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Antimicrobial Agents and Chemotherapy May 2023Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including...
Fosmanogepix (FMGX), a novel antifungal available in intravenous (IV) and oral formulations, has broad-spectrum activity against pathogenic yeasts and molds, including fungi resistant to standard of care antifungals. This multicenter, open-label, single-arm study evaluated FMGX safety and efficacy for treatment of candidemia and/or invasive candidiasis caused by Candida auris. Eligible participants were ≥18 years, with established candidemia and/or invasive candidiasis caused by C. auris, (cultured within 120 h [for candidemia] or 168 h [for invasive candidiasis without candidemia] with accompanying clinical signs) and limited treatment options. Participants were treated with FMGX (≤42 days; loading dose: 1000 mg IV twice daily [Day 1], followed by 600 mg IV once daily [QD]). Switching to oral FMGX 800 mg QD was permitted from Day 4. Primary endpoint was treatment success (survival and clearance of C. auris from blood/tissue cultures without additional antifungals) at the end of the study treatment (EOST), assessed by an independent data review committee (DRC). Day 30 survival was a secondary endpoint. susceptibility of isolates was assessed. Nine participants with candidemia (male:6, female:3; 21 to 76 years) in intensive care units in South Africa were enrolled; all received IV FMGX only. DRC-assessed treatment success at EOST and Day 30 survival were 89% (8/9). No treatment related adverse events or study drug discontinuations were reported. FMGX demonstrated potent activity against all C. auris isolates (MIC range: 0.008 to 0.015 μg/mL [CLSI]; 0.004-0.03 μg/mL [EUCAST]), with the lowest MICs compared to other antifungals tested. Thus, the results showed that FMGX was safe, well-tolerated, and efficacious in participants with candidemia caused by C. auris.
Topics: Humans; Male; Female; Antifungal Agents; Candidemia; Candida auris; Candidiasis, Invasive; Treatment Outcome; Microbial Sensitivity Tests
PubMed: 37022196
DOI: 10.1128/aac.01419-22 -
Annals of the New York Academy of... Nov 2020Methyl isocyanate (MIC, "Bhopal agent") is a highly reactive, toxic industrial chemical. Inhalation of high levels (500-1000 ppm) of MIC vapor is almost uniformly fatal....
Methyl isocyanate (MIC, "Bhopal agent") is a highly reactive, toxic industrial chemical. Inhalation of high levels (500-1000 ppm) of MIC vapor is almost uniformly fatal. No therapeutic interventions other than supportive care have been described that can delay the onset of illness or death due to MIC. Recently, we found that inhalation of MIC caused the appearance of activated tissue factor in circulation with subsequent activation of the coagulation cascade. Herein, we report that MIC exposure (500 ppm for 30 min, nose-only) caused deposition of fibrin-rich casts in the conducting airways resulting in respiratory failure and death within 24 h in a rat model (LC ). We thus investigated the effect of airway delivery of the fibrinolytic agent tissue plasminogen activator (tPA) on mortality and morbidity in this model. Intratracheal administration of tPA was initiated 11 h post MIC exposure and repeated every 4 h for the duration of the study. Treatment with tPA afforded nearly 60% survival at 24 h post MIC exposure and was associated with decreased airway fibrin casts, stabilization of hypoxemia and respiratory distress, and improved acidosis. This work supports the potential of airway-delivered tPA therapy as a useful countermeasure in stabilizing victims of high-level MIC exposure.
Topics: Airway Obstruction; Animals; Disease Models, Animal; Isocyanates; Male; Rats; Rats, Sprague-Dawley; Tissue Plasminogen Activator
PubMed: 32233099
DOI: 10.1111/nyas.14344 -
Environmental Science and Pollution... Apr 2021Methylcarbamoyl mercapturic acid (MCAMA, N-acetyl-S-(N-methylcarbamoyl)-L-cysteine) is a urinary metabolite of N,N-dimethylformamide and methyl isocyanate, which are...
Characterization of US population levels of urinary methylcarbamoyl mercapturic acid, a metabolite of N,N-dimethylformamide and methyl isocyanate, in the National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2011-2016.
Methylcarbamoyl mercapturic acid (MCAMA, N-acetyl-S-(N-methylcarbamoyl)-L-cysteine) is a urinary metabolite of N,N-dimethylformamide and methyl isocyanate, which are volatile organic compounds that are harmful to humans. N,N-dimethylformamide exposure causes liver damage, and methyl isocyanate inhalation damages the lining of the respiratory tract, which can increase risk of chronic obstructive pulmonary disease and asthma. This study characterizes urinary MCAMA levels in the US population and explores associations of MCAMA concentrations with select demographic and environmental factors. We used liquid chromatography tandem mass spectrometry to measure MCAMA in urine collected from study participants ≥ 12 years old (N = 8272) as part of the National Health and Nutrition Examination Survey 2005-2006 and 2011-2016. We produced multiple regression models with MCAMA concentrations as the dependent variable and sex, age, fasting time, race/ethnicity, diet, and cigarette smoking as independent variables. Cigarette smokers and nonsmokers had median urinary MCAMA concentrations of 517 μg/g creatinine and 127 μg/g creatinine, respectively. Sample-weighted multiple regression analysis showed that MCAMA was positively associated with serum cotinine (p < 0.0001). Compared to non-exposed participants (serum cotinine ≤ 0.015 ng/mL), presumptive exposure to second-hand tobacco smoke (serum cotinine > 0.015-≤ 10 ng/mL and 0 cigarettes smoked per day) was associated with 20% higher MCAMA (p < 0.0001). Additionally, smoking 1-10 cigarettes per day was associated with 261% higher MCAMA (p < 0.0001), smoking 11-20 cigarettes per day was associated with 357% higher MCAMA (p < 0.0001), and smoking > 20 cigarettes per day was associated with 416% higher MCAMA (p < 0.0001). These findings underscore the strong association of tobacco smoke exposure with urinary MCAMA biomarker levels.
Topics: Acetylcysteine; Biomarkers; Child; Cotinine; Dimethylformamide; Humans; Isocyanates; Nutrition Surveys; Tobacco Smoke Pollution
PubMed: 33398732
DOI: 10.1007/s11356-020-12135-7 -
Organic Process Research & Development Dec 2020The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more...
The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.
PubMed: 33958851
DOI: 10.1021/acs.oprd.0c00470 -
Bulletin of the World Health... Apr 2022Multiple environmental health issues resulting from pollution and climate change threaten public health in India.
PROBLEM
Multiple environmental health issues resulting from pollution and climate change threaten public health in India.
APPROACH
The Government of India recognized the need for a permanent environmental health research institute; the Indian Council of Medical Research therefore established the National Institute for Research in Environmental Health in Bhopal in 2010. Scientists at the institute assessed the multiple long-term health effects of exposure to methyl isocyanate, and are now conducting research on a wide array of locally relevant environmental health issues.
LOCAL SETTING
The Union Carbide India Limited pesticide factory in Bhopal was the site of a methyl isocyanate gas leak in 1984, which affected half a million people. The Indian Council of Medical Research set up a coordinating unit in the immediate aftermath, which was upgraded to the Bhopal Gas Disaster Research Centre in 1986 and then the Centre for Rehabilitation Studies in 1995.
RELEVANT CHANGES
Scientists at the institute undertake environmental monitoring and health risk assessment studies among communities located near polluted areas, such as industrial areas. They are also assessing the training needs of practising physicians, with the aim of developing a curated curriculum to meet the deficiencies in environmental health education in the country.
LESSONS LEARNT
Environmental legislation was introduced in the wake of the disaster and a research institute in environmental health was established. Researchers at the institute have recognized the importance of engaging communities in environmental health research, as well as knowledge dissemination to relevant stakeholders.
Topics: Academies and Institutes; Environmental Exposure; Environmental Health; Environmental Pollution; Humans; India; Industry
PubMed: 35386553
DOI: 10.2471/BLT.21.286680 -
Ciencia & Saude Coletiva Oct 2020There is credible evidence that the 1984-Bhopal-methyl isocyanate (MIC)-gas-exposed long-term survivors and their offspring born post-exposure are susceptible to...
There is credible evidence that the 1984-Bhopal-methyl isocyanate (MIC)-gas-exposed long-term survivors and their offspring born post-exposure are susceptible to infectious/communicable and non-communicable diseases. Bhopal's COVID-19 fatality rate suggests that the MIC-gas tragedy survivors are at higher risk, owing to a weakened immune system and co-morbidities. This situation emboldened us to ponder over what we know, what we don't, and what we should know about their susceptibility to COVID-19. This article aims at answering these three questions that emerge in the minds of public health officials concerning prevention strategies against COVID-19 and health promotion in the Bhopal MIC-affected population (BMAP). Our views and opinions presented in this article will draw attention to prevent and reduce the consequences of COVID-19 in BMAP. From the perspective of COVID-19 prophylaxis, the high-risk individuals from BMAP with co-morbidities need to be identified through a door-to-door visit to the severely gas-affected regions and advised to maintain good respiratory hygiene, regular intake of immune-boosting diet, and follow healthy lifestyle practices.
Topics: Betacoronavirus; COVID-19; Communicable Disease Control; Coronavirus Infections; Disasters; Disease Susceptibility; Environmental Exposure; Humans; Immunocompromised Host; India; Isocyanates; Pandemics; Pneumonia, Viral; SARS-CoV-2; Self Care; Survivors; Vulnerable Populations
PubMed: 33027359
DOI: 10.1590/1413-812320202510.2.28682020 -
Pharmaceuticals (Basel, Switzerland) Jan 2023On the basis of previous reports, novel 2-benzoylhydrazine-1-carboxamides were designed as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase...
On the basis of previous reports, novel 2-benzoylhydrazine-1-carboxamides were designed as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Inhibitors of these enzymes have many clinical applications. 2-(Substituted benzoyl)hydrazine-1-carboxamides decorated with -methyl or tridecyl were prepared with three methods from commercially available or self-prepared hydrazides and isocyanates. For methyl derivatives, -succinimidyl -methylcarbamate was used or methyl isocyanate was prepared via Curtius rearrangement. Tridecyl isocyanate was synthesized again via Curtius rearrangement or from triphosgene and tridecylamine. The compounds were evaluated for the inhibition of AChE and BChE using Ellman's spectrophotometric method. Most of the derivatives showed the dual inhibition of both enzymes with IC values of 44-100 µM for AChE and from 22 µM for BChE. In general, the carboxamides inhibited AChE more strongly. A large number of the compounds showed better or quite comparable inhibition of cholinesterases in vitro than that of the drug rivastigmine. Molecular docking was performed to investigate the possible conformation of the compounds and their interactions with target enzymes. In both AChE and BChE, the compounds occupied the enzyme active cavity, and, especially in the case of BChE, the compounds were placed in close proximity to the catalytic triad.
PubMed: 37259322
DOI: 10.3390/ph16020172 -
Environment International Apr 2022We report on the concentration ranges and combustion source-related emission profiles of organic and inorganic species released during 34 major industrial fires in the...
We report on the concentration ranges and combustion source-related emission profiles of organic and inorganic species released during 34 major industrial fires in the UK. These episodic events tend to be acute in nature and demand a rapid public health risk assessment to indicate the likely impact on exposed populations. The objective of this paper is to improve our understanding of the nature, composition and potential health impacts of emissions from major incident fires and so support the risk assessment process. Real world monitoring data was obtained from portable Fourier Transform Infrared (FTIR) monitoring (Gasmet DX-4030/40) carried out as part of the UK's Air Quality in Major Incidents service. The measured substances include carbon monoxide, sulphur dioxide, nitrogen dioxide, ammonia, hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen cyanide, formaldehyde, 1,3-butadiene, benzene, toluene, xylenes, ethyl benzene, acrolein, phosgene, arsine, phosphine and methyl isocyanate. We evaluate the reported concentrations against Acute Exposure Guideline Values (AEGLs) and Emergency Response Planning Guidelines (ERPGs), as well as against UK, EU and WHO short-term ambient guideline values. Most exceedances of AEGL or ERPG guideline values were at levels likely only to cause discomfort to exposed populations (hydrogen cyanide, hydrogen chloride, hydrogen fluoride and formaldehyde), though for several substances the exceedances could have potentially given rise to more serious health effects (acrolein, phosphine, phosgene and methyl isocyanate). In the latter cases, the observed high concentrations are likely to be due to cross-interference from other substances that absorb in the mid-range of the infrared spectrum, particularly when the ground level plume is very concentrated.
Topics: Acrolein; Air Pollutants; Benzene; Environmental Monitoring; Fires; Formaldehyde; Humans; Hydrochloric Acid; Hydrogen; Phosgene
PubMed: 35231840
DOI: 10.1016/j.envint.2022.107152 -
The Journal of Antimicrobial... Mar 2024Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure....
BACKGROUND
Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown.
OBJECTIVES
To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients.
PATIENTS AND METHODS
Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe.
RESULTS
The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L.
CONCLUSIONS
Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.
Topics: Humans; Linezolid; Critical Illness; Brain; Anti-Bacterial Agents; Plasma; Isocyanates
PubMed: 38323369
DOI: 10.1093/jac/dkae025 -
Frontiers in Cellular and Infection... 2023This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of...
OBJECTIVE
This study aimed to investigate sudapyridine (WX-081) antibacterial activity against and its effect on bacterial growth and host survival using a zebrafish model of infection.
METHODS
WX-081 antibacterial activity was assessed based on growth inhibition of standard strain ATCC19977 and 36 clinical isolates. Maximum tolerated concentrations (MTCs) of WX-081, bedaquiline, and azithromycin and inhibition of growth were assessed after fluorescently labelled bacilli and drugs were injected into zebrafish. Bacterial counts were analysed using one-way ANOVA and fluorescence intensities of zebrafish tissues were analysed and expressed as the mean ± SE. Moreover, Kaplan-Meier survival analysis was conducted to assess intergroup differences in survival of -infected zebrafish treated with different drug concentrations using a log-rank test, with a p value <0.05 indicating a difference was statistically significant.
RESULTS
Drug sensitivity testing of standard strain ATCC19977 and 36 clinical isolates revealed MICs ranging from 0.12-0.96 µg/mL and MIC and MIC values of 0.48 µg/mL and 0.96 µg/mL, respectively. Fluorescence intensities of -infected zebrafish tissues was lower after treatment with the WX-081 MTC (62.5 µg/mL) than after treatment with the azithromycin MTC (62.5 µg/mL) and the bedaquiline MTC (15.6 µg/mL). When the concentration of WX-081 increased from 1.95µg/mL to 1/8 MTC(7.81µg/mL), the survival rate of zebrafish at 4-9 dpf decreased from 90.00% to 81.67%.
CONCLUSION
WX-081 effectively inhibited growth and and prolonged survival of -infected zebrafish, thus indicating that WX-081 holds promise as a clinical treatment for infection.
Topics: Animals; Azithromycin; Mycobacterium abscessus; Zebrafish; Anti-Bacterial Agents
PubMed: 37662015
DOI: 10.3389/fcimb.2023.1217975