RESUMO
Dekkera bruxellensis has been studied for several aspects of its metabolism over the past years, which has expanded our comprehension on its importance to industrial fermentation processes and uncovered its industrial relevance. Acetate is a metabolite often found in D. bruxellensis aerobic cultivations, whereas its production is linked to decreased ethanol yields. In a previous work, we aimed to understand how acetate metabolism affected the fermentation capacity of D. bruxellensis. In the present work, we evaluated the role of acetate metabolism in respiring cells using ammonium or nitrate as nitrogen sources. Our results showed that galactose is a strictly respiratory sugar and that a relevant part of its carbon is lost, while the remaining is metabolised through the Pdh bypass pathway before being assimilated into biomass. When this pathway was blocked, yeast growth was reduced while more carbon was assimilated to the biomass. In nitrate, more acetate was produced as expected, which increased carbon assimilation, although less galactose was uptaken from the medium. This scenario was not affected by the Pdh bypass inhibition. The confirmation that acetate production was crucial for carbon assimilation was brought by cultivations in pyruvate. All physiological data were connected to the expression patterns of PFK1, PDC1, ADH1, ALD3, ALD5 and ATP1 genes. Other respiring carbon sources could only be properly used by the cells when some external acetate was supplied. Therefore, the results reported herein helped in providing valuable contributions to the understanding of the oxidative metabolism in this potential industrial yeast.
Assuntos
Carbono , Nitratos , Nitratos/metabolismo , Carbono/metabolismo , Galactose , Fermentação , AcetatosRESUMO
Oxidative stress plays a central role in the pathophysiology of melanoma. Curcumin (CUR) is a polyphenolic phytochemical that stimulates reactive oxygen species (ROS) production, while disulfiram (DSS) is a US FDA-approved drug for the treatment of alcoholism that can act by inhibiting the intracellular antioxidant system. Therefore, we hypothesized that they act synergistically against melanoma cells. Herein, we aimed to study the antitumor potential of the combination of CUR with DSS in B16-F10 melanoma cells using in vitro and in vivo models. The cytotoxic effects of different combination ratios of CUR and DSS were evaluated using the Alamar Blue method, allowing the production of isobolograms. Apoptosis detection, DNA fragmentation, cell cycle distribution, and mitochondrial superoxide levels were quantified by flow cytometry. Tumor development in vivo was evaluated using C57BL/6 mice bearing B16-F10 cells. The combinations ratios of 1:2, 1:3, and 2:3 showed synergic effects. B16-F10 cells treated with these combinations showed improved apoptotic cell death and DNA fragmentation. Enhanced mitochondrial superoxide levels were observed at combination ratios of 1:2 and 1:3, indicating increased oxidative stress. In vivo tumor growth inhibition for CUR (20 mg/kg), DSS (60 mg/kg), and their combination were 17.0%, 19.8%, and 28.8%, respectively. This study provided data on the potential cytotoxic activity of the combination of CUR with DSS and may provide a useful tool for the development of a therapeutic combination against melanoma.
Assuntos
Antineoplásicos , Curcumina , Melanoma Experimental , Camundongos , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Dissulfiram/farmacologia , Linhagem Celular Tumoral , Superóxidos/metabolismo , Camundongos Endogâmicos C57BL , Melanoma Experimental/metabolismo , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estresse OxidativoRESUMO
The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , Ensaios Clínicos como Assunto , Química Computacional , Cisteína , Dissulfiram/metabolismo , Dissulfiram/farmacologia , Humanos , Simulação de Acoplamento Molecular , Papaína , Peptídeo Hidrolases , Inibidores de Proteases/química , SulfóxidosRESUMO
Chagas disease (CD) affects at least 6 million people in 21 South American countries besides several thousand in other nations all over the world. It is estimated that at least 14,000 people die every year of CD. Since vaccines are not available, chemotherapy remains of pivotal relevance. About 30% of the treated patients cannot complete the therapy because of severe adverse reactions. Thus, the search for novel drugs is required. Here we tested the benznidazole (BZ) combination with the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) upon Trypanosoma cruzi in vitro and in vivo. DETC-BZ combination was synergistic diminishing epimastigote proliferation and enhancing selective indexes up to over 10-fold. DETC was effective upon amastigotes of the BZ- partially resistant Y and the BZ-resistant Colombiana strains. The combination reduced proliferation even using low concentrations (e.g., 2.5 µM). Scanning electron microscopy revealed membrane discontinuities and cell body volume reduction. Transmission electron microscopy revealed remarkable enlargement of endoplasmic reticulum cisternae besides, dilated mitochondria with decreased electron density and disorganized kinetoplast DNA. At advanced stages, the cytoplasm vacuolation apparently impaired compartmentation. The fluorescent probe H2-DCFDA indicates the increased production of reactive oxygen species associated with enhanced lipid peroxidation in parasites incubated with DETC. The biochemical measurement indicates the downmodulation of thiol expression. DETC inhibited superoxide dismutase activity on parasites was more pronounced than in infected mice. In order to approach the DETC effects on intracellular infection, peritoneal macrophages were infected with Colombiana trypomastigotes. DETC addition diminished parasite numbers and the DETC-BZ combination was effective, despite the low concentrations used. In the murine infection, the combination significantly enhanced animal survival, decreasing parasitemia over BZ. Histopathology revealed that low doses of BZ-treated animals presented myocardial amastigote, not observed in combination-treated animals. The picrosirius collagen staining showed reduced myocardial fibrosis. Aminotransferase de aspartate, Aminotransferase de alanine, Creatine kinase, and urea plasma levels demonstrated that the combination was non-toxic. As DSF and DETC can reduce the toxicity of other drugs and resistance phenotypes, such a combination may be safe and effective.
Assuntos
Doença de Chagas , Tripanossomicidas , Animais , Doença de Chagas/parasitologia , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Resistência a Medicamentos , Humanos , Camundongos , Nitroimidazóis , Transaminases/uso terapêutico , Tripanossomicidas/farmacologiaRESUMO
The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of bacterial infections. Five scientific databases (PubMed, Embase, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature) were searched to retrieve the maximum literature regarding the study's aim. The search strategy retrieved a total of 870 studies, of which 31 were included and 19 approached disulfiram as the primary aim and 12 included it as a secondary finding from other investigational objectives. The evidence pointed out five main aspects of pre-clinical testing regarding disulfiram antibacterial activity, namely spectrum of antimicrobial action, drug combinations, intracellular studies, animal studies and bacterial targets. Findings to emerge from this study are the observed potential of disulfiram as a non-antibiotic drug being proposed as a potential drug to contribute to the treatment of bacterial diseases usually with few treatment alternatives in the context of drug resistance. We evaluated the potency and selectivity of disulfiram, which indeed until now shows potential to be explored for use as an adjunctive chemical to antimicrobial ones. Even with the level of evidence being reserved, the potential of combining disulfiram with other drugs, already used or new to be used for the treatment of mycobacterial diseases, as well as its likely immunomodulatory effect, deserve to be further investigated. Furthermore, the copper-dependent mode of action in Gram-positive bacteria is an alternative to be explored in drug design or repurposing of chemicals.
Assuntos
Anti-Infecciosos , Infecções Bacterianas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Bactérias Gram-PositivasRESUMO
BACKGROUND: Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully address alcohol-induced neuroadaptive changes. Understanding the effects of pharmacotherapies for AUD on the human brain may lead to tailored, more effective treatments, and improved individual clinical outcomes. OBJECTIVES: We systematically reviewed the literature for studies investigating pharmacotherapies for AUD that included neuroimaging-based treatment outcomes. We searched the PubMed, Scielo, and PsycINFO databases up to January 2021. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Eligible studies included those investigating pharmacotherapies for AUD and employing functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and/or proton magnetic resonance spectroscopy (H-MRS). STUDY APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers screened studies' titles and abstracts for inclusion. Data extraction forms were shared among all the authors to standardize data collection. We gathered information on the following variables: sample size; mean age; sociodemographic and clinical characteristics; alcohol use status; study design and methodology; main neuroimaging findings and brain-regions of interest (i.e., brain areas activated by alcohol use and possible pharmacological interactions); and limitations of each study. RESULTS: Out of 177 studies selected, 20 studies provided relevant data for the research topic. Findings indicate that: (1) Acamprosate and gabapentin may selectively modulate limbic regions and the anterior cingulate cortex; (2) Naltrexone and disulfiram effects may involve prefrontal, premotor, and cerebellar regions; (3) Pharmacotherapies acting on glutamate and GABA neurotransmission involve primarily areas underpinning reward and negative affective states, and; (4) Pharmacotherapies acting on opioid and dopamine systems may affect areas responsible for the cognitive and motor factors of AUD. LIMITATIONS: Most of the studies were focused on naltrexone. A small number of studies investigated the action of disulfiram and gabapentin, and no neuroimaging studies investigated topiramate. In addition, the time between medication and neuroimaging scans varied widely across studies. CONCLUSIONS: We identified key-brain regions modulated by treatments available for AUD. Some of the regions modulated by naltrexone are not specific to the brain reward system, such as the parahippocampal gyrus (temporal lobe), parietal and occipital lobes. Other treatments also modulate not specific regions of the reward system, but play a role in the addictive behaviors, including the insula and dorsolateral prefrontal cortex. The role of these brain regions in mediating the AUD pharmacotherapy response warrants investigation in future research studies.
RESUMO
Abstract Substance use disorder is one of the major social and public health problems in the world. The present study analyzed the pharmacoepidemiological profile of patients treated at the Psychosocial Treatment Center for Alcohol and Substance Use Disorders (CAPS-AD) for treatment of alcohol use disorders (AUD), cocaine use disorders (CUD) and concomitant alcohol and cocaine use disorders (A-CUD) in the city of Betim-MG. The study used quantitative and descriptive data and was based on the evaluation of medical records of patients attended from January to December 2016. After analyzing 295 medical records, the majority of study participants were male (83.7 %) with an average age of 46.26 for AUD, 28.88 for CUD and 34.29 for A-CUD. The most prescribed drugs for AUD were diazepam (54.1 %), thiamine (37 %), complex B vitamins (29.5 %), and disulfiram (2.7 %); for CUD, diazepam (26.9 %) and haloperidol (23.1 %). It should be noticed that although contraindicated by the guidelines, chlorpromazine (42.3 %, 25.3 %, 20.3 %) was prescribed for CUD, AUD, and A-CUD respectively. Knowing the pharmacoepidemiological profile of CAPS-AD patients is extremely important for making decisions regarding which medicines to make available to the population.
Assuntos
Humanos , Masculino , Feminino , Adulto , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Tratamento Farmacológico/instrumentação , Pacientes/classificação , Clorpromazina/efeitos adversos , Saúde Pública/instrumentação , Diazepam/efeitos adversos , Dissulfiram/efeitos adversos , Dissulfiram/agonistasRESUMO
BACKGROUND: Copper (Cu) is a transition metal active in Fenton redox cycling from reduced Cu+ and H2O2, to oxidized Cu2+ and the hydroxyl radical (·OH) highly reactive oxygen species (ROS). At homeostatic Cu levels, ROS promote cell proliferation, migration, angiogenesis, and wound repair. To limit ROS toxicity, cells use Cu-dependent chaperone proteins, Cu-binding ceruloplasmin, and Cu-modulated enzymes like superoxide dismutases (SOD) like SOD1 and SOD3 to scavenge excess superoxide anions which favour Cu+ reduction, and mitochondrial cytochrome c oxidase, important in aerobic energy production. Because Cu helps drive tumor cell proliferation by promoting growth factor-independent receptor tyrosine kinase signaling, and Cu-dependent MEK1 involved in oncogenic BRAF-V600E signaling, further augmenting bioavailable Cu may promote ROS overproduction, cancer progression and eventually tumor cell death. For these reasons, the following clinically approved copper chelators are being repurposed as anti-cancer agents: a) ammonium tetrathiomolybdate (TTM) used to treat Wilson's disease (copper overload) and Menkes disease (copper deficiency); b) Disulfiram (DSF), used against alcoholism, since it inhibits Aldehyde Dehydrogenase (ALDH1) enzyme, important in ethanol detoxification, and a key target against cancer stem cells. Moreover, TTM and DSF are also relevant in cancer clinical trials, because they increase the uptake of both Cu and Platinum (Pt)-containing anti-cancer drugs, since Pt and Cu share the same CTR1 copper transporter. PURPOSE: The majority of reports on Cu chelators dealt separately with either TTM, DSF or others. Here, we compare in parallel, the anti-cancer efficacy of low doses of TTM and DSF, asking whether they can be synergistic or antagonistic. The relevance of their unequal ROS inducing abilities and their different behavior as ionophores is also addressed. SIGNIFICANCE: The potential of Cu chelators as repurposed anti-cancer drugs, should be greater in patients with higher endogenous Cu levels. Since platinum and Cu share uptake receptors, the synergism by drugs containing these metals should not be under-estimated. The potential of disulfiram or its metabolically active Cu-containing form, to inhibit ALDH1-positive tumor cells is therapeutically very important.
Assuntos
Dissulfiram , Neoplasias , Linhagem Celular Tumoral , Cobre , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Humanos , Peróxido de Hidrogênio , Molibdênio , Neoplasias/tratamento farmacológico , Oxirredução , Espécies Reativas de OxigênioRESUMO
The repositioning of approved drugs is atopic of interest for the academy and the pharmaceutical industry. The synergistic combination of these drugs can be successful in the treatment of infections caused by resistant bacteria. This study aimed to assess the in vitro synergistic antibacterial activity of sertraline and disulfiram and their interaction with ciprofloxacin and sulfamethoxazole/trimethoprim. We determined the minimum inhibitory concentration, the minimum bactericidal concentration and the fractional inhibitory concentration index. Eighteen bacterial strains were used, being nine American Type Culture Collection reference strains and nine multidrug resistant clinical isolates. Synergy was detected between sertraline and disulfiram against a strain of Staphylococcus aureusATCC 25923 and a clinical isolate of S. aureus. When associated to sulfamethoxazole/trimethoprim and ciprofloxacin, sertraline and disulfiram showed eight synergistic events, which occurred against three different standard strains and two multidrug resistant clinical isolates. When the minimum bactericidal concentration was determined, the bactericidal activity of sertraline was enhanced with disulfiram. Our results suggest that these drugs, widely used to treat depression and chronic alcoholism, have antibacterial potential individually, in association, and combined with antimicrobials, what makes their repositioning a promising therapeutic alternative for the effective treatment of infections caused by multidrug resistant bacteria.
RESUMO
Dekkera bruxellensis is continuously changing its status in fermentation processes, ranging from a contaminant or spoiling yeast to a microorganism with potential to produce metabolites of biotechnological interest. In spite of that, several major aspects of its physiology are still poorly understood. As an acetogenic yeast, minimal oxygen concentrations are able to drive glucose assimilation to oxidative metabolism, in order to produce biomass and acetate, with consequent low yield in ethanol. In the present study, we used disulfiram to inhibit acetaldehyde dehydrogenase activity to evaluate the influence of cytosolic acetate on cell metabolism. D. bruxellensis was more tolerant to disulfiram than Saccharomyces cerevisiae and the use of different carbon sources revealed that the former yeast might be able to export acetate (or acetyl-CoA) from mitochondria to cytoplasm. Fermentation assays showed that acetaldehyde dehydrogenase inhibition re-oriented yeast central metabolism to increase ethanol production and decrease biomass formation. However, glucose uptake was reduced, which ultimately represents economical loss to the fermentation process. This might be the major challenge for future metabolic engineering enterprises on this yeast.
Assuntos
Acetatos/metabolismo , Dekkera/metabolismo , Etanol/metabolismo , Fermentação , Acetatos/análise , Aldeído Oxirredutases/antagonistas & inibidores , Carbono/metabolismo , Meios de Cultura , Dekkera/efeitos dos fármacos , Dissulfiram/farmacologia , Glucose/metabolismo , Microbiologia Industrial , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how their metal-binding ability is related to their anticancer activity. This review aims to summarize chemical features and metal-binding activity of disulfiram and its metabolite DEDTC, and discuss different mechanisms of action of disulfiram and their contributions to the drug's anticancer activity. METHODS: We undertook a disulfiram-related search on bibliographic databases of peerreviewed research literature, including many historic papers and in vitro, in vivo, preclinical and clinical studies. The selected papers were carefully reviewed and summarized. RESULTS: More than five hundreds of papers were obtained in the initial search and one hundred eighteen (118) papers were included in the review, most of which deal with chemical and biological aspects of Disulfiram and the relationship of its chemical and biological properties. Eighty one (81) papers outline biological aspects of dithiocarbamates, and fifty seven (57) papers report biological activity of Disulfiram as an inhibitor of proteasomes or inhibitor of aldehyde dehydrogenase enzymes, interaction with other anticancer drugs, or mechanism of action related to reactive oxygen species. Other papers reviewed focus on chemical aspects of dithiocarbamates. CONCLUSION: This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Dissulfiram/química , Dissulfiram/farmacologia , Metais/química , Inibidores de Acetaldeído Desidrogenases/química , Inibidores de Acetaldeído Desidrogenases/farmacologia , Reposicionamento de Medicamentos , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Urease is a nickel-dependent amidohydrolase that catalyses the decomposition of urea into carbamate and ammonia, a reaction that constitutes an important source of nitrogen for bacteria, fungi and plants. It is recognized as a potential antimicrobial target with an impact on medicine, agriculture, and the environment. The list of possible urease inhibitors is continuously increasing, with a special interest in those that interact with and block the flexible active site flap. We show that disulfiram inhibits urease in Citrullus vulgaris (CVU), following a non-competitive mechanism, and may be one of this kind of inhibitors. Disulfiram is a well-known thiol reagent that has been approved by the FDA for treatment of chronic alcoholism. We also found that other thiol reactive compounds (l-captopril and Bithionol) and quercetin inhibits CVU. These inhibitors protect the enzyme against its full inactivation by the thiol-specific reagent Aldrithiol (2,2'-dipyridyl disulphide, DPS), suggesting that the three drugs bind to the same subsite. Enzyme kinetics, competing inhibition experiments, auto-fluorescence binding experiments, and docking suggest that the disulfiram reactive site is Cys592, which has been proposed as a "hinge" located in the flexible active site flap. This study presents the basis for the use of disulfiram as one potential inhibitor to control urease activity.
Assuntos
Dissulfiram/farmacologia , Inibidores Enzimáticos/farmacologia , Reagentes de Sulfidrila/farmacologia , Urease/antagonistas & inibidores , Aprovação de Drogas/legislação & jurisprudência , Cinética , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Cu/Zn superoxide dismutases (SODs) like the extracellular SOD3 and cytoplasmic SOD1 regulate cell proliferation by generating hydrogen peroxide (H2O2). This pro-oxidant inactivates essential cysteine residues in protein tyrosine phosphatases (PTP) helping receptor tyrosine kinase activation by growth factor signaling, and further promoting downstream MEK/ERK linked cell proliferation. Disulfiram (DSF), currently in clinical cancer trials is activated by copper chelation, being potentially capable of diminishing the copper dependent activation of MEK1/2 and SOD1/SOD3 and promoting reactive oxygen species (ROS) toxicity. However, copper (Cu) overload may occur when co-administered with DSF, resulting in toxicity and mutagenicity against normal tissue, through generation of the hydroxyl radical (â¢OH) by the Fenton reaction. PURPOSE: To investigate: a) whether sub-toxic DSF efficacy can be increased without Cu overload against human melanoma cells with unequal BRAF(V600E) mutant status and Her2-overexpressing SKBR3 breast cancer cells, by increasing H2O2 from exogenous SOD; b) to compare the anti-tumor efficacy of DSF with that of another clinically used copper chelator, tetrathiomolybdate (TTM). RESULTS: a) without copper supplementation, exogenous SOD potentiated sub-toxic DSF toxicity antagonized by sub-toxic TTM or by the anti-oxidant N-acetylcysteine; b) exogenous glucose oxidase, another H2O2 generator resembled exogenous SOD in potentiating sub-toxic DSF. CONCLUSIONS: potentiation of sub-lethal DSF toxicity by extracellular H2O2 against the human tumor cell lines investigated, only requires basal Cu and increased ROS production, being unrelated to non-specific or TTM copper chelator sequestration. SIGNIFICANCE: These findings emphasize the relevance of extracellular H2O2 as a novel mechanism to improve disulfiram anticancer effects minimizing copper toxicity.
Assuntos
Antineoplásicos/farmacologia , Dissulfiram/farmacologia , Peróxido de Hidrogênio/metabolismo , Molibdênio/farmacologia , Acetilcisteína/farmacologia , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/farmacologia , Cobre/metabolismo , Sequestradores de Radicais Livres/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Superóxido Dismutase/farmacologiaRESUMO
El disulfiram (Antabuse®) es un fármaco que se usa ampliamente en pacientes con consumo crónico de alcohol,como parte del tratamiento del alcoholismo, con el fin de producir síntomas desagradables al mezclarsecon etanol, por incremento de acetaldehído. Aunque se han descrito casos de intoxicación aun sin ingesta dealcohol con dosis terapéuticas y más comúnmente por sobredosis en adultos, son pocos los casos que se handescrito en niños.Se presenta a continuación el caso de un niño con intoxicación aguda por disulfiram, quien presentó en la faseaguda somnolencia que evolucionó a estupor; concomitantemente presentó crisis convulsivas, vómito, deshidratación,rigidez, temblor distal y diaforesis; al egreso, con secuelas neurológicas severas, caracterizadas pordistonía bilateral y signos piramidales como resultado de lesión bilateral de los ganglios basales documentadapor imagenología.
Disulfiram (Antabuse ®) is a drug that is widely used in patients with chronic alcohol consumption as part of treatment for alcoholism, in order to produce unpleasant symptoms when mixed with ethanol, acetaldehyde increased.Although there have been cases of poisoning even without alcohol intake at therapeutic doses and overdose most commonly in adults, few cases have been reported in children. We present a Child with disulfiram intoxication, who presented in acute sleepiness, progressing to stupor concomitantly presented seizures, vomiting, dehydration, rigidity, tremor and sweating; in output with severe neurological sequelae characterized by bilateral dystonia and pyramidal signs as a result of bilateral basal ganglia lesion documented by imaging.
Assuntos
Humanos , Gânglios da Base , IntoxicaçãoRESUMO
A intoxicação medicamentosa por dissulfiram é uma situação rara, mas, que pode se apresentar com manifestações cardiovasculares graves e potencialmente fatais, como choque cardiogênico. É apresentado o caso de uma paciente com choque refratário, após intoxicação voluntária por dissulfiram. A avaliação clínica e bioquímica, junto à avaliação ecocardiográfica e à monitorização invasiva, confirmaram tratar-se de um choque cardiogênico associado a esse fármaco. São discutidos os mecanismos de ação conhecidos do dissulfiram e descritos os principais efeitos colaterais, especialmente os cardiovasculares, alertando para a importância da suspeição diagnóstica e da abordagem terapêutica imediata mais adequada nesse contexto.
Drug intoxication with disulfiram is a rare condition that may lead to severe and potentially fatal cardiovascular manifestations such as cardiogenic shock. We report the case of a female patient with refractory shock after deliberate self-poisoning with disulfiram. Clinical, biochemical and echocardiographic assessment, as well as invasive monitoring confirmed cardiogenic shock associated with this drug. The known mechanisms of action of disulfiram are discussed, and the major collateral effects, especially cardiovascular effects, are described. We underscore the importance of suspecting this diagnosis and of adopting prompt and the most adequate therapeutic approach in this context.
La intoxicación medicamentosa por disulfiram es una situación rara, aunque puede presentarse con manifestaciones cardiovasculares graves y potencialmente fatales, como el shock cardiogénico. Este relato presenta el caso de una paciente con shock refractario, tras intoxicación voluntaria por disulfiram. La evaluación clínica y bioquímica, junto a la evaluación ecocardiográfica y el monitoreo invasivo, confirmaron tratarse de un shock cardiogénico asociado a ese fármaco. A lo largo del presente relato se discuten los mecanismos de acción del disulfiram conocidos, así como se describen los principales efectos colaterales, específicamente los cardiovasculares. En este sentido, también se alerta para la importancia de la sospecha diagnóstica y del abordaje terapéutico inmediato más adecuado a este contexto.
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Dissuasores de Álcool/intoxicação , Dissulfiram/intoxicação , Choque Cardiogênico/induzido quimicamente , Tentativa de Suicídio , Choque Cardiogênico/diagnósticoRESUMO
El objetivo de la presente actualización farmacológica es abordar la problemática de la dependencia alcohólica. Partiendo de las bases biológicas y del impacto del etanol sobre los sistemas neurobiológicos y de neurotransmisión, se hará una revisión de las principales herramientas farmacológicas para el tratamiento de la dependencia alcohólica. El disulfiram, la naltrexona y el acamprosato, todas ellas con aprobación por la FDA (Food and Drug Administration) han mostrado mecanismos de acción, perfiles de eficacia, tolerabilidad y adherencia dispares. También nos referiremos al topiramato, el que está siendo estudiado actualmente con relación a esta indicación.
The aim of the present pharmacological update is to revise the problem of alcohol dependence. Starting from the biological bases and the impact of alcohol on the neurobiological and neurotransmission systems, a revision of the main pharmacological tools for alcohol dependence treatment will be done. Disulfiram, naltrexone, acamprosate, all of them approved by the FDA (Food and Drug Administration), have shown mechanisms of action, efficacy, tolerance and adherence dissimilar. We will also refer to topiramate, which is being studied for this indication.