Seizures and severe methaemoglobinaemia following accidental ingestion of amyl nitrite.

We present a case of a man in his late 40s presenting with generalised tonic-clonic seizures and profound methaemoglobinaemia shortly after inadvertent ingestion of amyl nitrite. Arterial blood gas analysis demonstrated methaemoglobin levels exceeding the upper detection threshold of our analyser, accompanied with profound cyanosis despite apparent oxygen saturations of 94%. Prompt administration of intravenous methylene blue led to a rapid and complete recovery. This case highlights the importance of swift recognition and treatment of methaemoglobinaemia particularly when the precipitating factor may be unknown at the time of presentation. This case also demonstrates the potential limitations of bedside blood gas analysers in diagnosis.

Photodynamic therapy repairs medication-related osteonecrosis of the jaw by reducing NF-kB protein in rats.

OBJECTIVE: To evaluate whether antimicrobial photodynamic therapy (aPDT) repairs bisphosphonate-related osteonecrosis of the jaw (BRONJ) modulated by the reduction of NF-kB protein in a murine model. METHODOLOGY: Male Wistar rats (N=30) were divided into the following groups (n=6/group): negative control (NC); experimental osteonecrosis (ONE); ONE + photosensitizer (PS); ONE + photobiomodulation (PBM); and ONE + aPDT. Over 8 weeks, ONE was induced by zoledronic acid 250 µg/kg injections, except in the NC group, which received sterile 0.9% saline, followed by extraction of the lower left first molar. Red light laser irradiation (wavelength ~660 nm, power 50 mW, energy of 2 J, energy dose of 66.67 J/cm2 for 40 s) was performed once a week for 4 weeks. Methylene blue 0.3% was used as PS. The animals were euthanized and examined macroscopically for the presence of exposed bone and epithelial repair and microscopically by histochemical (hematoxylin-eosin and Masson's trichrome staining) and immunohistochemical (anti-NF-kB) methods. Macroscopic and histomorphometric data were analyzed by one-way ANOVA and Tukey's post-test (p<0.05). RESULTS: Mucosal repair, viable osteocytes, and NF-kB immunostaining were observed in the NC, ONE+PS, ONE+PBM, and ONE+aPDT groups. The ONE group showed no mucosal repair, showing empty lacunae and multifocal immunostaining for NF-kB. The ONE+PBM and ONE+aPDT groups had greater deposition of extracellular matrix and less necrotic bone tissue (p<0.05). CONCLUSION: PBM and aPDT treatments for BRONJ were effective for bone and epithelial repair, in addition to reducing inflammation mediated by the decrease of NF-kB protein in the irradiated regions.

A rare case of methemoglobinemia in a preterm newborn with unclear etiology.

 Cyanosis is a bluish discoloration of the tissues due to increased levels of deoxygenated hemoglobin in capillaries. It is a common finding in newborn infants that can be caused by different diseases, including pulmonary, cardiac, infectious, and hematological disorders. Methemoglobinemia is a rare cause of cyanosis, in which hemoglobin is oxidized, changing its heme iron configuration from the ferrous (Fe2 +) to the ferric (Fe3 +) state, creating methemoglobin (Met-Hb), a form that does not bind oxygen, leading to decreased oxygen delivery to the tissues and cyanosis. We report a rare case of a preterm newborn, who developed cyanosis and worsening hypoxemia on day ten of life, she was found to have elevated Met-Hb percentage in blood gas analysis that required treatment with intravenous methylene blue. Her symptoms resolved after a period of maintenance treatment with oral methylene blue and ascorbic acid, and the etiology of her disease remains unclear.

Intravital Microscopy Evidence That Methylene Blue Should Be a Vasopressor-Sparing Agent in Sepsis Vasoplegia.

Microvasculature failure is expected in sepsis and at higher amine concentrations. Therefore, special attention focused individually on microcirculation is needed. Here, we present that methylene blue can prevent leukocytes from adhering to the endothelium in a rat model of lipopolysaccharide-induced endotoxemia. As hypothesis evidence, an intravital microscopy image is presented.

Use of hydroxocobalamin to treat intraoperative vasoplegic syndrome refractory to vasopressors and methylene blue during liver transplantation.

INTRODUCTION: For patients with catecholamine-resistant vasoplegic syndrome (VS) during liver transplantation (LT), treatment with methylene blue (MB) and/or hydroxocobalamin (B12) has been an acceptable therapy. However, data on the effectiveness of B12 is limited to case reports and case series. METHODS: We retrospectively reviewed records of patients undergoing LT from January 2016 through March 2022. We identified patients with VS treated with vasopressors and MB, and abstracted hemodynamic parameters, vasopressor requirements, and B12 administration from the records. The primary aim was to describe the treatment efficacy of B12 for VS refractory to vasopressors and MB, measured as no vasopressor requirement at the conclusion of the surgery. RESULTS: One hundred one patients received intraoperative VS treatment. For the 35 (34.7%) patients with successful VS treatment, 14 received MB only and 21 received both MB and B12. Of the 21 patients with VS resolution after receiving both MB and B12, 17 (89.5%) showed immediate, but transient, hemodynamic improvements at the time of MB administration and later showed sustained response to B12. CONCLUSION: Immediate but transient hemodynamic response to MB in VS patients during LT supports the diagnosis of VS and should prompt B12 administration for sustained treatment response.

The impact of methylene blue in colorectal cancer: Systematic review and meta-analysis study.

PURPOSE: In patients with colorectal cancer (CRC), the most important factor to decide the need of adjuvant chemotherapy is the histological lymph node (LN) evaluation. Our work aimed to give a broad view over the use of methylene blue and its consequences in the number of lymph node harvest. METHODS: PUBMED, WEB OF SCIENCE and EMBASE databases were consulted, retrieving clinical trials, which mentioned the used of intra-arterial methylene blue in patients with colorectal cancer. RESULTS: Eighteen clinical trials analyzing the use of intra-arterial methylene blue in specimens of colorectal cancer were selected. The articles show a statistical difference between the use of methylene blue and the classical dissection in both variable at study. The results of the statistical analysis of the lymph node harvest variable demonstrate a significant statistical difference between the group that received methylene blue injection and the group that underwent conventional dissection. There is a significant statistical difference between the experimental and control groups for the ideal lymph node harvest (lymph node harvest count greater than 12). CONCLUSION: The use of intra-arterial methylene blue revealed a high potential for the quantification of lymph nodes, considering the increase of lymph node harvest and the higher percentage of cases with more than 12 lymph nodes count, albeit the high heterogeneity between the studies in terms of reported results. Future investigations with controlled double blinded studies obtaining better categorized results should be conducted in order to better evaluate this technique and compare it to the current paradigm.

Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease.

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.

Evaluation of antimicrobial photodynamic action of a pluronic and pectin based film loaded with methylene blue against methicillin resistantStaphylococcus aureus.

Antimicrobial wound dressings play a crucial role in treatment of wound infections. However, existing commercial options fall short due to antibiotic resistance and the limited spectrum of activity of newly emerging antimicrobials against bacteria that are frequently encountered in wound infections. Antimicrobial photodynamic therapy (aPDT) is very promising alternative therapeutic approach against antibiotic resistant microbes such as methicillin resistantStaphylococcus aureus (MRSA). However, delivery of the photosensitizer (PS) homogeneously to the wound site is a challenge. Though polymeric wound dressings based on synthetic and biopolymers are being explored for aPDT, there is paucity of data regarding theirin vivoefficacy. Moreover, there are no studies on use of PS loaded, pluoronic (PL) and pectin (PC) based films for aPDT. We report development of a polymeric film for potential use in aPDT. The film was prepared using PL and PC via solvent casting approach and impregnated with methylene blue (MB) for photodynamic inactivation of MRSAin vitroandin vivo. Atomic force microscopic imaging of the films yielded vivid pictures of surface topography, with rough surfaces, pores, and furrows. The PL:PC ratio (2:3) was optimized that would result in an intact film but exhibit rapid release of MB in time scale suitable for aPDT. The film showed good antibacterial activity against planktonic suspension, biofilm of MRSA upon exposure to red light. Investigations on MRSA infected excisional wounds of mice reveal that topical application of MB loaded film for 30 min followed by red light exposure for 5 min (fluence; ∼30 J cm-2) or 10 min (fluence; ∼60 J cm-2) reduces ∼80% or ∼92% of bioburden, respectively. Importantly, the film elicits no significant cytotoxicity against keratinocytes and human adipose derived mesenchymal stem cells. Taken together, our data demonstrate that PS-loaded PL-PC based films are a promising new tool for treatment of MRSA infected wounds.

Adjuvant effect of antimicrobial photodynamic therapy (aPDT) in the treatment of diabetic foot ulcers: A case series.

This study aimed to evaluate the clinical evolution of patients with diabetic foot ulcer treated with antimicrobial photodynamic therapy (aPDT) using the Bates-Jensen (BJ) scale. A total of 21 patients were monitored, with an average age of 58 years. Patients underwent the standard treatment protocol of the institution, supplemented with aPDT utilizing 0.01% methylene blue (MB) and laser irradiation (660 nm, 100 mW, 6 J per point). Following aPDT, the lesions were protected with hydrofiber dressings containing silver. The Bates-Jensen Scale was employed at pre-treatment and post-aPDT sessions to assess lesion progression. The results demonstrated a significant difference between pre- and post-treatment values in the overall BJ score. The use of MB in aPDT proved to be an effective, safe, well-tolerated treatment with high patient adherence and the potential for implementation in the care of diabetic foot conditions.

Effect of methylene blue on outcomes in patients with distributive shock: a meta-analysis of randomised controlled trials.

OBJECTIVE: This meta-analysis aimed to demonstrate the effect of methylene blue (MB) in patients with distributive shock. DESIGN: Meta-analysis. METHODS: According to the Prospective International Register of Systematic Reviews (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched the relevant randomised controlled trials (RCTs) via PubMed, Embase and Cochrane Library from the date of database inception to 19 April 2023. The primary outcome was mortality during follow-up, and secondary outcomes included mean arterial pressure (mm Hg), mechanical ventilation time (hours), intensive care unit (ICU) length of stay (LOS) (days), hospital LOS (days) and heart rate (times/min). RESULTS: This study included six RCTs with 265 participants. The study showed no significant difference in mortality between the MB and placebo groups (ORs: 0.59; 95% CI 0.32 to -1.06). However, MB reduced the duration of mechanical ventilation (mean difference (MD): -0.68; 95% CI -1.23 to -0.14), ICU LOS (MD: -1.54; 95% CI -2.61 to -0.48) and hospital LOS (MD: -1.97; 95% CI -3.92 to -0.11). CONCLUSIONS: The use of MB may not reduce mortality in patients with distributive shock, but may shorten the duration of mechanical ventilation, ICU LOS and hospital LOS. More clinical studies are needed to confirm these findings in the future. TRIAL REGISTRATION NUMBER: CRD42023415938.

Medium-term antifungal effects of methylene blue versus flavin mononucleotide in the treatment of moderate toenail onychomycosis.

BACKGROUND: Methylene blue (MB) and flavin mononucleotide (FMN)-mediated photodynamic therapy (PDT) have demonstrated local antimicrobial effect, but no direct comparative study has been published so far for the treatment of toenail onychomycosis. OBJECTIVES: To directly compare the short and medium-term efficacy of MB versus FMN as photosensitizers in PDT for toenail onychomycosis by applying them in a 40% w/w urea cream in two different dye concentrations. METHODS: Forty toenails with distal and lateral subungual moderate onychomycosis due to dermatophyte fungi were randomised to receive 10 weekly sessions of PDT mediated by four topical formulations including MB or FMN at two different concentrations: Group I: 0.1% w/w MB; Group II: 2% w/w MB; Group III: 0.1% w/w FMN; and Group IV: 2% w/w FMN. Photographs were used for onychomycosis severity index (OSI) estimation allowing clinical assessment at any point of the study. Microscopic and microbiological evaluations were carried out at baseline, 27- and 35-week follow-ups. Side effects were recorded along with patient satisfaction. RESULTS: At week 27, mycological cure rates were 60%, 30%, 50% and 40% and complete cure rates were 0%, 20%, 10% and 20%, for Groups I, II, III and IV respectively. At week 35, mycological cure rates were 70%, 70%, 70% and 60% and complete cure rates were 30%, 50%, 70% and 30%, for Groups I, II, III and IV respectively. All cream formulations were safe and patients were fairly satisfied. CONCLUSIONS: Results of the present work confirm PDT as a therapeutic alternative for onychomycosis. Although all cream formulations were safe and effective, with a good degree of satisfaction, higher cure rates were obtained with 2% w/w MB cream and 0.1% w/w FMN cream.

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Association of active oxygen-releasing gel and photodynamic therapy in the treatment of residual periodontal pockets in type 2 diabetic patients: A randomized controlled clinical study.

BACKGROUND: The aim of this study was to evaluate the effect of active oxygen-releasing gel as an adjuvant, with and without antimicrobial photodynamic therapy (aPDT), in the treatment of residual pockets in periodontal patients with type 2 diabetes mellitus (DM2). METHODS: Patients with residual pockets with probing depth (PD) ≥4 mm and bleeding on probing (BOP) were divided into the following groups: SI (n = 17)-subgingival instrumentation in a single session; BM (n = 17)-SI followed by local application of active oxygen-releasing gel inside the periodontal pocket for 3 min; BM + aPDT (n = 17)-SI followed by application of BM for 3 min and pocket irrigation with methylene blue, and 660-nm diode laser irradiation at 100 mW for 50 s. The periodontal clinical parameters, serum levels of glycated hemoglobin, and immunological analysis of crevicular fluid were evaluated. All data were submitted to statistical analysis (α = 5%). RESULTS: A significant reduction in BOP was verified at 90 and 180 days in the BM + aPDT group. The percentage of sites with PD ≥ 4 mm was significantly reduced at 90 days in BM + aPDT and BM, whereas after 180 days only BM showed a significant reduction. In the BM + aPDT group, there was a significant reduction in tumor necrosis factor α levels at 90 days. There were no differences between the treatments. CONCLUSION: The use of adjuvant active oxygen-releasing gel, with or without aPDT, resulted in the same clinical benefits as SI in the treatment of residual pockets in poorly controlled DM2 patients.

Anticholinergic Toxidrome as a Possible Explanation for Methylene Blue Toxicity.

BACKGROUND Methylene blue has multiple uses in medicine. It is generally used to treat refractory vasoplegia and methemoglobin toxicity, and can be used as a dye to localize the parathyroid glands intra-operatively. In refractory vasoplegia, methylene blue inhibits endothelial nitric oxide and guanylate cyclase, causing vasoconstriction and potentially stabilizing blood pressure. Multiple complications have been associated with the use of methylene blue. These are related to either the sole effect of methylene blue or the combined effect of methylene blue and certain antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). To the best of our knowledge, in the setting of post-cardiac surgery vasoplegia, there have been no reports of the neurological toxicity of methylene blue in the absence of SSRI use. In this case report, we describe the anticholinergic manifestations associated with the use of methylene blue in post-cardiac surgery vasoplegia. CASE REPORT A male patient in his mid-sixties with severe mitral regurgitation underwent elective mitral valve replacement. Postoperatively, he was hypotensive and required a high dose of vasopressors. Methylene blue was administered to treat refractory vasoplegia. The patient became anuric and febrile, with bilateral mydriasis. Internal cooling and continuous renal replacement therapy were initiated, and symptoms rapidly resolved. The patient was discharged after prolonged hospitalization with a permanent catheter for hemodialysis. CONCLUSIONS Anticholinergic toxidrome may explain the neurological adverse effects associated with high doses of methylene blue. Physicians should be cautious when using methylene blue in combination with other anticholinergic drugs and in conditions of renal failure. The development of methylene blue toxicity warrants the urgent discontinuation of the agent and early drug elimination.

Antibacterial and anti-corona virus (229E) activity of Nigella sativa oil combined with photodynamic therapy based on methylene blue in wound infection: in vitro and in vivo study.

Microbial skin infections, antibiotic resistance, and poor wound healing are major problems, and new treatments are needed. Our study targeted solving this problem with Nigella sativa (NS) oil and photodynamic therapy based on methylene blue (MB-PDT). Antibacterial activity and minimum inhibitory concentration (MIC) were determined via agar well diffusion assay and broth microdilution, respectively. Transmission electron microscopy (TEM) proved deformations in Staphylococcus aureus ATCC 6538. Gas chromatography-mass spectrometry identified useful compounds that were suggested to be responsible for the potency of the oil. NS oil was tested as an antivirus against low pathogenic coronavirus (229E). Therapies examined, MB-PDT, NS, and MB-PDT + NS oil, to accelerate wound healing. The antibacterial efficacy against S. aureus was promising, with a MIC of 12.5% and TEM showing injured cells treated with NS oil. This oil inhibited 229E virus up to 42.85% and 32.14%. All tested therapies were successful in accelerating wound healing. The most successful was combined therapy (MB-PDT + NS oil), with a faster healing time. The combined therapy (MB-PDT + NS oil) reduced bacterial counts, which may be a key factor in accelerating wound healing. Skin wound histology was investigated; blood hematology and biochemical analysis did not change significantly after the safe combination treatment. A combination treatment could facilitate healing in a simple and inexpensive way in the future. Based on the results of the in vitro and in vivo studies, it was determined that NS oil had antibacterial and anti-corona virus activity when used in conjunction with photodynamic treatment based on methylene blue to treat wound infections.

Adjunctive methylene blue antimicrobial photodynamic therapy for mucocutaneous lesions of mycoses: three case reports.

Dermatophytosis, paracoccidioidomycosis and sporotrichosis are mycoses caused by different fungal species with significant prevalence in Brazil and other countries. In some situations, they affect quality of life, especially in the most vulnerable populations. Antifungal drug therapy is the conventional treatment for these diseases, although some difficulties may occur. Adjunctive use of antimicrobial photodynamic therapy (aPDT) may reduce these challenges. Three patients were treated with aPDT and conventional antifungals. In all cases, the patients did not report pain, discomfort or side effects during or after the aPDT intervention. The adjunctive use of aPDT in the cases presented proved to be a safe, low-cost tool that may be promising for the treatment of different mycoses.

Some fungal diseases are very common in Brazil and other countries and, in some cases, treatment may be difficult. The combination of a type of laser may help the treatment of these diseases. Here, three cases of fungal diseases that were treated with laser, dye and conventional antifungals are presented.

Duodenal mucosal resurfacing with photodynamic therapy using methylene blue in a mouse model.

BACKGROUND: The duodenum has emerged as a key player in metabolic diseases. The objective was to evaluate the safety and efficacy of intra-duodenal PDT using methylene blue in managing glycemic control and weight reduction. METHODS: Optimal concentration of methylene blue and conditions for intra-duodenal PDT were determined through in vitro experiments. After injecting methylene blue into the duodenum, we performed intra-duodenal PDT. High-fat diet rats were used to assess the efficacy of intra-duodenal PDT through measures of oral glucose tolerance, insulin sensitivity, and weight change. Immunohistochemical staining was also conducted to examine GLP-1 and GIP-producing cells in the ileum and duodenum, respectively. RESULTS: Introduodenal PDT reduced villous height of duodenum at 48 h, which was fully recovered at 30 days without complications. Rats treated with PDT showed significantly lower blood glucose levels with glucose loading and improved insulin sensitivity than rats in the sham-treatment group. The PDT group also had a significant reduction in body weight compared to the sham-treatment group at 30 days after intervention, although food intake was not significantly different between the two groups. Numbers of GLP-1 and GIP producing cells in the ileum and irradiated area were significantly higher in the PDT group than in the sham-treatment group. CONCLUSIONS: Intra-duodenal PDT using methylene blue showed a feasible therapeutic modality in improving metabolic parameters. However, large animal experiments and mechanism studies are needed to determine the clinical relevance. The possibility of repeating this treatment every 30 days and its accompanying complications should be further studied.