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2.
Nat Commun ; 11(1): 6094, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323937

RESUMO

Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite.


Assuntos
Antivenenos/administração & dosagem , Antivenenos/uso terapêutico , Mordeduras de Serpentes/tratamento farmacológico , Animais , Ásia , América Central , Dimercaprol/farmacologia , Dimercaprol/uso terapêutico , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Guanidinas , Estimativa de Kaplan-Meier , Masculino , Camundongos , Testes de Neutralização , Serina Proteases/efeitos dos fármacos , Toxinas Biológicas , Venenos de Víboras
3.
Artigo em Inglês | MEDLINE | ID: mdl-32122813

RESUMO

Cases of severe childhood lead poisoning (a blood lead level (BLL) ≥45 mcg/dL) in the United States have decreased with time. Clinicians will encounter such cases only rarely. When such cases arise, however, recognizing their complexities and identifying resources that can help in management are important. We present here a case of severe childhood lead poisoning, highlighting the variable presentation, the rebound phenomenon of BLL after chelation, the usefulness of the zinc protoporphyrin as an adjunctive monitoring parameter, and the importance of early involvement of an inter-professional team.


Assuntos
Quelantes/uso terapêutico , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/tratamento farmacológico , Pré-Escolar , Dimercaprol/uso terapêutico , Feminino , Hospitalização , Humanos , Massachusetts
4.
Biomolecules ; 10(2)2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033229

RESUMO

: High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.


Assuntos
Antídotos/uso terapêutico , Intoxicação por Arsênico/tratamento farmacológico , Arsênio/toxicidade , Quelantes/uso terapêutico , Animais , Antídotos/química , Antídotos/farmacologia , Arsênio/efeitos adversos , Intoxicação por Arsênico/etiologia , Intoxicação por Arsênico/metabolismo , Arsenicais/efeitos adversos , Quelantes/química , Quelantes/farmacologia , Dimercaprol/análogos & derivados , Dimercaprol/farmacologia , Dimercaprol/uso terapêutico , Água Potável/efeitos adversos , Humanos , Modelos Moleculares , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Succímero/química , Succímero/farmacologia , Succímero/uso terapêutico , Unitiol/química , Unitiol/farmacologia , Unitiol/uso terapêutico , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/toxicidade
5.
BMC Nephrol ; 20(1): 374, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623560

RESUMO

BACKGROUND: Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered. CASE PRESENTATION: We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance. CONCLUSION: Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.


Assuntos
Anuria/complicações , Intoxicação por Arsênico/terapia , Quelantes/uso terapêutico , Terapia de Substituição Renal Contínua , Falência Renal Crônica/complicações , Intoxicação por Chumbo/terapia , Adulto , Animais , Intoxicação por Arsênico/complicações , Dimercaprol/uso terapêutico , Ácido Edético/uso terapêutico , Humanos , Falência Renal Crônica/terapia , Intoxicação por Chumbo/complicações , Masculino , Diálise Renal , Succímero/uso terapêutico , Unitiol/uso terapêutico
8.
Environ Technol ; 40(15): 2011-2017, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29409397

RESUMO

An ultrafiltration membrane prepared by polyethersulfone (PES) was modified with Bismuth-BAL chelate (BisBAL) and was used in submerged membrane bioreactor system. Moreover, a control membrane reactor was also tasked to evaluate the effect of BisBAL on the membrane performance. The flux profile, transmembrane pressure, the effect of chemical treatment, cake layer formation, anti-fouling properties against extracellular polymeric substances (EPS) and soluble microbial products (SMP) were studied. The UF modified membrane demonstrated a sustained permeability, low cleaning frequency, and longer filtration time. In terms of anti-EPS and SMP accumulation, the modified membrane showed a lower membrane resistance. It can be illustrated from scanning electron microscopy and confocal laser scanning microscope images that the modified membrane had presented better properties than bare PES membrane, as it was looser and thinner. Thus, the UF membrane proved to be more efficient in terms of permeability and lifetime.


Assuntos
Bismuto , Compostos Organometálicos , Reatores Biológicos , Dimercaprol/análogos & derivados , Membranas Artificiais , Esgotos
9.
Environ Technol ; 40(1): 19-28, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28880121

RESUMO

In this study, hollow fiber membranes with and without bismuth dimercaptopropanol (Bis-BAL) additive were fabricated. Membranes were characterized in terms of permeability, surface properties, anti-biofouling and antibacterial properties. Membranes were operated in a lab-scale submerged membrane bioreactor (MBR). During the MBR operation, flux, chemical oxygen demand, volatile suspended solids and suspended solids were calculated for 30 days. Results showed that extracellular polymeric substance and soluble microbial product amounts were decreased in BisBAL-containing membranes. BisBAL-added membranes had the ability to inhibit the growth of Escherichia coli. BisBAL as an additive for membranes was found to be an effective, cheap alternative for enhancing anti-biofouling properties of the membranes.


Assuntos
Incrustação Biológica , Reatores Biológicos , Bismuto , Dimercaprol/análogos & derivados , Matriz Extracelular de Substâncias Poliméricas , Membranas Artificiais , Compostos Organometálicos
10.
Int J Nanomedicine ; 13: 6089-6097, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323596

RESUMO

Aim: The objective of this study was to evaluate the antitumor activity of lipophilic bismuth nanoparticles (BisBAL NPs) on breast cancer cells. Materials and methods: The effect of varying concentrations of BisBAL NPs was evaluated on human MCF-7 breast cancer cells and on MCF-10A fibrocystic mammary epitheliocytes as noncancer control cells. Cell viability was evaluated with the MTT assay, plasma membrane integrity was analyzed with the calcein AM assay, genotoxicity with the comet assay, and apoptosis with the Annexin V/7-AAD assay. Results: BisBAL NPs were spherical in shape (average diameter, 28 nm) and agglomerated into dense electronic clusters. BisBAL NP induced a dose-dependent growth inhibition. Most importantly, growth inhibition was higher for MCF-7 cells than for MCF-10A cells. At 1 µM BisBAL NP, MCF-7 growth inhibition was 51%, while it was 11% for MCF-10A; at 25 µM BisBAL NP, the growth inhibition was 81% for MCF-7 and 24% for MCF-10A. With respect to mechanisms of action, a 24-hour exposure of 10 and 100 µM BisBAL NP caused loss of cell membrane integrity and fragmentation of tumor cell DNA. BisBAL NPs at 10 µM were genotoxic to and caused apoptosis of breast cancer cells. Conclusion: BisBAL NP-induced growth inhibition is dose dependent, and breast cancer cells are more vulnerable than noncancer breast cells. The mechanism of action of BisBAL NPs may include loss of plasma membrane integrity and a genotoxic effect on the genomic DNA of breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Bismuto/farmacologia , Neoplasias da Mama/patologia , Dimercaprol/análogos & derivados , Nanopartículas/química , Compostos Organometálicos/farmacologia , Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Dimercaprol/farmacologia , Feminino , Humanos , Células MCF-7 , Nanopartículas/ultraestrutura
12.
Cochrane Database Syst Rev ; 2: CD003328, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29473717

RESUMO

BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. SELECTION CRITERIA: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. MAIN RESULTS: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. AUTHORS' CONCLUSIONS: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.


Assuntos
Acetaminofen/envenenamento , Analgésicos não Narcóticos/envenenamento , Acetaminofen/farmacocinética , Acetilcisteína/uso terapêutico , Analgésicos não Narcóticos/farmacocinética , Antídotos/uso terapêutico , Carvão Vegetal/uso terapêutico , Cisteamina/uso terapêutico , Dimercaprol/uso terapêutico , Overdose de Drogas/mortalidade , Overdose de Drogas/terapia , Lavagem Gástrica , Humanos , Absorção Intestinal , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Metionina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
J Neurochem ; 141(5): 708-720, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28301040

RESUMO

Acrolein is one of the most toxic byproducts of lipid peroxidation, and it has been shown to be associated with multiple pathological processes in trauma and diseases, including spinal cord injury, multiple sclerosis, and Alzheimer's disease. Therefore, suppressing acrolein using acrolein scavengers has been suggested as a novel strategy of neuroprotection. In an effort to identify effective acrolein scavengers, we have confirmed that dimercaprol, which possesses thiol functional groups, could bind and trap acrolein. We demonstrated the reaction between acrolein and dimercaprol in an abiotic condition by nuclear magnetic resonance spectroscopy. Specifically, dimercaprol is able to bind to both the carbon double bond and aldehyde group of acrolein. Its acrolein scavenging capability was further demonstrated by in vitro results that showed that dimercaprol could significantly protect PC-12 cells from acrolein-mediated cell death in a dose-dependent manner. Furthermore, dimercaprol, when applied systemically through intraperitoneal injection, could significantly reduce acrolein contents in spinal cord tissue following a spinal cord contusion injury in rats, a condition known to have elevated acrolein concentration. Taken together, dimercaprol may be an effective acrolein scavenger and a viable candidate for acrolein detoxification.


Assuntos
Acroleína/toxicidade , Dimercaprol/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Traumatismos da Medula Espinal/induzido quimicamente , Traumatismos da Medula Espinal/tratamento farmacológico , Acroleína/química , Acroleína/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Dimercaprol/química , Dimercaprol/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Sequestradores de Radicais Livres/farmacologia , L-Lactato Desidrogenase/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Células PC12/efeitos dos fármacos , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
14.
Mil Med ; 182(3): e1843-e1848, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28290970

RESUMO

INTRODUCTION: Despite greater than 60,000 nonfatal firearm injuries per year in the United States, retained shrapnel is a relatively rare cause of systemic lead toxicity with less than 100 cases reported in the medical literature since 1867. While intra-articular retained shrapnel as a cause of lead toxicity is well-described, extra-articular fragments are less well known to cause symptomatic disease. CASE REPORT: A 31-year-old man initially presented with abdominal pain, constipation, jaundice, and elevated liver transaminases approximately 3 weeks after suffering a left lower extremity injury during athletic activity. The patient was found to have steatohepatitis after extensive inpatient and outpatient gastroenterological workup to include upper and lower endoscopy, liver ultrasound, and biopsy of the liver to confirm the diagnosis. Imaging was incidentally notable for retained gunshot in the left flank and large shell fragment containing seroma in the left thigh. The patient was initially discharged with improved pain, but later presented to a primary care clinic with weight loss and continued pain. This was followed by a subsequent progression to diffuse weakness, ultimately resulting in an inability to ambulate. The patient was readmitted to a tertiary care medical center, 3 months after the initial presentation. Physical exam was then notable for 70-lb weight loss from initial admission and diffuse peripheral weakness with global muscle atrophy. Following a broad differential workup, he was found to have a blood lead level of 129 µg/dL, and hemoglobin of 7.7 g/dL with basophilic stippling on peripheral smear. The patient was transferred to the intensive care unit for chelation therapy with dimercaprol and calcium ethylenediaminetetraacetic acid. Lead levels initially decreased, but rose when patient was transitioned to oral therapy with succimer. Surgery was consulted for removal of multiple retained fragments, which were analyzed by the Joint Pathology Center and found to contain lead. The patient's motor function gradually improved on oral chelation and he was discharged to a subacute rehabilitation facility. CONCLUSION: This complex case describes a rare cause for a relatively common clinical presentation, jaundice and hepatitis, and reinforces the importance of longitudinal follow up and reassessment of a patient with an unknown illness and worsening clinical condition. Diagnosis of systemic lead toxicity is challenging because of its protean clinical manifestations, and relative rarity with the advent of strict environmental lead controls and decrease in lead-based paint and industrial products. Furthermore, extra-articular lead remains a rare cause of systemic toxicity, and the surgical standard of care has been to not remove these fragments in gunshot victims. This case adds to a small amount of evidence that lead screening may be of value in selected patients with extra-articular retained shrapnel, especially those with seroma and osteophyte formation in the wound.


Assuntos
Corpos Estranhos/complicações , Intoxicação por Chumbo/etiologia , Chumbo/toxicidade , Ferimentos por Arma de Fogo/complicações , Dor Abdominal/etiologia , Adulto , Quelantes/farmacologia , Quelantes/uso terapêutico , Terapia por Quelação/métodos , Constipação Intestinal/etiologia , Dimercaprol/farmacologia , Dimercaprol/uso terapêutico , Hepatite/etiologia , Humanos , Icterícia/etiologia , Intoxicação por Chumbo/diagnóstico , Masculino , Ferimentos por Arma de Fogo/cirurgia
15.
J Biol Chem ; 292(13): 5532-5545, 2017 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-28202547

RESUMO

Neuroinflammation and oxidative stress are hallmarks of various neurological diseases. However, whether and how the redox processes control neuroinflammation is incompletely understood. We hypothesized that increasing cellular glutathione (GSH) levels would inhibit neuroinflammation. A series of thiol compounds were identified to elevate cellular GSH levels by a novel approach (i.e. post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis). These small thiol-containing compounds were examined for their ability to increase intracellular GSH levels in a murine microglial cell line (BV2), of which dimercaprol (2,3-dimercapto-1-propanol (DMP)) was found to be the most effective compound. DMP increased GCL activity and decreased LPS-induced production of pro-inflammatory cytokines and inducible nitric-oxide synthase induction in BV2 cells in a concentration-dependent manner. The ability of DMP to elevate GSH levels and attenuate LPS-induced pro-inflammatory cytokine production was inhibited by buthionine sulfoximine, an inhibitor of GCL. DMP increased the expression of GCL holoenzyme without altering the expression of its subunits or Nrf2 target proteins (NQO1 and HO-1), suggesting a post-translational mechanism. DMP attenuated LPS-induced MAPK activation in BV2 cells, suggesting the MAPK pathway as the signaling mechanism underlying the effect of DMP. Finally, the ability of DMP to increase GSH via GCL activation was observed in mixed cerebrocortical cultures and N27 dopaminergic cells. Together, the data demonstrate a novel mechanism of GSH elevation by post-translational activation of GCL. Post-translational activation of GCL offers a novel targeted approach to control inflammation in chronic neuronal disorders associated with impaired adaptive responses.


Assuntos
Dimercaprol/farmacologia , Glutamato-Cisteína Ligase/metabolismo , Inflamação/prevenção & controle , Animais , Linhagem Celular , Citocinas/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Glutamato-Cisteína Ligase/efeitos dos fármacos , Glutationa/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Sistema Nervoso/patologia , Oxirredução , Ratos , Compostos de Sulfidrila/metabolismo
16.
Ann N Y Acad Sci ; 1378(1): 143-157, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27636894

RESUMO

Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. On the basis of these observations, and considering the low cost and simple methods of their bulk syntheses, these agents were thought to be appropriate for chemical warfare. Among these, the best-known agent that was synthesized and weaponized during World War I (WWI) is Lewisite. Exposure to Lewisite causes painful inflammatory and blistering responses in the skin, lung, and eye. These chemicals also manifest systemic tissue injury following their cutaneous exposure. Although largely discontinued after WWI, stockpiles are still known to exist in the former Soviet Union, Germany, Italy, the United States, and Asia. Thus, access by terrorists or accidental exposure could be highly dangerous for humans and the environment. This review summarizes studies that describe the biological, pathophysiological, toxicological, and environmental effects of exposure to arsenicals, with a major focus on cutaneous injury. Studies related to the development of novel molecular pathobiology-based antidotes against these agents are also described.


Assuntos
Intoxicação por Arsênico/metabolismo , Arsenicais/administração & dosagem , Substâncias para a Guerra Química/envenenamento , Exposição Ambiental/efeitos adversos , Animais , Intoxicação por Arsênico/tratamento farmacológico , Intoxicação por Arsênico/epidemiologia , Guerra Química/tendências , Dimercaprol/uso terapêutico , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
17.
Anal Chim Acta ; 934: 231-8, 2016 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-27506365

RESUMO

We developed a new fast and selective analytical method for the determination of inorganic arsenic (iAs) in rice by a gas chromatography - tandem mass spectrometry (GC-MS/MS) in combination with one step derivatization of inorganic arsenic (iAs) with British Anti-Lewsite (BAL). Two step derivatization of iAs with BAL has been previously performed for the GC-MS analysis. In this paper, the quantitative one step derivatization condition was successfully established. The GC-MS/MS was carried out with a short nonpolar capillary column (0.25 mm × 10 m) under the conditions of fast oven temperature ramp rate (4 °C/s) and high linear velocity (108.8 cm/s) of the carrier gas. The established GC-MS/MS method showed an excellent linearity (r(2) > 0.999) in a tested range (0.2-100.0 µg L(-1)), ultra-low limit of detection (LOD, 0.08 pg), and high precision and accuracy. The GC-MS/MS technique showed far greater selectivity (22.5 fold higher signal to noise ratio in rice sample) on iAs than GC-MS method. The gas chromatographic running time was only 2.5 min with the iAs retention time of 1.98 min. The established method was successfully applied to quantify the iAs contents in polished rice. The mean iAs content in the Korean polished rice (n = 27) was 66.1 µg kg(-1) with the range of 37.5-125.0 µg kg(-1). This represents the first report on the GC-tandem mass spectrometry in combination with the one step derivatization with BAL for the iAs speciation in rice. This GC-MS/MS method would be a simple, useful and reliable measure for the iAs analysis in rice in the laboratories in which the expensive and element specific HPLC-ICP-MS is not available.


Assuntos
Arsênio/análise , Dimercaprol/química , Oryza/química , Cromatografia Gasosa , Espectrometria de Massas em Tandem
18.
J Nanosci Nanotechnol ; 16(1): 203-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27398446

RESUMO

Bismuth nanoparticles have many interesting properties to be applied in biomedical and medicinal sectors, however their safety in humans have not been comprehensively investigated. The objective of this research was to determine the cytotoxic effect of bismuth dimercaptopropanol nanoparticles (BisBAL NPs) on epithelial cells. The nanoparticles are composed of 18.7 nm crystallites on average and have a rhombohedral structure, agglomerating into chains-like or clusters of small nanoparticles. Based on MTT viability assay and fluorescence microscopy, cytotoxicity was not observed on monkey kidney cells after growing with 5 µM of BisBAL NPs for 24 h. Employing same techniques, identical results were obtained with human epithelial cells (HeLa), showing a not strain-dependent phenomenon. The absence of toxic effects on epithelial cells growing with BisBAL NPs was corroborated with long-time experiments (24-72 hrs.), showing no difference in comparison with growing control (cells without nanoparticles). Further, genotoxicity assays, comet assay and fluorescent microscopy and electrophoresis in bromide-stained agarose gel revealed no damage to genomic DNA of MA104 cells after 24 h. of exposition to BisBAL NPs. Finally, the effect of bismuth nanoparticles on protein synthesis was studied in cells growing with BisBAL NPs for 24 h. SDS-PAGE assays showed no difference between treated and untreated cells, suggesting that BisBAL NPs did not interfere with protein synthesis. Hence BisBAL NPs do not appear to exert cytotoxic effects suggesting their biological compatibility with epithelial cells.


Assuntos
Bismuto , Citotoxinas , Dimercaprol/análogos & derivados , Células Epiteliais/metabolismo , Nanopartículas/química , Compostos Organometálicos , Animais , Bismuto/química , Bismuto/farmacologia , Chlorocebus aethiops , Citotoxinas/química , Citotoxinas/farmacologia , Dimercaprol/química , Dimercaprol/farmacologia , Células Epiteliais/citologia , Humanos , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia
19.
Trop Doct ; 46(2): 93-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26508422

RESUMO

Acute arsenicosis, although having a 'historical' background, is not common in our times. This report describes a case of acute arsenic poisoning, missed initially due to its gastroenteritis-like presentation, but suspected and confirmed much later, when the patient sought medical help for delayed complications after about 2 months.


Assuntos
Intoxicação por Arsênico/diagnóstico , Adolescente , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/tratamento farmacológico , Quelantes/administração & dosagem , Quelantes/uso terapêutico , Diagnóstico Diferencial , Dimercaprol/administração & dosagem , Dimercaprol/uso terapêutico , Humanos , Injeções Intramusculares , Masculino
20.
J Inorg Biochem ; 153: 60-67, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26479948

RESUMO

Dithiols such as British anti-lewisite (BAL, rac-2,3-dimercaptopropanol) are an important class of antidotes for the blister agent lewisite (trans-2-chlorovinyldichloroarsine) and, more generally, are chelating agents for arsenic and other toxic metals. The reaction of the vicinal thiols of BAL with lewisite through the chelation of the As(III) center has been modeled using density functional theory (DFT) and solvent-assisted proton exchange (SAPE), a microsolvation method that uses a network of water molecules to mimic the role of bulk solvent in models of aqueous phase chemical reactions. The small activation barriers for the stepwise SN2-type nucleophilic attack of BAL on lewisite (0.7-4.9kcal/mol) are consistent with the favorable leaving group properties of the chloride and the affinity of As(III) for soft sulfur nucleophiles. Small, but insignificant, differences in activation barriers were found for the initial attack of the primary versus secondary thiol of BAL and the R vs S enantiomer. An examination of the relative stability of various dithiol-lewisite complexes shows that ethanedithiols like BAL form the most favorable chelation complexes because the angles formed in five-membered ring are most consistent with the hybridization of As(III). More obtuse S-As-S angles are required for larger chelate rings, but internal As⋯N or As⋯O interactions can enhance the stability of moderate-sized rings. The low barriers for lewisite detoxification by BAL and the greater stability of the chelation complexes of small dithiols are consistent with the rapid reversal of toxicity demonstrated in previously reported animal models.


Assuntos
Arsênio/química , Arsenicais/química , Quelantes/química , Dimercaprol/química , Substâncias para a Guerra Química/química , Modelos Químicos , Prótons , Teoria Quântica , Água/química
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