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Aim: Evaluate the anticandidal effect of Croton heliotropiifolius Kunth essential oil and its interaction with azoles and N-acetylcysteine (NAC) against planktonic cells and biofilms. Materials & methods: Broth microdilution and checkerboard methods were used to evaluate the individual and combined activity with fluconazole and itraconazole (ITRA). The antibiofilm effect of the oil was assessed in 96-well plates alone and combined with ITRA and NAC, and cytotoxicity determined by MTT. Results: The oil inhibited all Candida species growth. The activity was enhanced when associated with ITRA and NAC for planktonic cells and biofilms in formation. The effective concentrations were lower than the toxic ones to V79 cells. Conclusion: C. heliotropiifolius Kunth essential oil is an anticandidal alternative, and can be associated with ITRA and NAC.
Candida is a type of fungus that can cause disease in people. In recent years, the number of available drugs to treat this disease have declined. It is important to search for new drugs. Plants are often used to improve health, so we tested the essential oil of a plant called Croton heliotropiifolius to see if it could kill the fungus. We found that the essential oil could kill the fungus, and could be used with other drugs to improve their effects.
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Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.
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Acetilcisteína , Antioxidantes , Ácido Ascórbico , Desferroxamina , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Humanos , Antioxidantes/farmacocinética , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Masculino , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacocinética , Acetilcisteína/efeitos adversos , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/efeitos adversos , Adulto , Estresse Oxidativo/efeitos dos fármacos , Feminino , Desferroxamina/farmacocinética , Desferroxamina/administração & dosagem , Desferroxamina/efeitos adversos , Voluntários Saudáveis , Adulto Jovem , Infusões Intravenosas , Pessoa de Meia-Idade , Método Duplo-Cego , Quimioterapia Combinada , Biomarcadores/sangueRESUMO
Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP® 5 mg/kg or NAC® 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca+2, and Mg+2 ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.
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Acetilcisteína , Cisplatino , Pulmão , Ratos Wistar , Animais , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Acetilcisteína/farmacologia , Ratos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Glutationa/metabolismo , Fármacos Neuroprotetores/farmacologia , Antineoplásicos/efeitos adversosRESUMO
Glutamate is one of the predominant excitatory neurotransmitters released from the central nervous system; however, at high concentrations, this substance may induce excitotoxicity. This phenomenon is involved in numerous neuropathologies. At present, clinically available pharmacotherapeutic agents to counteract glutamatergic excitotoxicity are not completely effective; therefore, research to develop novel compounds is necessary. In this study, the main objective was to determine the pharmacotherapeutic potential of the hydroalcoholic extract of Psidium guajava (PG) in a model of oxidative stress-induced by exposure to glutamate utilizing Danio rerio larvae (zebrafish) as a model. Data showed that treatment with glutamate produced a significant increase in oxidative stress, chromatin damage, apoptosis, and locomotor dysfunction. All these effects were attenuated by pre-treatment with the classical antioxidant N-acetylcysteine (NAC). Treatment with PG inhibited oxidative stress responsible for cellular damage induced by glutamate. However, exposure to PG failed to prevent glutamate-initiated locomotor damage. Our findings suggest that under conditions of oxidative stress, PG can be considered as a promising candidate for treatment of glutamatergic excitotoxicity and consequent neurodegenerative diseases.
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Psidium , Peixe-Zebra , Animais , Glutamatos/toxicidade , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Folhas de PlantaRESUMO
Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.
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Arritmias Cardíacas , Dobutamina , Triazóis , Humanos , Ratos , Animais , Masculino , Espécies Reativas de Oxigênio , Ratos Wistar , Arritmias Cardíacas/induzido quimicamente , Acetilcisteína , Miócitos CardíacosRESUMO
RESUMEN Introducción: La cardiopatía isquémica es la principal causa de muerte en la República Argentina. La forma de presentación que prevalece es el infarto de miocardio (IM), caracterizado por insuficiente perfusión sanguínea, muerte celular y pérdida de masa contráctil. La evolución del remodelado ventricular provoca dilatación ventricular, deterioro hemodinámico, insuficiencia cardíaca y disminución de la sobrevida. Durante este proceso existe un estrés oxidativo miocárdico que podría ser atenuado mediante la administración de N-acetil cisteína (NAC), a través de un aumento de los niveles de glutatión. Objetivos: Evaluar el efecto de la NAC sobre el remodelado post IM. Material y métodos: Se estudiaron durante 28 días conejos neozelandeses en tres grupos experimentales: Control, IM e IM+NAC. Bajo anestesia general se realizó una toracotomía izquierda y, en los grupos con IM, ligadura de una rama de la coronaria izquierda. Al finalizar el período de seguimiento posterior al infarto, se realizaron estudios ecocardiográficos, hemodinámicos y morfológicos del ventrículo izquierdo (VI). Resultados: En los grupos IM e IM+NAC los infartos estaban ubicados en la pared libre del VI y tuvieron tamaños similares. La administración de NAC evitó el adelgazamiento de la zona no infartada y disminuyó la dilatación provocada por el infarto. También pudo observarse que preservó las funciones sistólica y diastólica del VI, con atenuación del deterioro que las mismas sufrieron como consecuencia del infarto. Conclusión: Estos resultados sugieren que la administración de NAC es una terapéutica promisoria para mitigar los efectos desfavorables del remodelado post IM.
ABSTRACT Background: Ischemic heart disease is the main cause of death in Argentina. The prevailing form of presentation is myocardial infarction (MI), characterized by insufficient blood perfusion, cell death and loss of contractile mass. The evolution of ventricular remodeling causes ventricular dilation, hemodynamic impairment, heart failure, and decreased survival. The oxidative stress occurring during this process could be attenuated by the administration of N-acetyl cysteine (NAC) through increased glutathione levels. Objectives: The aim of this study was to evaluate the effect of NAC administration on post-MI remodeling. Methods: New Zealand rabbits were divided into three experimental groups: Control, MI and MI+NAC. A left thoracotomy was performed under general anesthesia, and in the MI groups a branch of the left coronary artery was ligated. Echocardiographic, hemodynamic and morphological studies of the left ventricle were performed at the end of the 28-day post infarction follow-up period. Results: In the MI and MI+NAC groups, the infarcts were located in the left ventricular free wall and had similar sizes. The administration of NAC prevented non-infarcted area thinning and decreased the dilation caused by the infarction. It also preserved left ventricular systolic and diastolic functions, attenuating the impairment that they suffered as a consequence of the infarction. Conclusion: These results suggest that NAC administration is a promising therapy to mitigate the unfavorable effects of post-MI remodeling.
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Introducción: la hipersensibilidad por fármacos es inducida por una respuesta aberrante del sistema inmune; por lo general, impredecible, dosis independiente y amenazante para la vida del paciente. Las reacciones de hipersensibilidad por fármacos con compromiso mucocutáneo se dan en alrededor del 2 %-3 % de los pacientes hospitalizados. Objetivo: describir un caso de necrólisis tóxica epidérmica por un fármaco a base de caléndula y acetilcisteína como los presuntos desencadenantes. Presentación del caso: hombre de 39 años, quien asistió a emergencias, por malestar general, artralgias, mialgias, astenia y adinamia de un día de evolución. Tres días después refirió la aparición de lesiones purpúricas progre-sivas que se extendieron por cara, extremidades y glúteos; delimitadas; no dolorosas, y sin desaparecer a la digitopresión, asociado con disnea, inestabilidad hemodinámica y cardiovascular. Al sexto día de hos-pitalización, se interrogó al paciente, quien se había automedicado un fármaco de origen desconocido, presuntamente de extracto herbal a base de caléndula más acetilcisteína para artralgias, osteomialgias y disfagia. A la mañana siguiente, presentó lesiones purpúricas y ulcerativas extensas. Se observaron lesiones purpúricas progresivas y ulcerativas en cara extremidades y glúteos. Mediante la sospecha clínica y la evaluación histopatológica, se confirmó la necrólisis tóxica epidérmica. Conclusiones: las reacciones adversas medicamentosas severas que amenazan la vida del paciente son relativamente raras, pero representan un verdadero desafío diagnóstico y terapéutico. Es necesario profundizar en la investigación para esclarecer la causa de este tipo de reacción medicamentosa.
Introduction: Drug hypersensitivity is induced by an aberrant response from the immune system. It is usually unpredictable, dose-independent, and can be life-threatening to the patient. Drug-induced hypersensitivity reactions with mucocutaneous involvement occur in approximately 23% of hospitalized patients. However, Toxic Epidermal Necrolysis is a rare case. Aim: To describe a case of drug-induced toxic epidermal necrolysis triggered by Calendula officinalis and acetylcysteine. Case report: A 39-year-old male was pre-sented to the emergency room with malaise, arthralgia, myalgia, asthenia, and adynamia since day one. Three days later, he developed progressive purpuric lesions that spread to the face, extremities, and buttocks. These lesions were painless, not delineate, and did not blanch under pressure. They were asso-ciated with dyspnea and hemodynamic and cardiovascular instability. On the sixth day of hospitaliza-tion, the patient admitted to self-medicating with an unknown drug, presumably a herbal extract based on calendula and acetylcysteine, for arthralgia, myalgia, and dysphagia. The morning after the drug consumption, the patient developed extensive purpuric and ulcerative lesions. A diagnosis of toxic epi-dermal necrolysis was made based on clinical suspicion and histopathological confirmation. Conclusion:Severe adverse drug reactions that threaten a patient's life are relatively rare. However, they represent a real diagnostic and therapeutic challenge when they do occur
Introdução: a hipersensibilidade a drogas é induzida por uma resposta aberrante do sistema imunoló-gico; geralmente imprevisível, independente da dose e com risco de vida para o paciente. As reações de hipersensibilidade a drogas com comprometimento mucocutâneo estão em torno dos 2-3% dos pacien-tes hospitalizados. Objetivo: descrever um caso de necrólise epidérmica tóxica causada por uma droga à base de Calendula officinalis e acetilcisteína como os supostos desencadeantes. Apresentação do caso:homem, 39 anos, deu entrada no pronto-socorro manifestando mal-estar, artralgia, mialgia, astenia e adinamia há um dia. Posteriormente, três dias depois, relatou o aparecimento de lesões purpúricas pro-gressivas que se espalharam para a face, extremidades e nádegas; que são delimitadas, não dolorosas e não desaparecem com a acupressão associada a dispnéia, instabilidade hemodinâmica e cardiovascular. No sexto dia de internação, o paciente foi questionado, y disse que tinha se automedicado com uma droga de origem desconhecida, presumivelmente extrato de ervas à base de calêndula mais acetilcis-teína para artralgia, osteomialgia e disfagia. Na manhã seguinte, apresentou extensas lesões purpúricas e ulcerativas. Observam-se lesões purpúricas progressivas e ulcerativas que se estendem à face, extre-midades e nádegas. Pela suspeita clínica e confirmação histopatológica, confirma-se a necrólise epidér-mica tóxica. Conclusões: reações adversas graves a medicamentos que ameaçam a vida do paciente são relativamente raras, mas quando ocorrem representam um verdadeiro desafio a nível diagnóstico e terapêutico. São precisas mais pesquisas para esclarecer a causa desse tipo de reação medicamentosa.
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HumanosRESUMO
Lead (Pb2+) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb2+-induced cognitive impairment. The dams were divided into four groups: Control, Pb2+, NAC, and Pb2++NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb2++NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb2+ and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb2+ group. As expected, Pb2+ group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb2+ were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.
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This study aimed to evaluate the protective role of N-acetylcysteine (NAC) in cells and mice exposed to formaldehyde. For the in vitro study, J774A.1 macrophages cells were incubated for 8, 16 and 24 h with formaldehyde or NAC to assess cell viability and reactive oxygen species (ROS). In the in vivo study, C57BL/6 mice (n = 48) were divided into 6 groups: control (CG), vehicle (VG) that received saline by orogastric gavage, a group exposed to formaldehyde 1% (FG) and formaldehyde exposed groups that received NAC at doses of 100, 150 and 200 mg/Kg (FN100, FN150 and FN200) for a period of 5 days. In vitro, formaldehyde promoted a decrease in cell viability and increased ROS, while NAC reduced formaldehyde-induced ROS production. Animals exposed to formaldehyde presented higher leukocyte counts in the blood and in the bronchoalveolar lavage fluid, and promoted secretion of inflammatory markers IL-6, IL-15, and IL-10. The exposure to formaldehyde also promoted redox imbalance and oxidative damage characterized by increased activities of superoxide dismutase, catalase, decreased GSH/GSSG ratio, as well as it increased levels of protein carbonyls and lipid peroxidation. NAC administration after formaldehyde exposure attenuated oxidative stress markers, secretion of inflammatory mediators and lung inflammation. In conclusion, both in in vitro and in vivo models, NAC administration exerted protective effects, which modulated the inflammatory response and redox imbalance, thus preventing the development airway injury induced by formaldehyde exposure.
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Acetilcisteína , Pulmão , Camundongos , Animais , Acetilcisteína/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Oxirredução , Formaldeído/toxicidade , Formaldeído/metabolismo , Estresse Oxidativo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Antioxidantes/metabolismoRESUMO
Introduction: Currently there is no approved preventive or therapeutic pharmacological treatment to treat ototoxicity caused by cisplatin. N-acetyl cysteine (NAC) is a safe and inexpensive antioxidant that has been studied as an otoprotective alternative. Objective: To describe the efficacy of intratympanic infiltration of NAC as prevention and treatment of ototoxicity induced in patients treated with cisplatin. Material and methods: Open, longitudinal, prospective, randomized clinical trial in cancer patients treated with cisplatin who met the inclusion criteria. Out of the sample of 22 patients, 11 underwent intratympanic NAC infiltration and 11 were taken as a control group. It was performed an audiometry at the beginning and one month after on all patients. Results: A sample of 22 patients with a mean age of 53 (±13) was collected. In our sample of 11 patients with infiltration in both ears, 1 ear showed improvement; on the other hand, in the control group that was not infiltrated, 4 showed an increase in hearing loss from mild to moderate in all 4 cases, 2 in the left ear and 2 in the right ear (Spearman's Rho = 0.93, p ≤ 0.001). Relative risk was of 1.22. Conclusions: An association can be observed that intratympanic NAC could become an alternative for the prevention and treatment of cisplatin-induced ototoxicity.
Introducción: actualmente no existe ningún tratamiento farmacológico preventivo o terapéutico aprobado para tratar la ototoxicidad causada por el cisplatino. La N-acetilcisteína (NAC) es un antioxidante seguro y de bajo costo que ha sido estudiado como una alternativa otoprotectora. Objetivo: describir la eficacia de la infiltración intratimpánica de la NAC como prevención y tratamiento de la ototoxicidad generada en pacientes tratados con cisplatino. Material y métodos: ensayo clínico abierto, longitudinal, prospectivo, aleatorizado, en pacientes con cáncer tratados con cisplatino que cumplieron con los criterios de inclusión. De la muestra de 22 pacientes a 11 se les infiltró NAC intratimpánica y 11 se tomaron como grupo control. Se les realizó audiometría inicial y un mes después a la totalidad de los pacientes. Resultados: se recabó una muestra de 22 pacientes con edad promedio de 53 (±13). En nuestra muestra de 11 pacientes con infiltración en ambos oídos, un oído mostró mejoría; por otro lado, en el grupo control que no fue infiltrado 4 mostraron aumento en la hipoacusia y pasaron del nivel leve al moderado en los 4 casos, 2 en el oído izquierdo y 2 en el oído derecho (Rho de Spearman = 0.93, p ≤ 0.001). El riesgo relativo fue de 1.22. Conclusión: se puede observar una asociación de que la NAC intratimpánica pudiera llegar a ser una alternativa para la prevención y el tratamiento de la ototoxicidad inducida por cisplatino.