoming better known, such as occupational factors, infection, and
the role of air pollution. The prevalence of COPD varies by country, age and sex. The disease is
also associated with significant co-morbidities. COPD is a disorder involving various
phenotypes, the continuation of which remains under debate. The major challenge in the coming
years will be the early detection of the disease in the common people as well as stopping the
onset of smoking. The goal of this review is to evaluate the overall burden of disease, including
prevalence, morbidity, mortality, health care costs, and economic costs.
The research introduces a simple and green synthesizing method for selenium nanoparticles (Se-NPs) for the first time. It involves utilizing Trigonella foenum-graecum L seed extract as a stabilizer and reducing agent. The use of this plant in the study highlights the novelty of the current research. The optical, constructional, size, and morphological features of the results were checked and confirmed by the outcomes of DLS/Zeta potential, UV–Vis, XRD, FESEM/EDX, TEM, and FTIR techniques. The data of UV–Vis spectroscopy of Se-NPs exhibited a sharp peak at 265 nm and a bandgap at about 4.28 eV, whereas the FESEM/EDX and TEM images displayed their spherically shaped framework along the average size of around 97 nm and confirmed the correctness of the results. The photocatalytic application of synthesized nanoparticles was checked out in the direction of methylene blue pigment degradation under UVA light in water purification systems, and after 105 min the degradation percentage was observed at about 80%. We also investigated the cytotoxicity of Se-NPs towards the cancer Huh-7 cell line and attained the IC50 value of 575 µg/mL.
Present article delves into the synthesis and evaluation of zinc sulfide (ZnS) and indium-doped zinc sulfide (ZnIn2S4) or ZIS microspheres, focusing on their photocatalytic prowess. These microspheres were synthesized using a low-temperature, one-pot solution method.The photocatalytic performance was assessed using two distinct dye solutions, methylene blue (MB) and direct red 80 (DR-80), elucidating their efficacy in pollutant degradation. Remarkably, the addition of indium significantly augmented the optoelectronic and catalytic properties of the microspheres. The structural analysis via XRD and FESEM revealed distinct lattice structures, while UV–Vis spectroscopy showed different band gap values induced by indium doping viz. 3.8 eV for ZnS and 2.1 eV for ZnIn2S4. Zeta sizer, fluorescence spectroscopy, and TRPL provided insights into size, potential, and electron exciton lifetimes. ZnIn2S4 as compared to ZnS displayed superior photocatalytic activity, especially towards cationic dyes, emphasizing the significance of indium doping in enhancing photocatalytic efficiency and understanding structural-electronic characteristics in semiconductor microspheres.
Methylene blue (MB) has recently completed a Phase-3 clinical trial as leuco-methylthioninium (LMT) bis(hydromethanesulfonate) for treating Alzheimer’s disease. Herein, we investigated the mechanism underlying the MB inhibition of tubulin-associated unit (tau) aggregation by focusing on tau monomers. We found that MB causes disulfide bond formation, resulting in strong nuclear magnetic resonance chemical shift perturbations in a large area of tau proteins. The oxidized form of MB, namely methylthioninium (MT⁺), specifically catalyzed the oxidation of cysteine residues in tau proteins to form disulfide bonds directly using O2. This process is independent of the MT⁺-to-LMT redox cycle. Moreover, MT⁺ preferentially oxidized C291 and C322 in the lysine-rich R2 and R3 domains. Under in vivo brain physoxia conditions, LMT may convert to MT⁺, possibly interfering with tau fibrillation via disulfide bond formation.
Traumatic brain injury (TBI) and brain ischemia/reperfusion cause neurodegenerative processes that can continue after the acute stage with the development of severe brain atrophy with dementia. In this case, the long-term neurodegeneration of the brain is similar to the neurodegeneration characteristic of Alzheimer’s disease (AD) and is associated with the accumulation of beta amyloid and tau protein. In the pathogenesis of AD as well as in the pathogenesis of cerebral ischemia and TBI oxidative stress, progressive inflammation, glial activation, blood–brain barrier dysfunction, and excessive activation of autophagy are involved, which implies the presence of many targets that can be affected by neuroprotectors. That is, multivariate cascades of nerve tissue damage represent many potential targets for therapeutic interventions. One of such substances that can be used in multi-purpose therapeutic strategies is methylene blue (MB). This drug can have an antiapoptotic and anti-inflammatory effect, activate autophagy, inhibit the aggregation of proteins with an irregular shape, inhibit NO synthase, and bypass impaired electron transfer in the respiratory chain of mitochondria. MB is a well-described treatment for methemoglobinemia, malaria, and encephalopathy caused by ifosfamide. In recent years, this drug has attracted great interest as a potential treatment for a number of neurodegenerative disorders, including the effects of TBI, ischemia, and AD.
The application of various Fiber Reinforced Polymer (FRP) composite materials is very widespread in the world. The use of recycled materials in concrete, can improve some of the mechanical properties of concrete. In this laboratory research, the behavior of reinforced concrete beams with composite rebars with glass fibers made of concrete containing recycled materials such as glass, rubber and micro-silica with different mixing plans has been investigated. These mixing plans are such that recycled glass and rubber aggregates have replaced a percentage of fine and coarse concrete aggregates, and glass powder and micro-silica have also replaced a percentage of concrete cement. The results showed that the replacement of coarse rubber, glass powder, and micro-silica in concrete materials increases the bending strength and ductility of concrete beam. In examining the microstructure of concrete by Scanning Electron Microscope (SEM) the adhesiveness of the rubber Interfacial Transition Zone (ITZ) in concrete was suitable.
Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases associated with the accumulation of a disease-specific form of prion protein (PrP) in the brain. One approach to TSE therapeutics is the inhibition of PrP accumulation. Indeed, many inhibitors of the accumulation of PrP associated with scrapie (PrPSc) in scrapie-infected mouse neuroblastoma cells (ScN2a) also have antiscrapie activity in rodents. To expedite the search for potential TSE therapeutic agents, we have developed a high-throughput screening assay for PrPSc inhibitors using ScN2a cells in a 96-well format. A library of 2,000 drugs and natural products was screened in ScN2a cells infected with scrapie strain RML (Chandler) or 22L. Forty compounds were found to have concentrations causing 50% inhibition (IC50s) of PrPSc accumulation of ≤10 μM against both strains. Seventeen had IC50s of ≤1 μM against both strains. Several classes of compounds were represented in the 17 most potent inhibitors, including naturally occurring polyphenols (e.g., tannic acid and tea extracts), phenothiazines, antihistamines, statins, and antimalarial compounds. These 17 compounds were also evaluated in a solid-phase cell-free hamster PrP conversion assay. Only the polyphenols inhibited the cell-free reaction, and their IC50s were near 100 nM. Several of the new PrPSc inhibitors cross the blood-brain barrier and thus have potential to be effective after TSE infection reaches the brain. The fact that many are either approved human drugs or edible natural products should facilitate their use in animal testing and clinical trials.
The rate of reduction of cytochrome c by the ferredoxin-TPN reductase of spinach or by chicken liver xanthine dehydrogenase is markedly augmented by a variety of electron carriers. Menadione, flavin mononucleotide, flavin adenine dinucleotide, N-methylphenazinium methosulfate, methylene blue, and 2,6-dichlorobenzenone indophenol were all effective. When cytochrome c reduction was mediated aerobically by menadione, flavin mononucleotide, or flavin adenine dinucleotide, superoxide dismutase was an inhibitor. When cytochrome c reduction was mediated by these same electron carriers in the absence of molecular oxygen, superoxide dismutase was without effect. When cytochrome c reduction was mediated by N-methylphenazinium methosulfate, methylene blue, or 2,6-dichlorobenzenone indophenol, superoxide dismutase was without effect whether or not oxygen was present. These results indicate that of these electron carriers only the reduced forms of menadione and of the flavins preferentially reduce O2 to the superoxide radical in the presence of cytochrome c. In the absence of cytochrome c, it was shown that reduced methylene blue is likewise capable of the univalent reduction of oxygen. In this case O⁻2 was detected by its ability to oxidize epinephrine to adrenochrome.
Prion diseases in humans and animals are invariably fatal. Prions
are composed of a disease-causing isoform (PrPSc) of the
normal host prion protein (PrPC) and replicate by
stimulating the conversion of PrPC into nascent
PrPSc. We report here that tricyclic derivatives of
acridine and phenothiazine exhibit half-maximal inhibition of
PrPSc formation at effective concentrations
(EC50) between 0.3 μM and 3 μM in cultured cells
chronically infected with prions. The EC50 for
chlorpromazine was 3 μM, whereas quinacrine was 10 times more potent.
A variety of 9-substituted, acridine-based analogues of quinacrine were
synthesized, which demonstrated variable antiprion potencies similar to
those of chlorpromazine and emphasized the importance of the side chain
in mediating the inhibition of PrPSc formation. Thus, our
studies show that tricyclic compounds with an aliphatic side chain at
the middle ring moiety constitute a new class of antiprion reagents.
Because quinacrine and chlorpromazine have been used in humans for many
years as antimalarial and antipsychotic drugs, respectively, and are
known to pass the blood–brain barrier, we suggest that they are
immediate candidates for the treatment of Creutzfeldt–Jakob disease
and other prion diseases.
Methylene blue (MB) is a molecule that has been playing important roles in microbiology and pharmacology for some time. It has been widely used to stain living organisms, to treat methemoglobinemia, and lately it has been considered as a drug for photodynamic therapy (PDT). In this review, we start from the fun-damental photophysical, photochemical and photobiological characteristics of this molecule and evolved to show in vitro and in vivo applications related to PDT. The clinical cases shown include treatments of basal cell carcinoma, Kaposi's Sarcoma, melanoma, virus and fungal infections. We concluded that used together with a recently developed continuous light source (RL50 ®), MB has the potential to treat a variety of cancerous and non-cancerous diseases, with low toxicity and no side effects.
The relationship between methylene blue (MB) and Alzheimer's disease (AD) has recently attracted increasing scientific attention since it has been suggested that MB may slow down the progression of this disease. In fact, MB, in addition to its well characterized inhibitory actions on the cGMP pathway, affects numerous cellular and molecular events closely related to the progression of AD. Currently, MB has been shown to attenuate the formations of amyloid plaques and neurofibrillary tangles, and to partially repair impairments in mitochondrial function and cellular metabolism. Furthermore, various neurotransmitter systems (cholinergic, serotonergic and glutamatergic), believed to play important roles in the pathogenesis of AD and other cognitive disorders, are also influenced by MB. Recent studies suggest that the combination of diverse actions of MB on these cellular functions is likely to mediate potential beneficial effects of MB. This has lead to attempts to develop novel MB-based treatment modalities for AD. In this review article, actions of MB on neurotransmitter systems and multiple cellular and molecular targets are summarized with regard to their relevance to AD.
In a previous case report, published in this journal, we described a postoperative delirium in a patient during recovery from parathyroidectomy. We noted that the delirium resembled serotonin toxicity and that the patient had been taking paroxetine until 2 days before surgery. We offered several tentative explanations for this event, including an adverse interaction between paroxetine and other agent(s) used in the course of the anaesthesia. Recent developments in characterisation of serotonin toxicity have prompted us to re-examine the clinical details surrounding this life-threatening event. It is now known to be important that the patient was given methylene blue, pre-operatively, to enable visualisation of the parathyroid glands. Methylene blue has been found to be a potent inhibitor of monoamine oxidase (MAO), and several cases of serotonin toxicity have been reported recently following its administration. All these cases are consistent with the well-known risk of serotonin toxicity when drugs that augment serotonergic transmission are given in combination with an MAO inhibitor. Methylene blue is used in a variety of surgical settings as well as for treatment of various types of hypotensive shock and methemoglobinaemia. It is also being studied for treatment of Alzheimer's disease and malaria. In this paper, we outline the pharmacology of methylene blue and the aetiology of serotonin toxicity to help prevent further unintentional co-administration of drugs that risk precipitating this life-threatening drug interaction.
With the availability of new preventive and curative interventions, global malaria control has been strengthened significantly in recent years. Drugs effective in reducing malaria gametocytaemia might contribute to local elimination and possible long-term eradication. We here report on the effects of methylene blue (MB)-based malaria combination therapy on gametocytaemia during a randomised-controlled trial in Burkina Faso.
An open-label randomised controlled phase II study in 180 children aged 6-10 years with uncomplicated falciparum malaria was conducted in Nouna, north-western Burkina Faso. Children were randomised to MB-artesunate (AS), MB-amodiaquine (AQ), and AS-AQ (local standard of care). Overall follow-up was for 28 days, follow-up for gametocytaemia was for 14 days.
The treatment groups were similar in baseline characteristics and there was only one loss to follow-up. Compared to AS-AQ, both MB-containing regimens were associated with significantly reduced gametocyte carrier rates during follow-up days 3, 7, and 14. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline.
MB reveals pronounced gametocytocidal activity which appears to act against both existing and developing P. falciparum gametocytes. MB-based combination therapy thus has the potential to reduce transmission of P. falciparum malaria in endemic regions, which has important implications for future elimination and eradication strategies.
(ClinicalTrials.gov) NCT00354380.
The propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases.
Patients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585.
107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrollment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related.
Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.
Neurotoxicity has been reported in about 5% of children treated with ifosfamide for tumors not involving the central nervous system. The entity of ifosfamide neurotoxicity can be of different degree, from very light and transient to fatal.
All cases of ifosfamide neurotoxicity recorded at the Pediatric Hematology and Oncology Unit in the 15-year period between 1989 and 2003 are reported. Five cases of neurotoxicity occurring during or immediately after ifosfamide infusion were recorded in children with both solid tumors or leukemia. The drug was administered in different chemotherapeutic associations and dosages. Concomitant clinical conditions possibly playing a role as risk factors were the administration of other neurotoxic drugs, the presence of cerebral metastasis, a subclinical lysis syndrome, and altered respiratory function. Symptoms were transient in all cases and consisted in all but one of partial or generalized seizures. In four cases the treatment was continued, substituting ifosfamide with cyclophosphamide.
Particularly in patients presenting risk factors, we advise paying attention to the risk of ifosfamide neurotoxicity and rapidly suspending the drug administration to avoid irreparable damage to the central nervous system. Thereafter the treatment can be reassessed. If ifosfamide is considered the best option for the given case, it could be safely readministered in association with methylene blue or thiamine. If encephalopathy reappears, substitution of ifosfamide with cyclophosphamide could offer the same opportunities of cure to the patient.
The kinetic effects of a selection of triarylmethane, phenoxazine and phenothiazine dyes (pararosaniline (PR), malachite green (MG), methyl green (MeG); meldola blue (MB), nile blue (NB), nile red (NR); methylene blue (MethB)) and of ethopropazine on horse serum butyrylcholinesterase were studied spectrophotometrically at 25( degrees )C in 50mM MOPS buffer, pH 8, using butyrylthiocholine as substrate. PR, MeG, MB and ethopropazine acted as linear mixed type inhibitors of the enzyme, with respective K(i) values of 4.5+/-0.50 microM, 0.41+/-0.007 microM, 0.44+/-0.086 microM and 0.050+/-0.0074 microM. MG, NB, MethB and NR caused complex, nonlinear inhibition pointing to cooperative binding at two sites. Intrinsic K' values ( identical with[I](2)(0.5) extrapolated to [S]=0) for MG, NB, NR and MethB were 0.20+/-0.096 microM, 0.0018+/-0.0015 microM, 0.92+/-0.23 microM and 0.23+/-0.08 microM. NB stood out as a potent inhibitor effective at nM levels. Comparison of inhibitory effects on horse and human serum butyrylcholinesterases suggested that the two enzymes must have distinct microstructural features.
UNLABELLED: Methylene blue trihydrate has a variety of biomedical and biologically therapeutic applications. Methylene blue trihydrate was nominated by the National Cancer Institute (NCI) for carcinogenicity testing based on the numerous uses of this compound and the lack of long-term toxicity data, including epidemiological studies of methylene blue trihydrate, as well as the inadequate animal data on this compound. Male and female F344/N rats and B6C3F1 mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose by gavage for 1 month, 3 months, or 2 years. Genetic toxicology studies were conducted using Salmonella typhimurium, Escherichia coli, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 1-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study rats and groups of 10 male and 10 female clinical pathology study rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 5 weeks. In the 500 mg/kg groups, one male died the first week of the study and one male and four females died the second week of the study. All rats in the 1,000 mg/kg group died by study day 10, and all rats in the 2,000 mg/kg group died by study day 6. Final mean body weights of male and female rats in the 250 and 500 mg/kg groups were significantly less than those of the vehicle controls. Dosed rats developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in all surviving dosed groups. There were also significant decreases in the thymus weights of 250 and 500 mg/kg males and 125 and 250 mg/kg females. Spleen lesions associated with methylene blue trihydrate administration included hematopoietic cell proliferation, pigmentation, lymphoid depletion of the lymphoid follicles, and capsular fibrosis. Hyperplasia of the bone marrow occurred in all dosed groups of rats. Liver lesions associated with methylene blue exposure included centrilobular necrosis in rats dying early, hematopoietic cell proliferation, and Kupffer cell pigmentation with erythrophagocytosis. 1-MONTH STUDY IN MICE: Groups of 10 male and 10 female core study mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 5 weeks. None of the mice in the 500, 1,000, and 2,000 mg/kg groups survived to the end of the study. In the 250 mg/kg groups, two females died on days 16 and 18 and two males died on days 6 and 13. Mean body weights of surviving dosed mice were similar to those of the vehicle controls. Thinness, abnormal respiration, hypothermia, lethargy, ataxia, and ruffled fur were observed in a few surviving animals in the 250 mg/kg groups. Hypothermia and abnormal posture were observed in mice in the 500, 1,000, and 2,000 mg/kg groups. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in all surviving dosed groups of mice compared to vehicle controls. Significant decreases occurred in the thymus weights of 250 mg/kg males and females. The heart weights of 125 and 250 mg/kg females were significantly increased. Lesions in the spleen associated with methylene blue trihydrate administration included hematopoietic cell proliferation, pigmentation, and congestion. Liver lesions associated with methylene blue trihydrate administration included periportal degeneration, hematopoietic cell proliferation, and Kupffer cell pigmentation with erythrophagocytosis. The incidences of bone marrow pigmentation were significantly increased in all dosed groups of mice. Forestomach lesions that were related to methylene blue trihydrate administration included focal ulcer, inflammation, and squamous hyperplasia. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female core study rats and groups of 20 male and 20 female clinical pathology study rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 25, 50, 100 or 200 mg/kg, 5 days per week for 14 weeks. Mean body weights of males in the 200 mg/kg group were significantly less than those of the vehicle controls. Dosed rats developed methemoglobinemia and a regenerative Heinz body anemia. Significant increases in spleen weights occurred in males and females administered 50 mg/kg or greater. Thymus and lung weights of 50, 100, and 200 mg/kg males (except relative lung weight at 100 mg/kg) were significantly less than those of the vehicle controls. Spleen lesions in dosed rats included hematopoietic cell proliferation, congestion, lymphoid depletion of the lymphoid follicles, and capsular fibrosis. The incidences of bone marrow hyperplasia were significantly increased in groups administered 50 mg/kg or greater. There were no consistent effects of methylene blue trihydrate administration on reproductive system measures in male or female rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female core study mice and groups of 20 male and 20 female clinical pathology study mice were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 25, 50, 100, or 200 mg/kg, 5 days per week for 14 weeks. Mean body weights of all dosed groups were similar to or only slightly less than those of the vehicle control groups. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. Spleen weights of 100 and 200 mg/kg males and 50 mg/kg or greater females were significantly greater than those of the vehicle control groups. Heart weights were significantly increased in 200 mg/kg males. In females, there were significant decreases in thymus weights at 50 mg/kg or greater. Males had decreased sperm motility and increased epididymal sperm counts at 200 mg/kg. In all dosed groups, the incidences of hematopoietic cell proliferation and pigmentation in the spleen were significantly greater than those in the vehicle controls. In the liver, the incidences of hematopoietic cell proliferation were significantly increased in males and females in the 100 and 200 mg/kg groups, and the incidences of Kupffer cell pigmentation were significantly increased in groups administered 50 mg/kg or greater. The incidences of bone marrow pigmentation were significantly increased in all dosed groups of mice except 25 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered methylene blue trihydrate in 0.5% aqueous methylcellulose solution by gavage at doses of 0, 5, 25, or 50 mg/kg, 5 days per week for 2 years. Additional groups of 10 male and 10 female rats were administered the same doses for up to 18 months and were evaluated at 2 weeks and 3, 12, and 18 months for hematology. Survival of all dosed groups of rats was similar to that of the vehicle controls. Mean body weights of 25 and 50 mg/kg male rats were less than those of the vehicle controls after weeks 29 and 21, respectively. In the 25 and 50 mg/kg females, mean body weights were less after weeks 73 and 53. Dosed male and female rats developed methemoglobinemia, and females developed a regenerative Heinz body anemia. The incidences of pancreatic islet cell adenoma and adenoma or carcinoma (combined) were increased in all dosed groups of males, were significantly increased in 25 mg/kg males, and exceeded the historical range in controls (all routes). The incidence of pancreatic islet cell hyperplasia was significantly increased in the 50 mg/kg males. In the spleen, the incidence of hematopoietic cell proliferation in 50 mg/kg males was significantly increased; the incidences of capsular fibrosis were significantly increased in all dosed groups of males and in 5 and 50 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered methylene blue trihydrate in a 0.5% aqueous methylcellulose solution by gavage at doses of 0, 2.5, 12.5, or 25 mg/kg, 5 days per week for 2 years. Additional groups of 30 male and 30 female mice were administered the same doses for up to 18 months and were evaluated at 2 weeks and 3, 12, or 18 months for hematology. Survival of dosed male and female groups exceeded that of the vehicle controls in a generally dose-related manner. Mean body weights of dosed female mice began to increase after weeks 29, 61, and 85, reaching final values that were 113%, 111%, and 106% of vehicle controls for the 2.5, 12.5, and 25 mg/kg groups, respectively. Dosed mice developed methemoglobinemia and a regenerative Heinz body anemia. The incidences of carcinoma and of adenoma or carcinoma (combined) of the small intestine occurred with a positive trend in males. The incidences of malignant lymphoma occurred with a positive trend in females, and the incidence in 25 mg/kg males exceeded the historical control range. The incidences of hematopoietic cell proliferation of the spleen were significantly increased in 12.5 and 25 mg/kg males and in 25 mg/kg females. The incidences of inflammation of the nose were significantly increased in 12.5 and 25 mg/kg females.
Methaemoglobin is formed by oxidation of ferrous (FeII) haem to the ferric (FIII) state and the mechanisms by which this occurs are complex. Most cases are due to one of three processes. Firstly, direct oxidation of ferrohaemoglobin, which involves the transfer of electrons from ferrous haem to the oxidising compound. This mechanism proceeds most readily in the absence of oxygen. Secondly, indirect oxidation, a process of co-oxidation which requires haemoglobin-bound oxygen and is involved, for example, in nitrite-induced methaemoglobinaemia. Thirdly, biotransformation of a chemical to an active intermediate that initiates methaemoglobin formation by a variety of mechanisms. This is the means by which most aromatic compounds, such as amino- and nitro-derivatives of benzene, produce methaemoglobin. Methaemoglobinaemia is an uncommon occupational occurrence. Aromatic compounds are responsible for most cases, their lipophilic nature and volatility facilitating absorption during dermal and inhalational exposure, the principal routes implicated in the workplace. Methaemoglobinaemia presents clinically with symptoms and signs of tissue hypoxia. Concentrations around 80% are life-threatening. Features of toxicity may develop over hours or even days when exposure, whether by inhalation or repeated skin contact, is to relatively low concentrations of inducing chemical(s). Not all features observed in patients with methaemoglobinaemia are due to methaemoglobin formation. For example, the intravascular haemolysis caused by oxidising chemicals such as chlorates poses more risk to life than the methaemoglobinaemia that such chemicals induce. If an occupational history is taken, the diagnosis of methaemoglobinaemia should be relatively straightforward. In addition, two clinical observations may help: firstly, the victim is often less unwell than one would expect from the severity of ‘cyanosis’ and, secondly, the ‘cyanosis’ is unresponsive to oxygen therapy. Pulse oximetry is unreliable in the presence of methaemoglobinaemia. Arterial blood gas analysis is mandatory in severe poisoning and reveals normal partial pressures of oxygen (pO2) and carbon dioxide (pCO2,), a normal ‘calculated’ haemoglobin oxygen saturation, an increased methaemoglobin concentration and possibly a metabolic acidosis. Following decontamination, high-flow oxygen should be given to maximise oxygen carriage by remaining ferrous haem. No controlled trial of the efficacy of methylene blue has been performed but clinical experience suggests that methylene blue can increase the rate of methaemoglobin conversion to haemoglobin some 6-fold. Patients with features and/or methaemoglobin concentrations of 30–50%, should be administered methylene blue 1–2 mg/kg/bodyweight intravenously (the dose depending on the severity of the features), whereas those with methaemoglobin concentrations exceeding 50% should be given methylene blue 2 mg/kg intravenously. Symptomatic improvement usually occurs within 30 minutes and a second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methaemoglobin formation. Methylene blue is less effective or ineffective in the presence of glucose-6-phosphate dehydrogenase deficiency since its antidotal action is dependent on nicotinamide-adenine dinucleotide phosphate (NADP+). In addition, methylene blue is most effective in intact erythrocytes; efficacy is reduced in the presence of haemolysis. Moreover, in the presence of haemolysis, high dose methylene blue (20–30 mg/kg) can itself initiate methaemoglobin formation. Supplemental antioxidants such as ascorbic acid (vitamin C), N-acetylcysteine and tocopherol (vitamin E) have been used as adjuvants or alternatives to methylene blue with no confirmed benefit. Exchange transfusion may have a role in the management of severe haemolysis or in G-6-P-D deficiency associated with life-threatening methaemoglobinaemia where methylene blue is relatively contraindicated.
Congenital cyanosis due to an abnormal amount of methemoglobin was initially reported early in this century.1,2 It was first suggested by Hitzenberger3 in 1932 that this was an inherited metabolic disease. Gibson 4 in 1948 identified idiopathic methemoglobinemia as a disease due to an inborn error of metabolism. He demonstrated that methemoglobin reduction in normal erythrocytes took place through oxidation of triose phosphate and lactate and that there was deficiency in coenzyme factor I in patients with congenital methemoglobinemia. Scott,5 in 1960 in a study of Eskimo families with congenital methemoglobinemia, demonstrated the hereditary absence of activity of the erythrocyte enzyme diaphorase, which acts to reduce methemoglobin through the DPNH system. It is the purpose of this study to report a family with congenital methemoglobinemia who have a similar hereditary deficiency in erythrocyte diaphorase.
Materials and Methods
The family under study consisted of 189 known individuals both
MENINGITIS occurred in 19% of 84 cases of post-traumatic cerebrospinal fluid (CSF) rhinorrhea in one series.1 In the less common "spontaneous" CSF leaks, the incidence of meningitis is uncertain, since only a few isolated cases have been reported.2,3 Consequently, the prevention of meningitis may be one of the prime reasons for stopping the leak.
To help find the exact point of leakage, an easily identifiable substance is introduced into the subarachnoid space. Determination of the specific site of appearance of this substance then guides the surgeon to a precise localization for his reparative efforts. For this purpose, several dyes,4 radioactive isotopes,5-7 fluorescein,8 and iophendylate injection (Pantopaque)9,10 have been used.
Of the dye substances available for intrathecal instillation, methylene blue has been demonstrated to be noxious to the central nervous system.11 Apparently, the neural toxicity of methylene blue has not been sufficiently emphasized.
OBJECTIVE: To review a single surgeon's experience utilizing an intraoperative methylene blue infusion (IMBI) to identify parathyroid glands during neck exploration for primary hyperparathyroidism.
STUDY DESIGN AND SETTING: Retrospective review of 35 patients who underwent bilateral neck exploration utilizing an IMBI at a dose of 7.5 mg/kg following the induction of general anesthesia.
RESULTS: All patients reverted to normocalcemia with a mean follow-up of 17 months. IMBI facilitated the identification of abnormal parathyroid tissue in 34/35 patients (97%). A dark blue-purple staining was observed in 33/37 stained adenomas (89%). Four adenomas and four hyperplastic glands stained a lighter shade of blue-green. Among 89 normal glands, 41(46%) stained a pale green-grey color.
CONCLUSIONS: IMBI is a safe, readily available, cost-effective, and underutilized technique that facilitates rapid identification of parathyroid adenomas, helps distinguish normal glands from hyperplastic glands, and helps to locate ectopic glands. An overall reduction in operative time, especially for bilateral neck exploration, can be anticipated.
Since parathyroid glands are often inconspicuous, their identification can be a challenging problem when performing neck exploration for the treatment of hyperparathyroidism. Normal parathyroid glands can be a few millimeters in size (especially when suppressed by hypercalcemia), of variable color, and supernumerary. They may also be surrounded by or imbedded in adipose tissue or confused with small paratracheal lymph nodes. When thyroid surgery is performed by experienced surgeons, inadvertent parathyroidectomy may be as high as 9%. ¹ Abnormal parathyroid glands may be concealed beneath the thyroid capsule, intrathyroid, intrathymic, or inside the carotid sheath. Other ectopic locations in the neck or anterior mediastinum are also encountered. Furthermore, the distinction between true double adenomas and asymmetric hyperplasia continues to challenge even the most seasoned endocrine surgeon.
It has been argued that with the exception of a mediastinal parathyroid adenoma, localizing studies (eg, technetium-99m-sestamibi [Tc-MIBI] imaging, MRI, CT, and ultrasound [US]) add little to the overall success of parathyroidectomy, especially for primary explorations in the hands of experienced endocrine surgeons. However, for the less experienced surgeon, preoperative localization studies have been helpful in directing the side of the neck for initial exploration, and for reducing operative times and frustration. Revision parathyroidectomy, after a failed initial neck exploration, can be an exercise in futility without some form of localizing study, the cost of which is then always justified. Recent extramural pressures to perform “minimally invasive surgery,” limiting both the scope and duration of parathyroidectomy and reducing hospital length of stay, have popularized the use of preoperative parathyroid localizing studies. Over the past decade, Tc-MIBI imaging has become the “gold standard” for preoperative localization because of its high sensitivity and specificity, and its use has become routine in many centers. Intraoperative procedures such as Tc-MIBI localization using a hand-held gamma probe, intraoperative circulating iPTH assay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), have evolved to permit a more limited “minimally invasive” unilateral neck exploration. However, this approach is limited to patients for whom a preoperative Tc-MIBI strongly suggests the presence of a single adenoma. Even with this positive finding, Tc-MIBI will miss double adenomas and asymmetric four-gland hyperplasia in a significant number of patients. The additional radiation exposure to patient and personnel with radioguided surgery, the need for more than one scan, and complex scheduling issues for appropriate timing of the radiopharmaceutical administration may represent other disadvantages.
Es wird über schwerste Komplikationen nach intrathekaler Applikation von Methylenblau-Lösung zur Abklärung einer spontanen Rhinoliquorrhoe berichtet. Das Einbringen von Farbstofflösungen, besonders von Methylenblau, in den Liquorraum ist nach dem heutigen Stand der medizinischen Erkenntnis nicht mehr zulässig.
Summary
Very serious complications are reported following intrathecal injection of methylene blue. The clinical indication was to assess spontaneous rhinoliquorrhoe. It is now generally agreed that intrathecal application of dyestuff solutions, especially of methylene blue, is no longer permissible.
THE purple pigment in the cotyledons of unfermented Forastero cacao is distributed in separate cells which are readily seen in cut sections. These separate cells can also be seen in sections from the Pale Criollo cacaos, though they are not coloured purple.
To the Editor:
—I have just seen in The Journal, Dec. 3, 1932, page 1944, an article written by Dr. J. C. Geiger in which he mentioned several case histories of cyanide poisoning with and without the use of methylene blue (methylthionine chloride, U. S. P.).The action of methylene blue on cyanide and carbon monoxide has been known a long time in theoretical biology, but I was first to suggest that it be used as an antidote for cyanide and carbon monoxide poison cases, as a result of some studies which I made on animals under a grant from the medical school here, and as a result of extensive reading which I have done.At a meeting of the Society for Experimental Biology and Medicine, which took place last April, Dr. Hanzlik heard my paper on the use of methylene blue as an antidote for cyanide and carbon monoxide
The light-induced reactions of methylene blue and related phenothiazinium dyes with biological substrates are described. The properties of the excited states of the dyes, their reactions with nucleic acids and their photosensitised chemical modifications of nucleic acid bases are examined. Reports on phenothiazinium dye-induced damage to proteins, lipids, biological membranes, organelles, viruses, bacteria, mammalian cells and carcinomas are reviewed.
In 25-day-old rats, injected intraperitoneally with 0.2 ml aliquots of 6% methylene blue in saline over 1 hr followed by a single 4–6 ml intra-arterial injection; O2 pressurized to 45 lb/in2 was used to improve reblueing of 1.5–2 mm slices of cerebellum, thus increasing staining selectivity. Factors believed to influence this selectivity for axonal elements and fine dendrites are the rapidity and pressure (about 300 mm Hg) of the terminal intra-arterial injection, the hyperbaric O2 treatment of tissue slabs for 1 hr as a substiute for room air, and immersion in 6% ammonium molybdate for 1 hr before return to atmospheric conditions.
Introduction Intradermal methylene blue has been used successfully in pruritus ani. The mechanism is likely the destruction of dermal nerve endings. We report a new method in achieving postoperative pain relief using intradermal methylene blue injection to the perianal region after lateral anal sphincterotomy.
Methods Consecutive patients undergoing lateral anal sphincterotomy between July 2004 and January 2006 were studied prospectively. All were performed under local anesthesia. Four ml 1% methylene blue and 16 ml 1% lignocaine was injected into the perianal skin and intersphincteric space. Patients were asked to fill in a pain chart with a visual analog scale of 0 to 10.
Results There were 24 patients studied during this period. The median pain scores were under 2.5 for the first 4 days and were 0 from the 5th postoperative day. Nineteen out of 24 wound have healed by 2 weeks post sphincterotomy. There were no perianal complications.
Conclusion Intradermal injection of methylene blue together with local anesthetic gives good post‐operative pain control with minimal complications.
The intravenous infusion of methylene blue was investigated as a procedure that would identify parathyroid glands during operation in 17 patients with primary hyperparathyroidism. The dye was found to stain all adenomas, most hyperplastic glands and occasionally normal parathyroid glands. In addition, the frequency of glandular staining was directly related to the size of the gland, although size and histology may have been independent variables. Methylene blue infusion is a safe effective method of localizing abnormal parathyroid glands.
Methylene blue was administered orally to seven normal human subjects at a dose of 10 mg. in capsule form. Total urinary recovery ranged from 53 to 97% of the dose, with an average of 74%. Of the material recovered, an average of 78% was excreted as Ieucomethylene blue (stabilized in some salt, complex, or combination form) and the remainder as methylene blue. Some excretion rate-time plots of both methylene blue and leucomethylene blue showed evidence of a circadian rhythm. In a male dog and a female dog, administered 15 mg./kg. methylene blue orally, no drug was detected in blood. The female dog was catheterized and urine was collected for 10 hr. postdosing; recovery was 2.4% of the dose. The female dog was also administered a 10-mg. dose of methylene blue orally, and urine was collected by catheter over 14 hr. Recovery was 3.8% of the dose. It was concluded that methylene blue is well absorbed in man and poorly absorbed in the dog after oral administration.
1.
Methylene blue (50 and 100 mg/kg i.p. resp.) caused marked “sedation” and hypothermia in the rat. These effects are assumed to be due to the close chemical relation between methylene blue and chlorpromazine.
2.
Methylene blue inhibited effectively the monoamine oxidase (MAO) of the rat’s brain in vivo; it also increased the concentration of catecholamines (CA) and 5-hydroxytryptamine (5-HT) of the rat’s brain.
3.
Pretreatment of the animals with methylene blue inhibited the CA-increasing effect of nialamid, a long-acting, irreversible inhibitor of MAO. However, the MAO-inhibiting action of nialamid was not affected by pretreatment with methylene blue. Analogues results were obtained with another two MAO-inhibitors, namely harmine and iproniazid.
4.
The apparent discrepancy between inhibition of brain-MAO and lack of increase of brain-CA, and some implications of these results, are discussed.
GLUT1, the most ubiquitously expressed member of the GLUT family of glucose transporters, can be acutely activated by a variety of cell stresses. Methylene blue activates glucose transport activity of GLUT1 in L929 fibroblast cells presumably by a redox cycling of MB, which generates an oxidative stress. Data shown here reveal that methyl-β-cyclodextrin (MCD) blocks both the staining of cells and activation of glucose uptake by directly binding to MB. MCD binding to MB was qualitatively demonstrated by a significantly slower dialysis rate of MB in the presence of MCD. Analysis of the complete spectra of aqueous MB solutions and MB plus MCD solutions by a factor analysis program called SIVVU indicated that these equilibria can be modeled by three species: MB monomer, MB dimer, and MCD–MB inclusion complex. The molar extinction coefficients for each species from 500 to 700 nm were determined. The equilibrium association constant (Ka) for MB dimer formation was measured at 5846 ± 30 M−1 and the Ka for formation of the MCD–MB complex was 310 ± 10 M−1. MCD also dramatically enhances the destaining rate of MB-stained cells. The loss of MB from the cell is tightly correlated with the loss of activated glucose uptake. This suggests that the MB activation of glucose uptake is likely not caused by its redox cycling, but more likely the result of a specific interaction between MB and a protein directly involved in the activation of GLUT1.
We construct a data set of long-lived German patents of patent classes dyes (22) and dyeing (8) to measure the accumulation path of technological knowledge with respect to dyeing textiles. Using these data we show with a vector error correction model that in the German Empire inter-industry knowledge spill-over between the new chemical industry and the old textile industry created an upward circle of “endogenous growth.” The increasing demand for synthetic dyes of the prospering textile firms initiated further research and development projects of the chemical firms that led to new patents and via customer consulting and customer training to additional economic benefits of the textile industry.
In prion-infected mice, both the Notch-1 intracellular domain transcription factor (NICD) and the disease-causing prion protein (PrPSc) increase in the brain preceding dendritic atrophy and loss. Because the drug LY411575 inhibits the γ-secretase-catalyzed cleavage of Notch-1 that produces NICD, we asked whether this γ-secretase inhibitor (GSI) might prevent dendritic degeneration in mice with scrapie. At 50 d postinoculation with Rocky Mountain Laboratory (RML) prions, mice were given GSI orally for 43–60 d. Because we did not expect GSI to produce a reduction of PrPSc levels in brain, we added quinacrine (Qa) to the treatment regimen. Qa inhibits PrPSc formation in cultured cells. The combination of GSI and Qa reduced PrPSc by ≈95% in the neocortex and hippocampus but only ≈50% in the thalamus at the site of prion inoculation. The GSI plus Qa combination prevented dendritic atrophy and loss, but GSI alone did not. Even though GSI reduced NICD levels to a greater extent than GSI plus Qa, it was unable to prevent dendritic degeneration. Whether a balance between NICD and dendrite growth-stimulating factors was achieved with GSI plus Qa but not GSI alone remains to be determined. Although the combination of GSI and Qa diminished PrPSc in the brains of RML-infected mice, GSI toxicity prevented us from being able to assess the effect the GSI plus Qa combination on incubation times. Whether less toxic GSIs can be used in place of LY411575 to prolong survival remains to be determined.
• Creutzfeldt–Jakob disease
• neuropathology
• prion disease
• therapy
• scrapie
Two cationic phenoxazine dyes, meldola blue (MB) and nile blue (NB), and the structurally related phenothiazine, methylene blue (MethB), were found to act as complex inhibitors of human plasma cholinesterase (butyrylcholinesterase, BChE). Studied at 25 degrees C, in 100mM MOPS buffer (pH 8.0), with butyrylthiocholine as substrate, the kinetic pattern of inhibition indicated cooperative I binding at 2 sites. Intrinsic K' values ( identical with[I](0.5)(2) extrapolated to [S]=0) for MB, NB and MethB were 0.64+/-0.05, 0.085+/-0.026 and 0.42+/-0.04 microM, respectively. Under the same experimental conditions the dyes acted as single-occupancy, hyperbolic-mixed inhibitors of electric eel acetylcholinesterase (AChE), with K(i)=0.035+/-0.010, 0.026+/-0.0034 and 0.017+/-0.0063 microM (for MB, NB, MethB); alpha (coefficient of competitive interaction)=1.8-2.4 and beta (coefficient of noncompetitive interaction)=0.15-0.28. The complexity of the BChE inhibitory effect of phenoxazine/phenothiazine dyes contrasted with that of conventional ChE inhibitors which cause single-occupancy (n=1), competitive or mixed inhibition in both AChE and BChE and signaled novel modes of ligand interaction at (or remote from) the active site gorge of the latter enzyme.
Recent reports indicate that induction of nitric oxide (NO) evokes dopamine (DA) release from the striatum in vitro. In this study, we used L-arginine (L-Arg) to demonstrate the in vivo stimulation of DA release from the striatum of Mongolian gerbils using microdialysis. The content of DA in the striatal extracellular fluid (ECF) increased 7-15-fold in the presence of L-Arg in the perfusate as compared with that of the controls (DA level in drug-free perfusate varied from 0.050 +/- 0.009 to 0.092 +/- 0.023 pmol 10 microliters-1). Simultaneous perfusion of L-Arg with nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, markedly reduced the L-Arg effect on DA release from the striatum. The NLA-perfused animals contained DA levels significantly lower than those observed in the control striatal dialysate. These findings indicate for the first time that DA release in vivo can be induced by L-Arg, the precursor of NO. The data strongly suggest that NO may modulate striatal DA release.
Diss. med. Bern (kein Austausch). Literaturverz. Alcohol & alcoholism, vol. 35, no. 5, 2000, S. 424-426.
We appreciate the comments relating to our Review article (The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics. Nature Rev. Drug Discov. 7, 156–167 (2008)
Methylene blue (MB) infusion is frequently used to localize the parathyroid glands during parathyroidectomy and generally considered safe. Several recent reports suggest neurological toxicity and post-operative altered mental state typically after large dose infusions. The mechanism by which MB has neurotoxic effects in some patients remains uncertain.
A 67-year-old male underwent lumbar laminectomy followed by parathyroidectomy. Postoperatively, he was comatose (Glasgow Coma Scale of 7) and underwent extensive neurological evaluation. Brain computed tomography (CT) imaging and CT angiography revealed no ischemia, vessel occlusion, or hemorrhage. Electroencephalogram (EEG) showed only slowing of cerebral hemispheric activity bilaterally. Over the next 48 h, his mental status slowly improved and the patient made a full neurological recovery (Glasgow Coma Scale 15).
Methylene blue, when used in patients on antidepressant drugs, may be associated with a transient encephalopathic state and serotonin syndrome. Patients on antidepressants undergoing parathyroidectomy who may receive MB infusion should be considered for alternative parathyroid gland identification or discontinuation of the antidepressants before surgery. MB-associated serotonin syndrome is an increasing and under recognized ('green') post-operative encephalopathy that warrants education to critical care neurologists and other physicians.
The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities.
This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine.
Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15-4 mg/kg MTC; 0.1-0.5 mg/kg rivastigmine) in mono or combination treatment.
Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments.
In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.