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Purpose Methylene blue (MB) has been tested as a rescue therapy for patients with refractory septic shock. However, there is a lack of evidence on MB as an adjuvant therapy, its’ optimal timing, dosing and safety profile. We aimed to assess whether early adjunctive MB can reduce time to vasopressor discontinuation in patients with septic shock. Methods In this single-center randomized controlled trial, we assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days. Results Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59–83] vs 94 h [IQR 74–141]; p  < 0.001), one more day of vasopressor-free days at day 28 ( p  = 0.008), a shorter ICU length of stay by 1.5 days ( p  = 0.039) and shorter hospital length of stay by 2.7 days ( p  = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration. Conclusion In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials. Trial registration ClinicalTrials.gov registration number NCT04446871 , June 25, 2020, retrospectively registered.

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.

Background and ObjectivesErector spinae block is an ultrasound-guided interfascial plane block first described in 2016. The objectives of this cadaveric dye injection and dissection study were to simulate an erector spinae block to determine if dye would spread anteriorly to the involve origins of the ventral and dorsal branches of the spinal nerves.MethodsIn 10 unembalmed human cadavers, 20 mL of 0.25% methylene blue dye was injected bilaterally into the plane between the fifth thoracic transverse process and erector spinae muscle. An in-plane ultrasound-guided technique with the transducer orientated longitudinally was used. During dissection, superficial and deep muscles were identified, and extent of dye spread was documented in cephalocaudal and lateral directions. The ventral and dorsal rami of spinal nerves and dorsal root ganglion at each level were examined to determine if they were stained by dye.ResultsThere was extensive cephalocaudad and lateral spread of dye deep and superficial to the erector spinae muscles. Except for 1 injection (from 20), the ventral rami were not stained by the dye. In only 2 injections did the dye track posteriorly through the costotransverse foramen to the dorsal root ganglion. In all other cases, the dorsal root ganglia were not involved in the dye injection. The dye stained the dorsal rami posterior to the costotransverse foramen.ConclusionsThere was no spread of dye anteriorly to the paravertebral space to involve origins of the ventral and dorsal branches of the thoracic spinal nerves. Dorsal ramus involvement was posterior to the costotransverse foramen.

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.

Background Vasopressors are administered to critically ill patients with vasodilatory shock not responsive to volume resuscitation, and less often in cardiogenic shock, and hypovolemic shock. Objectives The objectives are to review safety and efficacy of vasopressors, pathophysiology, agents that decrease vasopressor dose, predictive biomarkers, β1-blockers, and directions for research. Methods The quality of evidence was evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results Vasopressors bind adrenergic: α1, α2, β1, β2; vasopressin: AVPR1a, AVPR1B, AVPR2; angiotensin II: AG1, AG2; and dopamine: DA1, DA2 receptors inducing vasoconstriction. Vasopressor choice and dose vary because of patients and physician practice. Adverse effects include excessive vasoconstriction, organ ischemia, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. No randomized controlled trials of vasopressors showed a significant difference in 28-day mortality rate. Norepinephrine is the first-choice vasopressor in vasodilatory shock after adequate volume resuscitation. Some strategies that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality while corticosteroids have decreased 28-day mortality significantly in some (two large trials) but not all trials. In norepinephrine-refractory patients, vasopressin or epinephrine may be added. A new vasopressor, angiotensin II, may be useful in profoundly hypotensive patients. Dobutamine may be added because vasopressors may decrease ventricular contractility. Dopamine is recommended only in bradycardic patients. There are potent vasopressors with limited evidence (e.g. methylene blue, metaraminol) and novel vasopressors in development (selepressin). Conclusions Norepinephrine is first choice followed by vasopressin or epinephrine. Angiotensin II and dopamine have limited indications. In future, predictive biomarkers may guide vasopressor selection and novel vasopressors may emerge.

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.

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.

Background Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax . In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum . MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria. Methods This systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017. Results Out of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction. Conclusions More studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs. Systematic review registration This study is registered at PROSPERO (registration number CRD42017062349 ).

The unavailability of clean drinking water is one of the significant health issues in modern times. Industrial dyes are one of the dominant chemicals that make water unfit for drinking. Among these dyes, methylene blue (MB) is toxic, carcinogenic, and non-biodegradable and can cause a severe threat to human health and environmental safety. It is usually released in natural water sources, which becomes a health threat to human beings and living organisms. Hence, there is a need to develop an environmentally friendly, efficient technology for removing MB from wastewater. Photodegradation is an advanced oxidation process widely used for MB removal. It has the advantages of complete mineralization of dye into simple and nontoxic species with the potential to decrease the processing cost. This review provides a tutorial basis for the readers working in the dye degradation research area. We not only covered the basic principles of the process but also provided a wide range of previously published work on advanced photocatalytic systems (single-component and multi-component photocatalysts). Our study has focused on critical parameters that can affect the photodegradation rate of MB, such as photocatalyst type and loading, irradiation reaction time, pH of reaction media, initial concentration of dye, radical scavengers and oxidising agents. The photodegradation mechanism, reaction pathways, intermediate products, and final products of MB are also summarized. An overview of the future perspectives to utilize MB at an industrial scale is also provided. This paper identifies strategies for the development of effective MB photodegradation systems.