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Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. Bill & Melinda Gates Foundation, European Research Council.

Antimicrobial photodynamic therapy (aPDT) is increasingly being explored for treatment of periodontitis. Here, we investigated the effect of aPDT on human dental plaque bacteria in suspensions and biofilms in vitro using methylene blue (MB)-loaded poly(lactic-co-glycolic) (PLGA) nanoparticles (MB-NP) and red light at 660 nm. The effect of MB-NP-based aPDT was also evaluated in a clinical pilot study with 10 adult human subjects with chronic periodontitis. Dental plaque samples from human subjects were exposed to aPDT—in planktonic and biofilm phases—with MB or MB-NP (25 µg/mL) at 20 J/cm2 in vitro. Patients were treated either with ultrasonic scaling and scaling and root planing (US + SRP) or ultrasonic scaling + SRP + aPDT with MB-NP (25 µg/mL and 20 J/cm2) in a split-mouth design. In biofilms, MB-NP eliminated approximately 25% more bacteria than free MB. The clinical study demonstrated the safety of aPDT. Both groups showed similar improvements of clinical parameters one month following treatments. However, at three months ultrasonic SRP + aPDT showed a greater effect (28.82%) on gingival bleeding index (GBI) compared to ultrasonic SRP. The utilization of PLGA nanoparticles encapsulated with MB may be a promising adjunct in antimicrobial periodontal treatment.

Warts are small, benign growths caused by human papilloma virus (HPV) infection of the skin or mucous membrane. Photodynamic therapy in dermatology is simplified by the accessibility of the skin to light application and allows using any light source with the appropriate spectrum. This study aimed to compare the efficacy and safety of daylight-PDT versus pro yellow laser (577 nm)-PDT mediated by 10% methylene blue (MB) gel in the treatment of plane warts. This prospective comparative study was carried out on 34 patients presented with common warts (≥ 1 warts). Patients were divided into two equal groups by simple randomization process. Group 1: treated with daylight PDT using MB (MB-DL PDT), group 2: treated with Pro yellow laser as PDT using MB. The results of the present study revealed excellent response of warts in 9 patients (52.9%), very good response in 4 patients (23.5%) and poor response in 2 patients (11.8%) of group (1). In group (2), excellent response of the treated warts was observed in 5 patients (29.4%), poor response in 5 patients (29.4%) and no response in 7 patients (41.2%). Daylight-photodynamic therapy (DL-PDT) using MB is an effective treatment, nearly pain free and of convenience to patients. Careful consideration should be given to patient-specific factors such as immune status and previous treatment history. Future research with larger sample sizes, HPV genotyping, and longer follow-up periods is warranted to optimize patient-tailored PDT protocols.

Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects. We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine. Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning. The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects. Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.

This study aimed to study the effect of combined antimicrobial photodynamic therapy (aPDT) and photobiomodulation therapy (PBMT) in the management of recurrent herpes labialis (RHL). Sixty participants were randomly assigned into three groups. Group 1 (control): 5% Acyclovir was applied as a topical cream, and a non-activating laser was applied. Group 2 (PBMT): PBMT was applied using a low-level laser therapy (LLLT) and a placebo cream. Group 3 (aPDT + PBMT): aPDT using 0.1% methylene blue with PBMT and a placebo cream. A laser diode emitting light at a wavelength of 650 nm and a power output of 100 mW was applied to each spot for 120 s. The parameters of aPDT were a wavelength of 650 nm, with power and energy density parameters set at 100 mW/ 0.1 W and 24 J/cm², respectively. Pain intensity was measured using a visual analog scale (VAS). At the baseline (t 0 ). After applying the laser (t 1 ). After 48 h (t 2 ). After utilizing the laser in the second session (t 3 ). After 7 days (t 4 ). The point of healing was the spontaneous shedding of the crust. The aPDT + PBMT group outperforms the control group in reducing pain intensity at t 1 ( p  = 0.011), t 2 ( p  = 0.041), and t 3 ( p  = 0.005). In addition, the aPDT + PBMT group outperformed the PBMT group at t 3 ( p  = 0.020). aPDT + PBMT outperforms control ( p  = 0.001) and PBMT ( p  = 0.090) groups in healing. The findings indicate that aPDT and PBMT offer a promising approach to treating RHL.

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

Background Around the world, the COVID-19 pandemic has presented many difficulties, and acute respiratory distress syndrome (ARDS) has become a major worry. The antiviral and anti-inflammatory characteristics of methylene blue (MB) have garnered interest for potential medicinal applications. The object of the current study is to assess the effect of orally administered MB on the treatment of ARDS associated with COVID-19. Method A randomized clinical study was carried out on 122 hospitalized patients who had ARDS related to COVID-19. Patients who met the eligibility requirements were randomized at random to either the control group (CG) ( n  = 60) or the intervention group (IG) ( n  = 62). Standard treatments were administered to both groups, with the addition of oral MB to the IG. Clinical outcomes, including SpO2 levels, CRP levels were assessed on the third and fifth days. Additionally, at the time of discharge, patients' assessments were made in terms of APACHE II scores, SOFA scores, LDH and CRP levels, SpO2, and respiratory rate in comparison to the day prior to the intervention. Patients were followed for mortality outcomes at one month and three months after the intervention. Results Significant changes were observed in SpO2 levels over time ( P  < 0.001) and between groups ( P  = 0.022), with higher levels in the MB-treated group. The interaction between time and group ( P  = 0.019) indicated a stronger increase in SpO2 in the IG, with the IG's SpO2 level increasing by 6.42%. Furthermore, CRP levels showed significant changes over time ( P  < 0.001), but not between groups ( P  = 0.092). However, the interaction between group and CRP change over time ( P  = 0.019) suggested a distinct pattern of CRP decrease in the IG. Significant improvement in RR, SpO2, CRP, and APACHE II score were found according to discharge results. However, in terms of SpO2 and the APACHE II score, this improvement was noteworthy for IG. The length of hospitalization and mortality rates at one- and three-month follow-ups did not differ significantly. Conclusion Oral administration of MB demonstrated positive effects on improving SpO2 levels and reducing inflammatory markers in COVID-19-related ARDS patients. Despite no significant impact on survival rates or hospitalization length, the study supports the potential efficacy of MB as an alternative treatment for COVID-19 ARDS. Trial Registration This study was registered with the Iranian Registry of Clinical Trials ( http://www.irct.ir ) under the registration code IRCT20200409047007N2 on 11/29/2021.

Artemisinin resistance is threatening global efforts for malaria control and elimination. Primaquine (PQ) and methylene blue (MB) are gametocytocidal drugs that can be combined with artemisinin-based combination therapy (ACT) to reduce malaria transmission, including resistant strains. Children (6-59 months) with uncomplicated falciparum malaria in Burkina Faso were treated with artesunate-amodiaquine (AS-AQ) and randomized to MB (15 mg/kg/day for 3 days) or PQ (0.25 mg/kg at day 2) with the aim to show non-inferiority of the MB regimen with regard to haematological recovery at day 7 (primary endpoint). MB-AS-AQ could not be shown to be non-inferior to PQ-AS-AQ (mean Hb difference between treatment groups on day 7 was -0.352, 95% CI -0.832-0.128, p = 0.0767), however, haemoglobin recovery following treatment was alike in the two study arms (day 7: mean 0.2±1.4 g/dl vs. 0.5±0.9 g/dl, p = 0.446). Occurrence of adverse events was similar in both groups, except for vomiting, which was more frequent in the MB than in the PQ arm (20/50 vs 7/50, p = 0.003). Adequate clinical and parasitological response was above 95% in both groups, but significantly more asexual parasites were cleared in the MB arm compared to the PQ arm already on day 1 (48/50, 96%, vs 40/50, 80%, p = 0.014). Moreover, P. falciparum gametocyte prevalence and density were lower in the MB arm than in the PQ arm, which reached statistical significance on day 2 (prevalence: 2/50, 4%, vs 15/49, 31%, p<0.001; density: 9.6 vs 41.1/μl, p = 0.024). However, it should be considered that PQ was given only on day 2. MB-ACT appears to be an interesting alternative to PQ-ACT for the treatment of falciparum malaria. While there is a need to further improve MB formulations, MB-ACT may already be considered useful to reduce falciparum malaria transmission intensity, to increase treatment efficacy, and to reduce the risk for resistance development and spread. Trial registration: ClinicalTrials.gov NCT02851108.

Our study aims to test the hypothesis that intraoperative methylene blue reduces the incidence of postoperative delirium (POD) following major abdominal surgery, and to evaluate the inflammatory biomarkers as potential mediators. A randomized, single blind clinical trial. University cancer center. Three hundred and fourteen patients scheduled for pancreatic surgery. Patients were randomly assigned to methylene blue group, who receiving intravenous infusion of 2 mg kg-1 methylene blue within 60 min immediately after anesthetic induction, followed by infusion of 1 mg kg-1 methylene blue within 30 min before the end of surgery, or control group, who receiving equal volume saline. The primary outcome was POD incidence. The secondary outcomes included plasma interleukin 6 (IL-6) and interleukin 8 (IL-8) concentrations before and after surgery, gene expressions in human brain microvascular endothelial cells (hCMEC/d3) and peripheral blood mononuclear cells (PBMCs) adhesion to hCMEC/d3. Perioperative adverse events were also documented. A total of 55 patients (17.5%) experienced POD, with a lower POD incidence in the methylene blue group than in the control group (11.5% vs. 23.6%, p = 0.005). The adverse events in the two groups were comparable. And postoperative plasma IL-6 but not IL-8 concentration was lower in the methylene blue group. Furthermore, endothelial TNF-α, MCP-1 and VCAM1 expressions were lower when treated with serum from the methylene blue group, and the number of PBMCs adhesion to hCMEC/d3 cells was also less in the methylene blue group. Intraoperative methylene blue use effectively and safely reduced the POD incidence in patients undergoing pancreatic surgery, which may be associated with decrease in systemic inflammation and immunovascular interactions. •Intraoperative methylene blue use effectively and safely reduced the POD incidence in patients undergoing pancreatic surgery.•Compared with control group, systemic IL-6 concentration in the methylene blue group was lower at postoperative first day.•Compared with normal saline, methylene blue significantly mitigated immunovascular interactions in vitro experiments.

Methylene blue (MB) has been proposed as an adjunctive therapy in the early management of septic shock; however, its effects on microcirculatory function remain poorly understood. This study aimed to investigate whether MB infusion improves sublingual microcirculatory parameters in patients with septic shock. In this single-center, randomized controlled trial, participants were allocated in a 1:1 ratio to either the MB group or the control group. The MB group received an intravenous bolus of 2 mg/kg MB over 15 minutes, followed by a continuous infusion of 1 mg/kg MB diluted in 500 mL of 0.9% saline via a central venous catheter for 12 hours. The control group received an equivalent volume of saline. The primary endpoint was the change in sublingual microcirculation parameters from baseline to 24 hours, assessed using a repeated-measures mixed-effects model. Secondary endpoints included 28-day organ support-free days and 28-day mortality. Among the 72 randomized participants, 70.8% (n=51) were male, with a mean age of 68.6±13.5 years. Following MB treatment, the mean microvascular flow index (MFI) in the MB group was 2.78, compared to 2.51 in the control group. MMRM analysis demonstrated that MB significantly improved MFI (least squares mean difference [95% CI]: 0.21 [0.09, 0.33], P=0.001), with significant increases observed as early as 1 hour post-intervention (T1: 0.24 [0.06, 0.42], P=0.009), and this effect persisted up to 24 hours (T24: P=0.005). However, no significant differences were observed between the groups in 28-day mortality (25.0% [9/36] vs 41.7% [15/36], P=0.200) or organ support-free days (20.0 [1.0-22.0] vs 16.0 [1.3-22.0], P=0.910). Although MB improved sublingual microcirculatory parameters, these improvements did not translate into benefits in organ function or survival outcomes. chictr.org.cn ChiCTR 2400081549.