Paracetamol is the most common drug taken in overdose in the UK. Although it has been used in overdose for about 50 years, there are many aspects of its toxicity and treatment that are not fully understood. In this thesis a series of related studies on paracetamol overdose are reported. The nephrotoxic effects of paracetamol in overdose have long been recognised. To better understand the mechanisms of this effect the effect of acute paracetamol overdose on plasma electrolytes were investigated, both retrospectively and, more intensively, prospectively. The results of these studies showed paracetamol overdose is associated with dose-related hypokalemia, and kaliuresis of short duration (<24h), suggesting a specific renal effect of paracetamol in overdose, perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol. In the third study the possible impact of features at admission, including renal impairment, on outcomes in a large cohort of patients who developed severe liver injury following paracetamol overdose was evaluated retrospectively. The key finding was that plasma creatinine, and gamma glutamyl transpeptidase, at first admission appeared to be useful predictors of poor outcome. The last three studies focus on antidote treatment of paracetamol overdose. Intravenous acetylcysteine (NAC) has been used as treatment of choice for over 30 years in patients who are at risk of hepatotoxicity. There are reports of liver failure and death in patients who have “non-toxic” plasma paracetamol concentrations on the UKL nomogram, and who are therefore not treated. To better understand this, the frequency of liver failure in patients who had low paracetamol was assessed by examining retrospective data from the Scottish Liver Unit over a 12-year period. Similar data was collected in the University of Newcastle upon Tyne by colleagues there. Only a small percentage of patients developed hepatotoxicity when initial paracetamol was low. It was concluded that on a cost-benefit basis the current thresholds for antidote treatment should not be lowered. The final 2 studies examine adverse reactions (ADRs) to NAC, a common clinical problem. The pattern and mechanisms of ADRs in man are not well described or understood. Factors influencing the frequency of adverse effects were studied in a prospective manner. Paracetamol concentration and male gender were protective and family history of allergy was a risk factor for adverse effects in this cohort. In a smaller focussed study the roles of histamine and other biomarkers as underlying pathophysiological mechanisms in ADR occurrence were studied. The severity of ADRs correlated with the extent of histamine release, which was independent of tryptase increase, suggesting a non-mast cell source. The mechanisms by which paracetamol might lessen histamine release require further investigation.

This doctoral dissertation work strived to contribute to the ever expanding knowledge about the mechanisms of polychlorinated biphenyl (PCB) toxicity using dietary strategies. PCBs are a family of persistent environmental pollutants with a wide range of toxicity. The toxicity of PCBs is largely dependent on the congener's chlorination pattern. Of particular interest to this work was 3,3',4,4',5-pentachlorobiphenyl (PCB 126), the most potent of the dioxin-like PCB congeners. I hypothesized that in vivo PCB 126 toxicity will be ameliorated by dietary selenium supplementation, lowered dietary copper, and dietary N-acetylcysteine (NAC) supplementation. Dioxin-like PCBs are known for diminishing hepatic selenium and selenium-dependent glutathione peroxidase (SeGPx), an antioxidant enzyme. In the first study, PCB 126 caused a dose-dependent decrease in hepatic selenium and SeGPx. Supplemental dietary selenium significantly increased hepatic selenium and SeGPx, and decreased incidence of apoptosis in these rats. The results from this study support that selenium plays a protective role, and differences in liver injuries of these rats may be reflected in their selenium status. The dose-dependent increase in hepatic copper caused by PCB 126 was a subject of interest and concern in the next study. Lowering dietary copper levels without negatively affecting the function of the essential antioxidant enzyme copper zinc superoxide dismutase did not result in reduction of PCB 126-induced toxicity. Copper metabolism was unlikely a main target of PCB 126 toxicity as increasing dietary copper did not significantly increase hepatic copper levels. Hepatic copper is highly regulated and likely does not play a significant role in PCB 126-induced toxicity. The effectiveness of NAC on restoring glutathione status and reducing PCB 126 toxicity was tested in the final study. While NAC did not restore glutathione status, NAC supplemented rats had significantly reduced severity of PCB 126-induced liver status. The results of this study are consistent with the theory that NAC has a glutathione-independent effect in improving mitochondrial energy metabolism. It also suggests that PCB 126-induced mitochondrial metabolic disruption of the liver is of greater concern than oxidative stress.

This study determined the effect of N-acetylcysteine (NAC) supplementation on recovery of strength following eccentric muscle injury. Female subjects (n = 21, age = 20.7 ± .10 yr, weight = 68.05 ± 10.3 kg, height = 1.69 ± .07 m) performed one bout of eccentric exercise involving the forearm flexor muscles. Subjects were given a placebo (food-grade cellulose; n = 10) or NAC supplement (10 mg·kg-1 bw·d-1; n = 11) for 7D prior to and 14D following the exercise bout. Maximal Voluntary Contraction (MVC) torque, muscle soreness, range of motion (ROM), and arm circumference were measured at pre-exercise, immediately post-exercise, and at 1D, 3D, 7D and 10D post-exercise. In addition, serum interleukin-6 (IL-6), serum creatine kinase (CK), and serum glutathione were measured. Subjects also completed a food frequency questionnaire to determine the antioxidant content of their diet. There was no difference in the loss and subsequent recovery of muscular strength between the placebo and NAC group immediately post-exercise (26.93 ± 6.4 vs. 24.95 ±9.4 Nm), 1D (27.83 ± 5.7 vs. 26.9 ± 8.5 Nm), 3D (38.35 ± 6.7 vs. 34.69 ± 10.2 Nm), 7D (46.9 ± 8.8 vs. 42.5 ± 11.8 Nm), or 10D (57.83 ± 11.7 vs. 52.92 ± 14.3 Nm) post-exercise (p = .274). In addition, there was no difference in muscle soreness (p = .752), arm circumference (p = .535), ROM (p = .539), serum CK (p = .449), serum glutathione (p = .967), or serum IL-6 (p = .360) at any time point. Scores on the food frequency questionnaire demonstrated that dietary antioxidant intake was not different between groups (41.04 ± 8.04 vs. 33.01 ± 12.6; p = .054). In conclusion, a bout of eccentric forearm flexor exercise resulted in muscle injury and a significant decrease in subjects’ ability to produce force. Supplementation with NAC had no effect on recovery of strength, arm circumference, ROM, serum CK, serum IL-6, or serum glutathione at any time point following the exercise bout. These results demonstrate that NAC has no effect on recovery of strength following eccentric muscle injury.

Class of 2010 Abstract / OBJECTIVES: The purpose of this study was to determine the incidence of contrast induced nephropathy (CIN) for patients receiving a pre-hydration regimen to prevent CIN. METHODS: This was a descriptive retrospective chart review study. Charts were reviewed from Banner Boswell Medical Center and a nephrologist’s office in Sun City, Arizona. RESULTS: There were a total of 12 patients included in the study. The population after completetion of chart reviews consisted of 6 male patients and 6 female patients. The age range of the patients included was 54-90 years old. CIN occurred in zero of the twelve patients. Half of the 12 patients had a decrease in serum creatinine ranging from 0.1- 0.6 mg/dL, 24-48 hours post-diagnostic procedure. CONCLUSIONS: There was no incidence of CIN after the 12 patients received the specific protocol. This study demonstrates the potential for this regimen as a pre-hydration option for individuals undergoing procedures in which radiocontrast is necessitated. A prospective observational study with a larger sample size would be warranted to determine the safety and efficacy of the protocol and increase the validity of the results of this descriptive study.

Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and anti-oxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GABAergic interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in both activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence, the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized levels of DHE oxidation in ganglionic eminence, and ameliorated the migration delay caused by prenatal stress. In adult male offspring, prenatally-stressed mice exhibited anxiety-like behavior on the elevated plus maze, impaired motor learning on the rotarod, cognitive flexibility on the water T-maze task, and deficits in sensorimotor gating in the pre-pulse inhibition task. Prenatally-stressed adult female offspring showed anxiety-like behavior, deficits in sociability and impaired motor learning. Maternal antioxidants prevented anxiety-like behaviors and improved sensorimotor gating in both sexes, and improved habitual learning and cognitive flexibility in adult female mice. Lastly, prenatal stress led to increases in PV+/GAD67+ cell ratios in mFC in male mice, but decreases in female mice, and antioxidant treatments eliminated those differences. Hippocampal GAD67+ cell densities were reduced by prenatal stress and restored by astaxanthin in male mice, and PV+/GAD67+ cell ratio was reduced by prenatal stress and partially restored by N-acetylcysteine in female mice. GAD67+ cell densities across regions correlated significantly with anxiety-like behavior in both male and female mice and social behavior in female mice. Through convergent redox manipulations, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development.

Diss. (sammanfattning) Göteborg : Göteborgs universitet , 2007. / Härtill 5 uppsatser.

Orientador: Sisi Marcondes Paschoal / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T16:04:16Z (GMT). No. of bitstreams: 1 Tangerino_DeboraJulianadosAnjos_M.pdf: 666295 bytes, checksum: d40f37f273e761c768f098ca04d15d89 (MD5) Previous issue date: 2013 / Resumo: A sepse caracteriza-se por uma reação inflamatória sistêmica e um quadro de estresse oxidativo em decorrência da grande formação de espécies reativas de oxigênio (EROs). Há trabalhos que mostram que as plaquetas são importantes neste quadro inflamatório, mas seu verdadeiro papel na sepse ainda não está bem elucidado. Portanto, o objetivo do presente trabalho foi avaliar o efeito temporal do uso do antioxidante N-acetilcisteína (NAC) na resposta inflamatória e na atividade plaquetária em modelo de sepse induzido por lipopolissacarídeo (LPS). Para tanto, ratos controle foram injetados com salina (300 ?l, i.p.) ou NAC (150 mg/kg, i.p.), enquanto os tratados foram injetados com LPS de E. coli (1 mg/kg, i.p.) ou com NAC 30 min ou 6h após a injeção de LPS. Após 48h da injeção de LPS o sangue foi coletado. O número de leucócitos totais e plaquetas foi determinado no sangue periférico. A concentração plasmática de TNF-? foi determinada utilizando kit comercial de ELISA. A agregação plaquetária foi avaliada em agregômetro de dois canais. A determinação de EROs em plaquetas foi feita por citometria de fluxo e a de GMPc por imunoensaio. A determinação da atividade da superóxido dismutase (SOD), glutationa peroxidase (GPx) e glutationa redutase (GR) foi feita através de kits comerciais. O LPS aumentou o número de leucócitos totais e reduziu o de plaquetas no sangue periférico. A NAC, 30 min ou 6h após a injeção de LPS, levou a contagem destas células para números semelhantes ao do grupo injetado com salina ou somente com NAC. A concentração plasmática aumentada de TNF-? nos ratos injetados com LPS foi reduzida por NAC para valores próximos aos encontrados no grupo salina. A agregação plaquetária induzida por ADP (10 ?) não foi afetada por NAC, mas foi 50% menor em ratos tratados com LPS. A inibição da agregação plaquetária foi revertida pela injeção de NAC 30 min ou 6h após a injeção de LPS. O LPS aumentou 2,2 vezes os níveis de GMPc em plaquetas estimuladas com ADP quando comparado com o grupo injetado com salina, o qual foi prevenido por NAC, quer em 30 min ou 6h após a injeção de LPS. Os níveis de GMPc em plaquetas de ratos injetados com NAC foram 45% menores do que os do grupo salina. A produção aumentada de EROs em plaquetas ativadas de ratos injetados com LPS foi reduzida por NAC para níveis semelhantes aos dos controle. A NAC reduziu significativamente a formação de EROs em plaquetas em comparação com o grupo salina. A atividade enzimática da SOD em plaquetas ativadas foi reduzida em 35% por NAC em comparação com o grupo salina. O LPS aumentou, discretamente, a atividade da SOD em plaquetas, sendo este prevenido pelo tratamento com NAC. Diferente do observado com SOD, as atividades enzimáticas da GPx e da GR em plaquetas ativadas foram significativamente aumentadas pelo LPS. A NAC não modificou a atividade da GPx e da GR em comparação com o grupo salina, mas reduziu cerca de 41% e 61% a atividade da GPx e GR, respectivamente, em plaquetas do grupo injetado com LPS. Nossos resultados mostraram que a NAC previne e reverte os efeitos do tratamento de ratos com LPS na atividade plaquetária. O restabelecimento da agregação plaquetária, dos níveis de GMPc e EROs intraplaquetário podem ter sido resultado de uma ação direta de NAC nas plaquetas e/ou em decorrência da melhora do quadro inflamatório do animal / Abstract: Sepsis is an oxidative stress condition characterized by a systemic inflammatory reaction. It has been demonstrated that platelets are important in this inflammatory condition, but their real role in sepsis has not been well elucidated yet. Therefore, the aim of this study was to evaluate the temporal effect of the use of the antioxidant Nacetylcysteine (NAC) in the inflammatory response and platelet activity in a model of sepsis induced by lipopolysaccharide (LPS). Control rats were injected with saline (300 ?l, i.p.) or NAC (150 mg/kg, i.p.), while those treated were injected with LPS from E. coli (1 mg/kg, i.p.) or with NAC 30 min or 6 h after LPS injection. Blood was collected 48 h after LPS injection. Total leukocytes and platelets number was determined in peripheral blood. The plasma concentration of TNF-? was determined using commercial ELISA kit. Platelet aggregation was measured in two-channel aggregometer. Determination of reactive oxygen species (ROS) in platelets was performed by flow cytometry and cGMP by immunoassay. Enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) was determinated using commercial kits. LPS increased the total leukocytes number and reduced platelets in peripheral blood. NAC, 30 min or 6 h after LPS injection, brought the cell counts to the similar values of rats injected with saline or with NAC. The increased plasma concentrations of TNF-? in rats injected with LPS was reduced by NAC to values close to those found in the saline group. ADP (10 ?M)-induced platelet aggregation was unaffected by NAC but was 50% lower in rats treated with LPS. Inhibition of platelet aggregation was reversed by the injection of NAC 30 min or 6 h after LPS injection. LPS increased intraplatelet cGMP levels by 2.2-fold compared to the group injected with saline, which was prevented by NAC either 30 min or 6 hours after LPS injection. cGMP levels in activated platelets of rat injected with NAC were 45% lower than those of the saline group. The increased production of ROS in activated platelets from rat injected with LPS was reduced by NAC to levels similar to the control. NAC significantly reduced the formation of ROS in platelets compared to the saline group. SOD activity in stimulated platelets was reduced 35% by NAC compared to the saline group. LPS slightly increased SOD activity in platelets, which is prevented by treatment with NAC. Different from that observed with SOD, the enzyme activities of GPx and GR in activated platelets were significantly increased by LPS. The NAC did not modify the activity of GPx and GR compared with the saline group, but decreased by 41% and 61% the GPx and GR activities, respectively, in platelets of LPS-injected group. Our results showed that NAC prevents and reverses the effects of in vivo LPS on platelet activity. Restoration of platelet aggregation and of intraplatelet cGMP and ROS levels of LPS-injected rats may be caused by a direct action of NAC in platelets or by the improvement of inflammatory condition in the animal / Mestrado / Farmacologia / Mestra em Farmacologia

Class of 2014 Abstract / Specific Aims: To determine the cost of treatment of oral and intravenous n-acetylcysteine (IV NAC) in acute acetaminophen (APAP) toxicity using the length of treatment and length of hospital stay. Methods: A retrospective chart review of Arizona Poison and Drug Information Center electronic records from 2009-2012 and January-June 2013 were evaluated. The following information was collected: age, sex, use oral or intravenous NAC, length of treatment, length of hospital stay (intensive care unit (ICU) and non-ICU) and use of antiemetic. The mean length of stay (MLOS) was calculated for each group as well as the cost of IV and oral NAC. These means were then compared using t-test for independent groups to test for significance. The average total cost of IV and oral NAC treatment was calculated by using monetary values from primary literature. A sensitivity analysis was performed to test the possible effects of an increase or decrease of the final costs by 5 to 10%. Main Results: Patients (≥18 yrs) being treated with IV or oral NAC for acute APAP toxicity (≤8 hours prior to ingestion) were included in this study. A total of 47 patients met the inclusion criteria. Length of hospital stay was shorter in patients receiving IV NAC (42.5% 24-24hr; 37.5% 48-72hr) compared to patients receiving oral NAC (28.6% 48-72hr, 71.4% >72hrs; p<0.001). Total cost of ICU/non-ICU stay in patients receiving IV NAC ($8,720/$3010) was less than patients receiving oral NAC ($12,321/$4703); however, cost of IV NAC-extended (37hrs) in ICU/non-ICU ($13,153/$5535) was greater than oral NAC. The sensitivity analysis performed demonstrated that an increase or a decrease by 5 to 10% in change of cost does not affect our final conclusion. Conclusion: The cost of treatment of IV NAC is lower due to shorter LOS of patients treated with IV NAC (p<0.001). However, when an extended course of treatment is medically necessary for patients on IV NAC then the cost of treatment with IV NAC exceeds the cost of treatment with oral NAC.

Due to the need for concurrent use of N-acetylcysteine (NAC) and ondansetron in the event of acetaminophen overdose, a Y-site intravenous (IV) apparatus for these drugs would be practical. It is known that nausea and vomiting are common side effects of both acetaminophen overdose and NAC administration. Current standard patient care using NAC involves interruption of IV NAC infusion to give an IV bolus dose of ondansetron, which creates an unnecessary opportunity for healthcare staff errors and patient complications. To evaluate the IV compatibility of NAC and ondansetron, medical grade tubing was connected via a closed-circuit IV pump with separate channels. Doses of NAC were circulated in individual channels based on weight-based dosing protocols (30-kg and 100-kg patient does). Ondansetron (4 mg) was introduced into the flow of NAC using the Y-site. Samples of the circulated solutions were gathered in triplicate at time points of 10, 20, and 30 minutes after combination of ondansetron and NAC. Concentrations of NAC were quantified using a validated high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection. Once the collected samples underwent HPLC-UV analysis, data was produced that showed promise for compatibility between ondansetron and NAC with Y-site infusions. Comparison of NAC concentrations for the channels with and without ondansetron yielded no statistically significant difference between the treatments (p-value of 0.05). From this experiment, we concluded that introduction of ondansetron into the flow of NAC IV would not impact NAC concentration. As mentioned before, this study was conducted using only two doses in vitro, which may be a point for further exploration of a varied number of N-acetylcysteine doses.

Orientador: Regina Paolucci El Dib / Resumo: Cirurgias cardíacas são procedimentos muito eficientes para tratar os sintomas do infarto miocárdico, e para realizar trocas e plastias valvares. Contudo, problemas clínicos ocorrem ao realizar-se tais procedimentos em razão da lesão de isquemia-reperfusão e estresse oxidativo. Ambos, a cirurgia e a circulação extracorpórea (CEC) causam liberação de citocinas inflamatórias (TNF-α, IL-6, IL-10) e ativação de espécies reativas de oxigênio (O2-, H2O2-). Glutationa peroxidase (GPO) é uma enzima antioxidante que exerce papel importante no equilíbrio oxidativo e tem sua atividade limitada pela depleção das reservas de glutationa (GSH). N-acetilcisteína (NAC) é um resíduo acetilado do composto cisteína, e é necessária à ressíntese da glutationa (GSH). Estudos têm demonstrado a ação antioxidante da NAC, e seus efeitos na proteção da função dos pulmões, rins e coração, com resultados conflitantes. Sendo assim, este estudo avaliou o papel da n-acetilcisteína na redução da morbimortalidade de pacientes submetidos a cirurgias cardíacas. Foi realizada uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) e quase-ECRs, sem restrições quanto a línguas. ECRs foram pesquisadas nas seguintes bases de dados: MEDLINE, EMBASE, CENTRAL e LILACS, e a última busca ocorreu em 10 de outubro de 2018. Dois revisores independentes (JEGP, RED) selecionaram e extraíram os dados dos estudos, e a abordagem GRADE foi utilizada para classificar a certeza das evidências para os desfechos ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Cardiac surgeries are very efficient procedures to treat acute myocardial infarction symptoms, and to perform heart valve repair or replacement. Nervertheless, clinical issues arise upon performing such procedures, like isquemia-reperfusion injury and oxidative stress. Both, surgery and the cardiopulmonary by-pass (CPB) cause liberation of inflammatory cytokines (TNF-α, IL-6, IL-10) and activation of reactive oxygen species (O2-, H2O2-). Glutathione peroxidase (GPO) is an enzymatic antioxidant and plays a major role on the oxidative balance, and its activity is limited due to glutathione (GSH) reserve depletion. N-acetylcysteine (NAC) is an acetylated residue of the cysteine compound, and is necessary for glutathione (GSH) resynthesis. Studies have demonstrated the antioxidant action of NAC, and its effects on the protection of lung, kidney and heart functions, although with conflicting results. Therefore, this study evaluated the role of NAC on the reduction of morbimortality of the patients submitted to cardiac surgeries. A Systematic review and metanalysis of randomized controlled trials (RCTs) and Quasi-RCTs, with no restrictions to languages, was performed. RCTs were searched from the following databases: MEDLINE, EMBASE, CENTRAL and LILACS, and the last search date was October 10th, 2018. Two independent reviewers have selected and extracted the data from the studies, and the GRADE approach was utilized to classify the certainty of the evidences for the outcomes assesse... (Complete abstract click electronic access below) / Doutor