Indicación de N-acetilcisteína en distintas formas de toxicidad por paracetamol / Indication of n-acetylcysteine in differents forms of paracetamol toxicity

Introducción: la hepatotoxicidad por paracetamol está relacionada con la formación del metabolito N-acetil-parabenzoquinoneimina (NAPQI) y su falta de detoxificación a través del glutatión, cuyas reservas se deplecionan en el contexto de una sobredosis. La administración de N-acetilcisteína (NAC) como sustancia dadora de grupos tioles (-SH) contribuye a la prevención del daño hepático que puede desarrollarse con dosis terapéuticas o tóxicas. Métodos: se comentan 5 casos de exposición a paracetamol en los cuales se administró NAC por alteración de la función hepática. La gravedad de los cuadros varió en función de las dosis y del tiempo de latencia hasta la consulta. Resultados: cuatro pacientes ingirieron una única dosis tóxica y una paciente recibió la dosis diaria máxima de paracetamol de 4000 mg/día durante 5 días. La paciente que consultó dentro de las 4 horas posteriores a la ingesta no presentó elevación de transaminasas. Todas las pacientes recibieron NAC y sus valores de enzimas hepáticas se normalizaron al momento del alta. Conclusión: la administración temprana de NAC puede ser útil para prevenir daño hepático tanto en ingestas de dosis tóxicas, como en casos de utilización de dosis terapéuticas máximas durante varios días. (AU)

Introduction: paracetamol hepatotoxicity is related to the formation of the metabolite N-acetyl-parabenzoquinoneimine (NAPQI) and its lack of detoxification through glutathione, whose reserves are depleted in paracetamol overdose. The administration of N-acetylcysteine (NAC) as a donor of sulfhydryl groups (-SH) can prevent liver damage that could even occur with therapeutic or toxic doses. Methods: 5 cases of exposure to paracetamol are discussed, in which NAC was administered due to impaired liver function. These manifestations presented different severity depending on the drug doses and the time until medical consultation. Results: four patients ingested single toxic doses and one patient received the maximum daily dose of paracetamol of 4000 mg/day for 5 days. The patient who consulted within 4 hours after ingestion did not present elevation of transaminases. All patients received NAC, with normal liver enzymes at discharge. Conclusion: the early administration of NAC may be useful to prevent liver damage both in toxic dose intakes and in cases of use of maximum therapeutic doses for several days. (AU)

Can paricalcitol increase the effectiveness of n-acetylcysteine in contrast induced acute kidney prophylaxis in rats? A biochemical and histopathological study / ¿Puede el paricalcitol aumentar la eficacia de la n-acetilcisteína en la profilaxis renal aguda inducida por contraste en ratas? Un estudio bioquímico e histopatológico

SUMMARY: N-Acetylcysteine (NAC) is used for contrast induced acut kidney injury (CI-AKI) prophylaxis because of its antioxidant effects. Paricalcitol, which has reno-protective effects, is likely to provide a more effective prophylaxis when added to NAC treatment. The study was designed based on this hypothesis. The study was organised to include 4 groups each consisting of 7 rats. Group 1 was the control group, and Group 2 included rats with CI-AKI. Rats in Group 3 were administered NAC at a dose of 100 mg/kg via oral gavage once a day for 5 days. Rats in group 4 were administered paricalcitol at a dose of 0.4 mcg/kg once a day for 5 days in addition to NAC. CI-AKI was induced after the treatments in both groups. The study was terminated on the sixth day. Samples were collected from the rats' sera and kidney tissues to study oxidant and antioxidant parameters; kidney function tests were also studied. There were significant differences between the contrast nephropathy group (Group 2) and NAC and NAC+paricalcitol groups with respect to serum urea and creatinine levels. When the same groups were compared regarding oxidant (TOS-MDA) and antioxidant (TAC-Paraoxonase) parameters, we observed that the oxidant parameters increased in serum and kidney tissue samples with NAC use, and that effect was strengthened by the addition of paricalcitol to NAC treatment. However, despite increased antioxidant effectiveness, we observed no decrease in urea and creatinine levels when paricalcitol was added for CI-AKI in rats. There was no significant difference between Group 3 and Group 4. Paricalcitol provides a more potent antioxidant effect in both serum and kidney tissue samples when added to NAC treatment in rats with CI-AKI. Despite increased antioxidant parameters, however, paricalcitol does not provide a significant decrease in urea and creatinine levels.

RESUMEN: Debido a sus efectos atioxidantes la N- acetilcisteína (NAC) se usa para la profilaxis de la lesión renal aguda inducida por contraste (CI-AKI). Es probable que el paricalcitol, que tiene efectos renoprotectores, proporcione una profilaxis más eficaz cuando se agrega al tratamiento con NAC. En base a esta hipótesis el estudio fue diseñado para incluir cuatro grupos cada uno compuesto por siete ratas. El grupo 1 fue el grupo control y el grupo 2 incluyó ratas con CI-AKI. A las ratas del Grupo 3 se les administró NAC con una dosis de 100 mg/kg por sonda oral una vez al día, durante 5 días. A las ratas del grupo 4 se les administró paricalcitol a una dosis de 0,4 mcg/kg una vez al día durante 5 días, además de NAC. Se indujo CI-AKI después de los tratamientos en ambos grupos. El estudio finalizó el sexto día. Se recolectaron muestras de suero y tejidos renales de ratas para estudiar los parámetros oxidantes y antioxidantes; También se estudiaron las pruebas de función renal. Hubo diferencias significativas entre el grupo de nefropatía por contraste (Grupo 2) y los grupos NAC y NAC+paricalcitol con respecto a los niveles séricos de urea y creatinina. Cuando se compararon los mismos grupos con respecto a los parámetros oxidantes (TOS-MDA) y antioxidantes (TAC-Paraoxonase), observamos que los parámetros oxidantes aumentaron en muestras de suero y tejido renal con el uso de NAC, y ese efecto se vio reforzado por la adición de paricalcitol a tratamiento NAC. Sin embargo, a pesar de una mayor eficacia antioxidante, no observamos una disminución en los niveles de urea y creatinina cuando se agregó paricalcitol para CI-AKI en ratas. No hubo diferencias significativas entre el Grupo 3 y el Grupo 4. El paricalcitol proporciona un efecto antioxidante más potente tanto en muestras de suero como de tejido renal cuando se agrega al tratamiento con NAC en ratas con CI-AKI. Sin embargo, a pesar del aumento de los parámetros antioxidantes, el paricalcitol no proporciona una disminución sig- nificativa en los niveles de urea y creatinina.

Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy / Efeito protetor da N-acetilcisteína na ototoxicidade por cisplatina em ratos: um estudo com testes auditivos e microscopia eletrônica de varredura

Abstract Introduction Ototoxicity is a health problem appearing after powerful treatments in serious health conditions. It is sometimes inevitable when treatment of the serious disease is required. Cisplatin is an antineoplastic agent which was investigated previously to reveal increased nitrogen and reactive oxygen radicals that damages hair cells, resulting in ototoxicity. N-acetylcysteine, previously shown to decrease ototoxicity caused by different agents, is known to be a powerful in vitro antioxidant. Probably N-acetylcysteine, in addition to its antioxidant effect, blocks a cascade where reactive oxygen species result in apoptosis in the cochlea. Objectives The possible preventive effect of N-acetylcysteine in cisplatin ototoxicity was studied with auditory brain stem responses, otoacoustic emissions, and histopathological investigation of the cochlea in a scanning electron microscopy. Methods This study was conducted on 21 Wistar Albino rats in four groups. 1 mL/kg/day three times in total intraperitoneal (i.p.) Saline (n = 5), 500 mg/kg/day i.p. three times in total N-acetylcysteine (n = 5), i.p. 15 mg/kg cisplatin alone (single dose) (n = 5) and i.p. 15 mg/kg cisplatin plus 500 mg/kg/day N-acetylcysteine (n = 6) were administered. The rats were anesthetized to study the hearing tests before and after the experiment. The rats were sacrificed to investigate the cochleas by scanning electron microscopy. Results Auditory brain stem responses and otoacoustic emissions values were attenuated in the cisplatin group. The group that received N-acetylcysteine in addition to cisplatin had better auditory brain stem responses thresholds and otoacoustic emissions. The samples obtained from the cisplatin group showed surface irregularities, degeneration areas, and total or partial severe stereocilia losses. The changes were milder in the cisplatin + N-acetylcysteine group. Conclusion Cisplatin ototoxicity can be detected by auditory brain stem responses and otoacoustic emissions testing in rats. N-acetylcysteine may protect the cochlear cells from histopathological changes. We concluded that N-acetylcysteine given 4 h after cisplatin injection has a potential otoprotective effect against cisplatin ototoxicity. which suggests it could be used in clinical trials.

Resumo Introdução A ototoxicidade é um problema que pode ocorrer após certos tipos de tratamentos para condições graves de saúde. Às vezes é inevitável quando o tratamento da doença é necessário. A cisplatina é um agente antineoplásico cujo uso em pesquisas anteriores demonstrou aumentar os radicais livres de nitrogênio e espécies reativas de oxigênio que danificam as células ciliadas e resultam em ototoxicidade. Por outro lado, a N-acetilcisteína, que já demonstrou diminuir a ototoxicidade causada por diferentes agentes, é conhecida por ser um potente antioxidante in vitro. Provavelmente a N-acetilcisteína, além de seu efeito antioxidante, bloqueia uma cascata onde espécies reativas de oxigênio resultam em apoptose na cóclea. Objetivos Estudar o possível efeito preventivo da N-acetilcisteína na ototoxicidade por cisplatina por meio de potencial evocado auditivo de tronco encefálico, emissões otoacústicas e investigação histopatológica da cóclea por microscopia eletrônica de varredura. Método Este estudo foi realizado em 21 ratos albinos Wistar, separados em quatro grupos. Foram administrados: 1 mL/kg/dia intraperitoneal (i.p.) de solução salina (n = 5), três vezes no total; 500 mg/kg/dia i.p. de N-acetilcisteína (n = 5), três vezes no total; 15 mg/kg i.p. (dose única) somente de cisplatina (n = 5) e 15 mg/kg i.p. de cisplatina e 500 mg/kg/dia i.p. de N-acetilcisteína (n = 6). Os ratos foram anestesiados para estudo dos testes auditivos antes e depois do experimento. Os ratos foram sacrificados para investigação da cóclea por microscopia eletrônica de varredura. Resultados Os potenciais evocados auditivos de tronco encefálico e os valores das emissões otoacústicas estavam atenuados no grupo cisplatina. O grupo que recebeu N-acetilcisteína além da cisplatina apresentou melhores limiares de respostas auditivas do tronco encefálico e emissões otoacústicas. As amostras obtidas do grupo cisplatina apresentaram irregularidades de superfície, áreas de degeneração, com perdas graves totais ou parciais de estereocílios. As alterações foram mais leves no grupo cisplatina + N-acetilcisteína. Conclusão A ototoxicidade por cisplatina pode ser detectada por meio de potenciais evocados auditivos de tronco encefálico e pelo teste de emissões otoacústicas em ratos. A N-acetilcisteína pode proteger as células cocleares contra alterações histopatológicas. Concluímos que a N-acetilcisteína administrada 4 horas após a injeção de cisplatina tem potencial efeito otoprotetor contra a ototoxicidade por cisplatina e pode ser utilizada em ensaios clínicos.

Efecto de la n-acetilcisteina inhalada en el desarrollo de fibrosis pulmonar de ratas intoxicadas con paraquat / Effect of n-acetylcisteine inhaled in the development of pulmonary fibrosis of intoxicated rats with paraquat

El Paraquat (PQ) es un herbicida de contacto bipiridilico ampliamente utilizado en agricultura. La intoxicación en humanos por este agente ocasiona fibrosis pulmonar. Evaluamos los cambios histológicos pulmonares de ratas intoxicadas con PQ y tratadas con N-aceticisteina (NAC) administrada vía inhalatoria. Realizamos un estudio experimental descriptivo con 25 ratas adultas, machos cepa Wistar, divididas en cinco grupos. Al grupo I no se les administro ni PQ ni NAC. Grupo II, recibió NAC inhalada a 15mg/kg diaria c/12 horas. Grupo III, PQ vía oral (VO) 15mg/kg. Grupo IV, PQ a 15mg/kg, por VO y a la hora NAC 150mg/kg. Grupo V, PQ a 15mg/kg, por VO y a las seis horas NAC dosis de 150mg/kg. Los pulmones fueron extraídos y se evaluaron mediante cortes histológicos. Resultados: Los grupos I y II (supervivencia del 100%, n=10) no desarrollaron sintomatología de intoxicación. Grupos III, IV y V predominaron síntomas respiratorios, diversos grados de edema pulmonar, enfisema, congestión vascular y hemorragia intra-alveolar focal. La eficacia de la NAC sobre la intoxicación por PQ en términos de sobrevivencia al primer día, fue del 100% y al segundo día, fue del 80% (p= 0,005; prueba Chi-cuadrado). El PQ indujo un proceso inflamatorio (agudo-crónico) por infiltrado de segmentados neutrófilos y linfocitos, lo cual fue revertido parcialmente por la administración inhalada de NAC. Conclusión: Los cambios histopatológicos observados a nivel pulmonar fueron aminorados por el tratamiento con NAC, lo que sugiere un posible efecto protector de este fármaco sobre el daño oxidativo inducido por el herbicida

Paraquat (PQ) is a bipyridyl contact herbicide widely used in agriculture. Intoxication in humans by this agent causes pulmonary fibrosis. We evaluated pulmonary histological changes of rats intoxicated with PQ and treated with N-acetycysteine (NAC) administered via inhalation. We conducted a descriptive experimental study with 25 adult rats, male Wistar strain, divided into five groups. Group I was not administered PQ or NAC. Group II, received NAC inhaled at 15mg/kg daily c/12 hours. Group III, PQ orally (VO) 15mg/ kg. Group IV, PQ at 15mg/kg, by VO and at hour NAC 150mg/ kg. Group V, PQ at 15mg/kg, by VO and at six hours NAC dose of 150mg/kg. The lungs were extracted and evaluated by histological sections. Results: Groups I and II (100% survival, n=10) did not develop intoxication symptoms. Groups III, IV and V predominantly respiratory symptoms, various degrees of pulmonary edema, emphysema, vascular congestion and focal intra-alveolar hemorrhage. The efficacy of NAC on PQ poisoning in terms of survival on the first day was 100% and on the second day it was 80% (p = 0.005, Chi-square test). The PQ induced an inflammatory process (acute-chronic) by infiltration of segmented neutrophils and lymphocytes, which was partially reversed by the inhaled administration of NAC. Conclusion: The histopathological changes observed at the pulmonary level were reduced by the treatment with NAC, which suggests a possible protective effect of this drug on the oxidative damage induced by the herbicide.

N-acetilcisteína e/ou ácido ursodeoxicólico associados à metformina na esteato-hepatite não alcoólica: um estudo aberto, multicêntrico, randomizado controlado / N-acetylcysteine and/or ursodeoxycholic acid associated with metformin in non-alcoholic steatohepatitis: an open-label multicenter randomized controlled trial

ABSTRACT BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH). METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks. RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age ±54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups. CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.

RESUMO CONTEXTO: Atualmente, o tratamento farmacológico da doença hepática gordurosa não alcoólica (DHGNA) ainda é limitado e baseia-se no tratamento de condições associadas às comorbidades. O estresse oxidativo e a resistência à insulina são os mecanismos que parecem estar mais envolvidos em sua patogênese. OBJETIVO: Avaliar a eficácia da N-acetilcisteína (NAC) em associação à metformina (MTF) e/ou ácido ursodesoxicólico (UDCA) no tratamento da EHNA. MÉTODOS: Estudo randomizado, multicêntrico e aberto, conduzido por 48 semanas. Incluiu pacientes com esteato-hepatite não alcoólica (EHNA) comprovada por biópsia. Os pacientes foram distribuídos aleatoriamente em três grupos: NAC (1,2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/dia) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/dia) (n=13); NAC (1,2 g) + MTF (850-1500 mg/dia) (n=14) durante 48 semanas. Os dados clínicos, laboratoriais e as segundas biópsias hepáticas foram realizados após 48 semanas. RESULTADOS - Um total de 53 pacientes foram avaliados; 17 (32,1%) eram do sexo masculino; idade mediana de ±54 (IQR=15, 21-71) anos. No baseline, nenhuma diferença foi observada entre os grupos de acordo com parâmetros clínicos e histológicos. Os grupos diferiram apenas em colesterol, LDL e triglicerídeos. Não foram encontradas diferenças significativas nos parâmetros bioquímicos e histológicos entre os três grupos após 48 semanas de tratamento. Contudo, na análise intragrupos (intenção de tratar) comparando características histológicas e bioquímicas, houve melhora significativa no grau de esteatose (P=0,014), balonização (P=0,027) e, consequentemente, no NAFLD Activity Score (NAS) (P=0,005), e nos níveis de ALT no final do tratamento apenas no grupo NAC+MTF. Nenhuma evidência significativa de modificaçãona fibrose hepática pôde ser observada em nenhum dos grupos. CONCLUSÃO: - Este estudo multicêntrico sugere que a associação de NAC+MTF poderia reduzir a atividade da doença hepática em pacientes com EHNA. Esses dados estimulam estudos adicionais controlados com essa terapia para esses pacientes.

Effects of N-acetylcysteine on amphetamine-induced sensitization in mice

Objective: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. Methods: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. Results: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. Conclusion: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.

N-acetylcysteine versus dopamine to prevent acute kidney injury after cardiac surgery in patients with preexisting moderate renal insufficiency

Abstract Objective: Acute kidney injury after cardiac surgery is associated with mortality and morbidity. Therefore, strategies to prevent acute kidney injury are very important. The aim of this placebo-controlled randomized double-blind study was to compare the prophylactic efficacy of N-Acetylcysteine and dopamine administration in patients with pre-existing moderate renal insufficiency who were undergoing cardiopulmonary bypass. Methods: This study included 135 patients with pre-existing moderate renal insufficiency who were scheduled for coronary artery bypass grafting surgery. Serum creatinine and GFR were recorded preoperatively and on the first and second postoperative days. Results: On the first and second postoperative days, the drugs used showed statistically significant differences among the creatinine groups (P<0.001). According to Tukey’s HSD, on the first and second PO, the creatinine of Group N, D and P were significantly different (P<0.001). On the first and second PO, the used drugs showed statistically significant differences among the effects of eGFR (P<0.001). According to Tukey’s HSD on the first postoperative day, the average eGFR score of Group N compared to D and P were significantly difference (P<0.001). On the second postoperative day, the eGFR of Group N and D showed no difference (P=0.37), but P showed a difference (P<0.001). Conclusion: We found that the prophylactic use of intravenous N-Acetylcysteine had a protective effect on renal function, whereas the application of renal dose dopamine did not have a protective effect in patients with pre-existing moderate renal failure.

Uso de N-acetilcisteína tópica en ictiosis: experiencia clínica en una serie de casos / Use of topical N-acetylcysteine ​​in ichthyosis: clinic experience in a series of cases

Las ictiosis son trastornos generalizados de la queratinización, que se caracterizan por presentar hiperqueratosis y/o descamación. El tratamiento es sintomático e incluye terapias tópicas y sistémicas. La N-Acetilcisteína (NAC) tópica ha mostrado utilidad en algunos reportes. Se describirá la experiencia con el uso de NAC 10% y urea 5% en novobase II (NB II) en 6 pacientes con distintos tipos de ictiosis hereditarias. Caso Nº1: Escolar masculino de 7 años con Ictiosis lamelar (IL) en tratamiento con fórmula de NAC hace 4 años con buena respuesta. Caso N°2, 3 y 4: Escolar masculino de 7 años, escolar masculino de 5 años y lactante masculino de 1 año 8 meses con Ictiosis recesiva ligada a X (IRLX), en tratamiento con fórmula de NAC con buena respuesta. Caso N°5: Mujer de 18 años con Eritrodermia ictiosiforme congénita (EIC), inicia tratamiento con fórmula de NAC, pero se suspende por mala tolerancia. Caso N°6: Preescolar femenina de 3 años, con Ictiosis epidermolítica (IE), inicia tratamiento con fórmula de NAC con mala tolerancia por lo que también se suspende. Se evaluaron los efectos de la fórmula de NAC en diferentes tipos de ictiosis, mostrando un buen perfil de seguridad y eficacia en IL e IRLX, sin embargo, en EIC e IE su uso estuvo restringido por efectos adversos. El tratamiento con fórmula de NAC presenta buena respuesta y tolerancia en pacientes con IL e IRLX, por lo que podría considerarse en el tratamiento habitual de estos pacientes.

Ichthyosis are generalized disorders of keratinization, characterized by hyperkeratosis and/or scaling. Treatment is symptomatic and includes topical and systemic therapies. Topical N-acetylcysteine (NAC) has shown utility in some reports. We describe the experience using 10% NAC and 5% urea in novobase II (NB II) in 6 patients with different types of hereditary ichthyosis. Case N°1: 7-year-old boy with lamellar Ichthyosis (IL) in treatment with NAC formula 4 years ago, with good response. Case N°2, 3 and 4: 7-year-old boy, 5-year-old boy and 1-year-8-month-old male infant, with X-recessive recessive Ichthyosis (IRLX) in treatment with NAC formula with good response. Case N°5: An 18-year-old woman with congenital ichthyosiform erythroderma (EIC) begins treatment with NAC formula but is discontinued because of poor tolerance. Case No. 6:3-year-old girl, with epidermolytic Ichthyosis (IE), starts treatment with NAC formula with poor tolerance and is also suspended. The effects of the NAC formula on different types of ichthyosis were evaluated, showing a good safety and efficacy profile in IL and IRLX, however, in EIC and IE, its use was restricted by adverse effects. Treatment with NAC formula has a good response and tolerance in patients with IL and IRLX, so it could be considered in the usual treatment of these patients.

Efecto otoprotector de N acetilcisteína en pacientes sometidos a quimioterapia con cisplatino: revisión de la literatura / Cytoprotective effect of N acetylcysteine patients undergoing chemotherapy cisplatin: literature review

The aim of this publication is to update information regarding auditory damage caused by cisplatin and its possible prevention with N acetylcysteine (NAC). Cisplatin is a drug used in the treatment of various cancers. It has various adverse effects including ototoxicity. Ototoxicity manifests as sensorineural high tone hearing loss variable intensities, usually bilateral, irreversible, and occurs primarily owing to the formation of oxygen derived free radicals that trigger apoptosis. High frequency audiometry and distortion-product otoacoustic emissions are the most sensitive tests for the detection of cisplatin ototoxicity and they are comparable. NAC is a thiol compound used as a mucolytic that can prevent ototoxicity by several mechanisms . In vitro, it has been shown to decrease the damage of inner ear hair cells and auditory neurons . In humans, oral and intratympanic NAC has been tested concomitant to cisplatin chemotherapy with variable results, tending to show less hearing damage produced by cisplatin...

N-acetilcisteína oral no tratamento do fenômeno de Raynaud secundário à esclerose sistêmica: ensaio clínico randomizado, placebo-controlado e duplo-cego / Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: A randomized, double-blind, placebo-controlled clinical trial

Objetivo Avaliar a segurança e a eficácia da N-acetilcisteína (NAC) por via oral sobre o fluxo sanguíneo da microcirculação digital em pacientes com fenômeno de Raynaud (FRy) secundário à esclerose sistêmica (ES). Métodos Este foi um estudo randomizado, duplo-cego e placebo-controlado, no qual 42 pacientes com ES receberam NAC oral na dose de 600 mg, três vezes ao dia (21 pacientes, idade média 45,6±9,5 anos) ou placebo (21 pacientes, idade média 45,0±12,7 anos) durante quatro semanas. O desfecho primário do estudo foi: melhora no fluxo sanguíneo da microcirculação cutânea antes e após estímulo frio avaliado pelo laser Doppler imaging (LDI) nas semanas 0 e 4. A frequência e a gravidade do FRy e o número de úlceras digitais também foram avaliados nas semanas 0 e 4. Os efeitos adversos foram registrados na quarta semana. Resultados Não houve mudança significativa no fluxo sanguíneo digital avaliado pelo LDI antes ou depois do estímulo frio após quatro semanas de NAC ou placebo. Ambos os grupos apresentaram melhora significativa na frequência e gravidade dos ataques de FRy, sem diferença entre os dois. O grupo placebo apresentou três úlceras digitais enquanto o grupo NAC não apresentou úlceras ao final do estudo. NAC foi bem tolerada e nenhum paciente descontinuou o tratamento. Conclusões NAC por via oral na dose de 1.800mg/dia não demonstrou efeito vasodilatador sobre a microcirculação das mãos após quatro semanas de tratamento em pacientes com FRy secundário à ES. .

Objective To evaluate the safety and efficacy of oral N-acetylcysteine (NAC) on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). Methods This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6±9.5 years) or placebo (21 patients, mean age 45.0±12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week. Results There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment. Conclusions NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands’ microcirculation after four weeks of treatment in patients with RP secondary to SSc. .

N-acetylcysteine improves morphologic and functional aspects of ovarian grafts in rats

PURPOSE: To evaluate morphological and functional aspects of the ovarian graft in transplanted rats treated with NAC. METHODS: Female Wistar rats, virgin, 3 to 4 months old, weighing 200-250 grams were used in experiments. The rats have been kept in proper sanitary conditions, receiving food and water ad libitum. Five groups (n=10, each) were constituted: 4 groups treated subcutaneously with NAC, at doses of 150, 300, 600 and 1200 mg/kg (NAC150, NAC300, NAC600 and NAC1200, respectively), one hour of before the ovarian transplantation and control group (GTx) - treated with physiological solution and submitted to ovarian transplantation. The rats were anesthetized and submitted to autologous left ovarian transplantation, without anastomosis in retroperitoneum, and contralateral oophorectomy. During follow-up of 4 or 15 days, the estrous cycle was evaluated by vaginal smears to determine cycle regularity. At the end of 4th or 15th days, rats were re-anesthetized and blood and graft were obtained to estradiol analysis and morphological assessment. Data were analysed by One Way Analysis of Variance (ANOVA) or ANOVA on ranks complemented by Student-Newman-Keuls test. RESULTS: At 4th day, viable follicles in the graft did not altered by NAC treatments. The NAC300 and NAC600 groups showed increasing in follicle atresia (p=0.012) compared to GTx and NAC1200 group. At 15th day, 50% of GTx, NAC150, and NAC300 rats showed regular oestrous cycle; 83% of NAC600 and 100% of NAC1200 rats returned to regular cycle. NAC1200 group showed increasing in primordial follicle compared to GTx, NAC150 or NAC300 (p=0.011). NAC did not interfere in estradiol levels after 4 or 15 days of transplantation. CONCLUSION: In autologous ovarian transplantation, high dose of NAC promotes graft viability with recovery of estrous cycle. .

Assessment of ocular surface toxicity after topical instillation of nitric oxide donors / Avaliação da toxicidade na superfície ocular após instilação tópica de doadores de óxido nítrico

PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.

OBJETIVO: Avaliar a toxidade na superfície ocular de dois compostos doadores de óxido nítrico em modelos ex vivo e in vivo: S-nitrosoglutationa (GSNO) e S-nitroso-N-acetilcisteína (SNAC), em uma matriz de hidroxipropil metilcelulose (HPMC) nas concentrações finais de 1,0 and 10,0 mM. MÉTODOS: As toxicidades de GSNO e SNAC foram avaliadas clinicamente e histologicamente em modelo ex vivo usando globos oculares porcinos recém excisados. Experimentos in vivo foram realizados com 20 coelhos albinos que foram randomizados em 4 grupos (5 animais em cada): Os grupos 1 e 2 receberam instilações de 150 µL de solução aquosa de HPMC contendo GSNO 1,0 e 10,0 mM, respectivamente, em um dos olhos; Os grupos 3 e 4 receberam instilações de 150 µL de solução aquosa de HPMC contendo SNAC 1,0 and 10,0 mM, respectivamente, em um dos olhos. Os olhos contralaterias em cada grupo receberam solução aquosa de HPMC como controle. Todos os animais foram clinicamente avaliados em lâmpada de fenda e os olhos foram pontuados de acordo com o teste de Draize modificado e analisados histologicamente. RESULTADOS: Os globos oculares porcinos não apresentaram sinais de perfuração, erosão, opacidade da córnea ou outros danos graves. Esses resultados foram confirmados pela análise histológica. Não houve diferença entre os olhos dos coelhos tratados e controles de acordo com a pontuação do teste de Draize em todos os grupos (p>0,05). Todas as formulações apresentaram um escore médio menor do que 1 e foram classificadas como "não-irritantes". Não houve evidência de toxicidade tecidual nas análises histológicas em todos os animais. CONCLUSÃO: Soluções aquosas de HPMC contendo GSNO e SNAC em concentrações até 10,0 mM não induzem irritação ocular.

Uso de N-acetilcisteína tópica en ictiosis lamelar / Topical use of N-acetylcysteine in lamellar ichthyosis

La ictiosis lamelar es una genodermatosis que se caracteriza por la presencia de grandes escamas hiperqueratóticas. Hasta la actualidad se utilizaban para su tratamiento diferentes agentes emolientes y queratolíticos tópicos y, en casos severos, retinoides orales. Desde hace algunos años se ha propuesto el uso de N-acetilcisteína tópica al 10% como una nueva opción terapéutica para esta enfermedad, obteniéndose muy buena respuesta y excelente tolerancia.

Lamellar ichthyosis is a genodermatosis characterized by thick hyperkeratotic scales. Therapy of ichthyosis consists mainly in emollients and topical keratolytics agents being oral retinoids the choice for severe cases. In the last years the use of topical N-acetylcysteine 10% has been proposed as a new therapeutic option for this condition, with significant improvement and excellent tolerance

The role of N-acetyl-cysteine in the lung remote injury after hepatic ischemia and reperfusion in rabbits / O papel da N-acetil-cisteína nas lesões pulmonares provocadas à distância pela isquemia e reperfusão hepática em coelhos

PURPOSE: To study the lesions in the lung of rabbits caused by ischemia/reperfusion hepatic (I/R) after the use of N-acetyl-cysteine (NAC). METHODS: Twenty-four rabbits distributed in two groups: control group GI (n = 12) 5 percent glucose solution and experiment group GII (n = 12) NAC. The animals were pre-anesthetized with 1 percent acepromazine maleate and anesthetized with ketamine 10 percent and 2 percent xylazine intramuscularly. The GI and GII were given glucose solution intravenously or NAC 15min before occlusion of the hepatic pedicle (30 min). After the period of reperfusion of 24h (n = 6) or 48h (n = 6), liver and lung samples were collected for histology and immunohistochemistry to assess the impairment of cell. RESULTS: The animals of GII and GII-24h-48h showed parenchyma liver close to normal, when using NAC. The GII and GII-24h-48h showed lower thickness of alveolar cells that GI and GI-24h-48h. The expression of caspase 3 in lung cells GII presented smaller value compared to the GI group. CONCLUSION: N-acetyl-cysteine administered 15min prior to the injury ischemia/reperfusion had a significant protective role by minimizing lung injury and apoptotic morphology in the period observed.

OBJETIVO: Estudar as lesões no fígado e no pulmão de coelhos, provocadas pela isquemia/reperfusão hepática (I/R) moduladas pelo uso da N-acetil-cisteína (NAC). MÉTODOS: Vinte e quatro coelhos distribuídos em dois grupos: Grupo controle GI (n=12) solução de glicose 5 por cento e Grupo experimento GII (n=12) NAC. Os animais foram pré-anestesiados com maleato de acepromazina 1 por cento e anestesiados com cloridrato de quetamina 10 por cento e xilazina 2 por cento via intramuscular. Os grupos GI e GII receberam solução glicosada ou NAC respectivamente via endovenosa 15min antes da oclusão do pedículo hepático (30 min). Após iniciou-se o período de reperfusão por 24h (n=6) ou 48h (n=6), terminada a reperfusão, amostras do fígado e pulmão foram coletadas para a histologia e imunoistoquímica para avaliar o comprometimento celular. RESULTADOS: Os animais do grupo GII-24h e GII-48h apresentaram arquitetura do parênquima hepático próximo do normal, quando se utilizou NAC. Os grupos GII-24h e GII-48h apresentaram menor espessura das células alveolares que os grupos GI-24h e GI-48h. A expressão da caspase 3 nas células pulmonares do grupo GII, apresentou valor menor comparada ao grupo GI. CONCLUSÃO: A N-acetil-cisteína administrada 15min prévios a lesão da isquemia/reperfusão teve um papel protetor significativo minimizando as lesões morfológicas e apoptóticas pulmonares nos períodos observados.

Efeitos da N-acetilcisteína no precondicionamento isquêmico: estudo em corações isolados de ratos / Effects of n-acetylcysteine on ischemic preconditioning: study in isolated rat hearts

OBJETIVO: Avaliar se a N-Acetilcisteína (NAC) altera o Precondicionamento Isquêmico (PC) em corações isolados de ratos usando apenas um ciclo de PC. MÉTODOS: Freqüência Cardíaca (FC), Fluxo Coronariano (FLC) e Contratilidade Miocárdica (dP/dt) foram registradas em 30 corações de ratos Wistar. Após anestesia, os corações foram perfundidos em sistema de Langendorff com solução de Krebs-Hensleit (K-H), equilibrada (95 por cento de O2 e 5 por cento de CO2). GI: Controle (n=6); GII: 20 min. isquemia (n=6); GIII: PC (n=6); GIV 50 µg/ml/min NAC antes do PC (n =6); GV: 100 µg/ml/min NAC antes do PC (n=6). Todos os parâmetros foram mensurados após 15 minutos de estabilização (T0) e T3, T5, T10, T15, T20, T25 e T30 minutos de reperfusão. Significância estatística foi considerada quando P<0,05. RESULTADOS: Foram observadas alterações na FC comparando GI com GII em T20 e T25 e comparando GI com GIII e GIV com GV em T10 e T20 (P<0,05). FLC foi diferente comparando GI com GII em T3 e T5, GI com GIV em T10 e GI com GV em T10 e T25 (P<0,05). dP/dt foi semelhante comparando GIII com GI e GV. GIII apresentou maior dP/dt que GIV, mas sem diferença estatística (P>0,05). dP/dt foi maior no GV comparado com GIV, mas com diferença estatisticamente significativa somente em T30. CONCLUSÃO: Os corações precondicionados tiveram melhor dP/dt, sendo alteradas pelo uso de NAC no GIV e não alteradas no GV.

OBJECTIVE: The aim of this study is to assess if N-Acetylcysteine (NAC) changes the Ischemic Preconditioning (IP) in isolated rat hearts using only one cycle of IP. METHODS: Heart Rate (HR), Coronary Flow (CF) and Myocardial Contractility (dP/dt) were registered in 30 Wistar rat's hearts. After anesthesia the hearts were removed and perfused with Krebes-Hensleit equilibrated solution with 95 percent of O2 and 5 percent of CO2 according Langendorff's method. GI: Control (n=6); GII: 20 min. ischemia (n=6); GIII: IP (n=6); GIV 50 µg/ml/min NAC before IP (n =6); GV: 100 µg/ ml/min NAC before IP (n=6). Parameters were measured after 15 min. of stabilization (T 0) and T3, T5, T10, T15, T20, T25 and T30 min. after reperfusion. Statistical significance was considered when P<0.05. RESULTS: There were changes on HR comparing GI with GII at T20 and T25 and comparing GI with GIII, GIV with GV at T10 and T20 (P<0.05). CF was different comparing GI with GII at T3 and T5, GI with GIV at T10 and GI with GV at T10 and T25 (P<0.05). Myocardial Contractility was similar comparing GIII with GI and GV. GIII had higher dP/dt than GIV but without statistical difference (P>0.05). dP/dt was higher in GV than GIV but with statistically significant difference only at T30. CONCLUSION: dP/dt was better in preconditioned hearts and was changed if using NAC in GIV. The use of NAC didn't change the effects of preconditioning on myocardial contractility in GV.

Management of acute paracetamol poisoning in a tertiary care hospital.

OBJECTIVES: To compare the management of acute paracetamol poisoning with the best evidence available, and to determine the effect of plasma paracetamol level estimation on the management. DESIGN: Descriptive study with an intervention. SETTING: Medical wards of the National Hospital of Sri Lanka, Colombo. PATIENTS: Patients admitted with a history of acute paracetamol poisoning. INTERVENTION: Measurement of plasma paracetamol. METHODS: Data were obtained from the patients, medical staff and medical records. Plasma paracetamol was estimated between 4-24 hours of paracetamol ingestion. The current management practices were compared with the best evidence on acute paracetamol poisoning management. RESULTS: 157 patients were included. The mean ingested dose of paracetamol was 333 mg/kg body weight. Majority of the patients (84%) were transfers. Induced emesis and activated charcoal were given to 91% of patients. N-acetylcysteine was given to 66, methionine to 55, and both to 2. Aclinically important delay in the administration of antidotes was noted; 68% of patients received antidotes after 8 hours of the acute ingestion. Only 31 (26%) had paracetamol levels above the Rumack-Matthew normogram. 74 patients received an antidote despite having a plasma paracetamol level below the toxic level according to the normogram. INTERPRETATION: Management of acute paracetamol poisoning could be improved by following best available evidence and adapting cheaper methods for plasma paracetamol estimation.

Nefropatia induzida por contraste: avaliação da proteção pela n-acetilcisteína e alopurinol em ratos uninefrectomizados / Contrast-induced nephropathy: evaluation of n-acetylcysteine and allopunirol protective effect in uninephrectomized rats

OBJETIVO: A nefropatia por contraste é a terceira causa de insuficiência renal aguda em pacientes hospitalizados. O objetivo deste estudo foi avaliar a ação da n-acetilcisteína e do alopurinol na proteção renal em ratos de ambos os sexos que receberam diatrizoato. MATERIAIS E MÉTODOS: Ratos Wistar adultos jovens, uninefrectomizados e submetidos a restrição hídrica, receberam solução salina (grupo 1: machos; grupo 2: fêmeas), diatrizoato (grupo 3: machos; grupo 4: fêmeas), diatrizoato e n-acetilcisteína (grupo 5: machos), diatrizoato e alopurinol (grupo 6: machos) e diatrizoato e n-acetilcisteína + alopurinol (grupo 7: machos). A filtração glomerular foi avaliada pela creatinina. O teste t de Student e o teste do sinal foram utilizados para análises estatísticas. RESULTADOS: Ratos que receberam diatrizoato apresentaram elevação estatisticamente significante da creatinina sérica, quando comparados aos controles, porém não houve diferença entre os sexos. Os animais que receberam alopurinol não mostraram aumento significante da creatinina, enquanto a administração de n-acetilcisteína não impediu a elevação da creatinina. CONCLUSÃO: O alopurinol mostrou-se mais efetivo que a n-acetilcisteína na proteção funcional renal ao dano induzido pelo diatrizoato de sódio. Não houve diferença entre os sexos na intensidade do dano renal pelo diatrizoato de sódio.

OBJECTIVE: Contrast medium-induced nephropathy is the third most frequent cause of iatrogenic acute renal failure involving inpatients. The present study was aimed at evaluating the protective effect of n-acetylcysteine and allopurinol in both male and female rats receiving diatrizoate. MATERIALS AND METHODS: Thirty-five young adult Wistar rats submitted to hydric restriction were divided into groups as follows: groups 1 and 2 (respectively male and female rats) receiving saline solution; groups 3 and 4 (respectively male and female rats) receiving diatrizoate; group 5 (male rats) receiving diatrizoate and n-acetylcysteine; group 6 (male rats) receiving diatrizoate and allopurinol; and group 7 (male rats) receiving diatrizoate and n-acetylcysteine + allopurinol. The glomerular filtration was evaluated by measurement of creatinine clearance. Student's t-test and the test of signal were utilized for statistical analysis. RESULTS: Animal models receiving allopurinol did not present a significant increase in the creatinine levels, while n-acetylcysteine did not prevent the creatinine levels increase. CONCLUSION: Allopurinol has shown to be more effective than n-acetylcysteine in the renal function protection against sodium diatrizoate-induced damages. No difference has been found between male and female groups as regards the intensity of sodium diatrizoate-induced renal damages.

Comparative study between different routes of n-acetylcysteine administration for patients undergoing coronary artery bypass grafting

Reactive oxygen species [ROS] have been shown to contribute to myocardial stress in patients undergoing coronary artery bypass surgery [CABG] with cardiopulmonary bypass [CPB]. N-acetylcysteine [NAC], a potent anti-inflammatory and antioxidant agent, is known to decrease the production ROS after CPB. The present study was designed to compare the effect of different routes of NAC administration in patients undergoing CABG using CPB on myocardial protection, renal function and clinical outcome. Forty five adult patients scheduled for elective CABG with CPB were randomly allocated to one of three equal groups [15 patients each]. Patients received NAC either intravenously as a bolus of 100 mg/kg over a 15 minute period immediately before skin incision, followed by infusion at 20 mg / kg / h until the end of CPB [Intravenous NAC Group], or received 100 mg / kg into the CPB prime, followed by infusion at 20 mg / kg / h until the end of CPB [NAC in CPB prime Group], or received NAC at a dose of 100 mg / kg within the antegrade cardioplegia [NAC in cardioplegia Group]. Hemodynamic and transesophageal echo [TEE] measurements were recorded before and after separation from CPB. Serial serum creatine kinase MB [CK-MB], Cardiac troponin I [CTnl], Malondialdehyde [MDA] and creatinine levels were evaluated perioperatively over 2 days. Several clinical variables were evaluated after surgery including death, myocardial infarction, bleeding, cerebrovascular accidents, arrhythmias, atrial fibrillation, and intensive care unit [ICU] and hospital lengths of stay. Compared to baseline measurements, CTnl and MDA levels were comparable among the three study groups at the 6th, 24th and 48th postoperative hours. At the Gthand 24th postoperative hours, CTnl and MDA levels were statistically higher in the intravenous group compared to the CPB prime and cardioplegia groups. There was no significant difference between the three groups regarding serum creatinine, serum CK-MB, global LV function and postoperative clinical variables. NAC administration into the CPB prime or within the cardioplegia for patients undergoing CABG using CPB resulted in better myocardial protection compared to intravenous administration. There was no significant change in the clinical outcome and renal function between the three groups

N-acetylcysteine attenuates cyclosporine-induced nephrotoxicity in male albino rats

Cyclosporine A [Cs A] is used for the treatment of autoimmune and inflammatory disorders. However, Cs A-induced nephrotoxicity remains an important clinical problem, and oxidative stress has been implicated as a possible responsible mechanism. We assessed the protective ability of N-acetylcysteine [NAC], an antioxidant, against Cs A-induced nephrotoxicity. Thirty adult male albino rats were used to study the effect of cyclosporine [Cs A] and the action of N-acetylcysteine [NAC] on certain renal parameters; Blood Urea Nitrogen [BUN] and creatinine. Malondialdehyde [MDA] and catalase [CAT] levels were used as biomarker for testing the antioxidant potential of the drug. Endothelin-l[ET-l] levels were estimated in plasma. Animals were randomly assigned into three groups. Group I rats as control, group 2 were treated with Cs A and group 3 with Cs A plus NAC. Cs A administration for 21 days produced elevated levels of MDA and decreased in antioxidant enzyme CAT and deteriorated the renal function as assessed by increased serum Blood Urea Nitrogen [BUN] and creatinine. Plasma ET-l was also elevated as compared to control groups. Oral administration of NAC [140 mg/kg/day] significantly attenuated renal dysfunction, reduced elevated levels of MDA, increased the level of CAT and decreased level of ET- 1. These results indicate that NAC produces a protective mechanism against Cs A-induced nephrotoxicity in rats and suggest a role of Cs A for oxidative stress and the nephroprotective role of NAC against Cs A-induced nephrotoxicity in rats