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1.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503814

RESUMO

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Assuntos
Acetilcisteína/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Colchicina/uso terapêutico , Cobre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Autofagia/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Colchicina/administração & dosagem , Colchicina/farmacologia , Cobre/administração & dosagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Inflamação , Óxido Nítrico/administração & dosagem , Óxido Nítrico/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
2.
Medicine (Baltimore) ; 99(7): e18882, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32049787

RESUMO

RATIONALE: Procalcitonin (PCT) is used as a biomarker for identifying the occurrence of sepsis. Previous studies have reported high levels of PCT with acetaminophen intoxication without evidence of infection. Here, we report two patients with acetaminophen intoxication with high levels of PCT without showing any symptoms of bacterial infection. PATIENT CONCERNS: This case study examined two unrelated patients with acetaminophen intoxication admitted to emergency at different times. The first patient was admitted to the emergency department after ingesting approximately 8000 mg (153.8 mg/kg) of acetaminophen. On admission, C-reactive protein (CRP), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) were normal. PCT and acetaminophen levels were 31.89 ng/mL and below 0.5 µg/mL, respectively. The second patient was admitted to the emergency department 8 h after ingesting ∼23,600 mg (280.6 mg/kg) of acetaminophen. By the second day of admission, GOT and GPT increased to 2508 and 1473 IU/L, respectively. PCT was 45.66 ng/mL with acetaminophen level at 116.9 µg/mL. Both patients were clear of symptoms associated with bacterial infection. DIAGNOSIS: Acetaminophen intoxication. INTERVENTIONS: N-acetylcysteine was given intravenously to both patients for 20 h per protocol. OUTCOMES: Both patients were discharged without complications. LESSONS: Observations suggests that elevated levels of PCT in patients intoxicated with acetaminophen may be associated with involvement of other organs impacted by cytokine stimuli from sterile inflammation resulting from hepatic damage rather than PCT secretion directly caused by hepatic cell damage.


Assuntos
Acetaminofen/toxicidade , Acetilcisteína/administração & dosagem , Overdose de Drogas/tratamento farmacológico , Pró-Calcitonina/metabolismo , Acetilcisteína/uso terapêutico , Alanina Transaminase/análise , Aspartato Aminotransferases/análise , Proteína C-Reativa/análise , Overdose de Drogas/diagnóstico , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
3.
Am J Kidney Dis ; 75(2): 187-194, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31547939

RESUMO

RATIONALE & OBJECTIVE: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. STUDY DESIGN: Longitudinal analysis. SETTING & PARTICIPANTS: A subset of participants from the PRESERVE trial. EXPOSURES: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. OUTCOMES: MAKE-D and CA-AKI. ANALYTICAL APPROACH: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. RESULTS: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (∼2,000 participants). LIMITATIONS: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. CONCLUSIONS: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.


Assuntos
Acetilcisteína/administração & dosagem , Lesão Renal Aguda/metabolismo , Proteínas da Fase Aguda/metabolismo , Angiografia/efeitos adversos , Meios de Contraste/efeitos adversos , Citocinas/metabolismo , Bicarbonato de Sódio/administração & dosagem , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Administração Oral , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Seguimentos , Depuradores de Radicais Livres/administração & dosagem , Taxa de Filtração Glomerular , Humanos , Infusões Intravenosas , Testes de Função Renal , Masculino , Prognóstico
4.
Food Chem Toxicol ; 135: 111038, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31825855

RESUMO

The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.


Assuntos
Antioxidantes/metabolismo , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Oxidantes/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Tadalafila/farmacologia , Acetilcisteína/administração & dosagem , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Nefropatias/enzimologia , Nefropatias/metabolismo , Masculino , Camundongos , Estresse Oxidativo , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
5.
Med J Aust ; 212(4): 175-183, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31786822

RESUMO

INTRODUCTION: Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. MAIN RECOMMENDATIONS (UNCHANGED FROM PREVIOUS GUIDELINES): The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. MAJOR CHANGES IN MANAGEMENT IN THE GUIDELINES: The new guidelines recommend a two-bag acetylcysteine infusion regimen (200 mg/kg over 4 h, then 100 mg/kg over 16 h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥ 10 g or ≥ 200 mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥ 30 g or ≥ 500 mg/kg should receive increased doses of acetylcysteine.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Analgésicos não Entorpecentes/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Overdose de Drogas/terapia , Administração Intravenosa , Antídotos/uso terapêutico , Austrália , Carvão Vegetal/uso terapêutico , Humanos , Nova Zelândia , Guias de Prática Clínica como Assunto
6.
Braz J Otorhinolaryngol ; 86(1): 30-37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30268784

RESUMO

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. 1mL/kg/day three times in total intraperitoneal (i.p.) Saline (n=5), 500mg/kg/day i.p. three times in total N-acetylcysteine (n=5), i.p. 15mg/kg cisplatin alone (single dose) (n=5) and i.p. 15mg/kg cisplatin plus 500mg/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 4h after cisplatin injection has a potential otoprotective effect against cisplatin ototoxicity. which suggests it could be used in clinical trials.


Assuntos
Acetilcisteína/administração & dosagem , Antineoplásicos/efeitos adversos , Antioxidantes/administração & dosagem , Cisplatino/efeitos adversos , Ototoxicidade/etiologia , Substâncias Protetoras/administração & dosagem , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose , Cóclea/efeitos dos fármacos , Cóclea/patologia , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/patologia , Testes Auditivos , Masculino , Microscopia Eletrônica de Varredura , Ototoxicidade/prevenção & controle , Substâncias Protetoras/farmacologia , Ratos Wistar , Razão Sinal-Ruído , Estereocílios/efeitos dos fármacos , Estereocílios/patologia
7.
Proc Natl Acad Sci U S A ; 117(1): 573-583, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31852820

RESUMO

Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.


Assuntos
Citocromo P-450 CYP1B1/metabolismo , Adutos de DNA/efeitos da radiação , Dano ao DNA/efeitos da radiação , Estrogênios/metabolismo , Distrofia Endotelial de Fuchs/etiologia , Raios Ultravioleta/efeitos adversos , Acetilcisteína/administração & dosagem , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Humor Aquoso/efeitos da radiação , Adutos de DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/metabolismo , DNA Mitocondrial/efeitos da radiação , Modelos Animais de Doenças , Epitélio Posterior/efeitos dos fármacos , Epitélio Posterior/patologia , Epitélio Posterior/efeitos da radiação , Feminino , Depuradores de Radicais Livres/administração & dosagem , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/patologia , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
8.
Surgery ; 167(1): 87-93, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521320

RESUMO

BACKGROUND: Anaplastic thyroid cancer is an aggressive and fatal malignancy. Many advanced cancers are characterized by glucose dependency, leading to oxidative stress and cellular proliferation. Therefore, we sought to determine if a low glucose environment (in vitro) or a ketogenic diet (in vivo) could inhibit anaplastic thyroid cancer tumor growth when combined with the antioxidant N-acetylcysteine. METHODS: In vivo, nude mice were injected with the anaplastic thyroid cancer cell line 8505C (n = 6/group). Group 1 was fed a standard diet; Group 2 was fed a ketogenic diet; Group 3 was given standard diet with N-acetylcysteine (40 mM in the drinking water); and Group 4 was fed ketogenic diet with N-acetylcysteine. Tumor volumes, ketones, and glucose were measured. H&E stains and immunohistochemistry for Ki-67 and Caspase 3 were performed on the tumors. In vitro, 8505C cells were cultured in high glucose (25 mM), low glucose (3 mM), high glucose plus N-acetylcysteine (200 uM), or low glucose plus N-acetylcysteine for 96 hours. We performed CyQUANT proliferation (Thermo Fisher Scientific, Waltham, MA), Seahorse glycolytic stress (Agilent, Santa Clara, CA), and reactive oxidative stress assays. RESULTS: Ketogenic diet plus N-acetylcysteine decreased in vivo tumor volume compared to standard diet (22.5 ± 12.4 mm3 vs 147 ± 54.4 mm3, P < .05) and standard diet plus N-acetylcysteine (P < .05). Blood ketone levels were significantly higher for the mice in the ketogenic diet group compared to standard diet (1.74 mmol/L vs 0.38 mmol/L at week 5, P < .001). However, blood glucose levels were not significantly different between ketogenic diet and standard diet groups. Cells cultured in low glucose plus N-acetylcysteine had significantly reduced proliferation compared to high glucose (98.1 ± 5.0 relative fluorescence units vs 157.8 ± 2.1 relative fluorescence units, P < .001). Addition of N-acetylcysteine to low glucose lowered glycolysis function compared to high glucose (39.0 ± 2.2 mpH/min/cell vs 89.1 ± 13.2 mpH/min/cell, P < .001) and high glucose plus N-acetylcysteine (37.4 ± 2.5 mpH/min/cell vs 70.3 ± 3.3 mpH/min/cell, P < .001). Low glucose plus N-acetylcysteine decreased reactive oxidative stress compared to high glucose (119 ± 34.7 relative fluorescence units vs 277 ± 16.0 relative fluorescence units, P = .014). CONCLUSION: The combination of a ketogenic diet or glucose restriction with the antioxidant- N-acetylcysteine significantly reduced tumor growth in vivo and in vitro. Further studies are warranted to explore these metabolic therapies in anaplastic thyroid cancer.


Assuntos
Acetilcisteína/administração & dosagem , Dieta Cetogênica , Depuradores de Radicais Livres/administração & dosagem , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Administração Oral , Animais , Linhagem Celular Tumoral , Feminino , Glucose/metabolismo , Humanos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Lakartidningen ; 1162019 Nov 01.
Artigo em Sueco | MEDLINE | ID: mdl-31688944

RESUMO

Since the late 1970s N-acetylcystein has been used as an antidote after paracetamol intoxication. The treatment is traditionally given as three consecutive infusions for 20 hours and 15 minutes. The total dose given is 300 mg/kg. Half of this amount is given as a bolus during the first 15 minutes of treatment.  This regime has proven very efficient in avoiding liver injury. However, side effects, caused by histamine release, are common (10-15%). Symptoms as flush, urticaria and, in rare cases, bronchospasm, angioedema and circulatory shock typically appear during the bolus dose and may lead to interrupted and inadequate treatment. In addition, the regime is complicated leading to a risk of administration errors. During the last years several publications have described the use of a model with two infusions instead of three. The first and the second infusions are merged and given over four hours. The third infusion and the total dose are left unchanged. This modified regime has been shown to reduce side effects and seems not to increase the risk of liver injury. As of November 1, 2019, the Swedish Poisons Information Centre will change its recommendations to the new two-infusion protocol.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Antídotos/administração & dosagem , Overdose de Drogas/tratamento farmacológico , Envenenamento/tratamento farmacológico , Acetilcisteína/efeitos adversos , Acetilcisteína/uso terapêutico , Administração Intravenosa , Antídotos/efeitos adversos , Antídotos/uso terapêutico , Humanos , Centros de Controle de Intoxicações , Guias de Prática Clínica como Assunto
10.
PLoS One ; 14(10): e0224087, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31639156

RESUMO

Oocyte cryopreservation is useful for preserving fertility and storing genetic resources. However, the small number of oocytes acquired using conventional treatment to induce superovulation and the reduction of fertility due to cryopreservation represent significant problems. Herein, we vitrified the oocytes derived through high-yield superovulation using inhibin antiserum and equine chorionic gonadotropin (IAS + eCG: IASe) and examined the yield of cryopreserved oocytes and survival rates relative to those of vitrified-warmed mouse oocytes derived through conventional superovulation using equine chorionic gonadotropin (eCG). Furthermore, we investigated the effects of N-acetyl cysteine on the fertility and developmental potential of vitrified-warmed oocytes derived using IASe. Compared with eCG, IASe increased the yield of cryopreserved oocytes and achieved equivalent survival rates. N-acetyl cysteine (0.5 mM) increased the fertilization rate of vitrified-warmed oocytes derived using IASe. Vitrification decreased thiol levels in the zona pellucida (ZP), while warming followed by N-acetyl cysteine treatment increased free thiol levels in ZP. Moreover, N-acetyl cysteine treatment recovered zona hardening by cleaving disulfide bonds and promoting the expansion of ZP. Two-cell embryos derived via in vitro fertilization using N-acetyl cysteine developed into normal pups through embryo transfer. Therefore, we developed an efficient technique for the production of cryopreserved oocytes using IASe through superovulation and found that N-acetyl cysteine improves the fertility of vitrified-warmed oocytes by cleaving the disulfide bonds and promoting the expansion of ZP.


Assuntos
Acetilcisteína/administração & dosagem , Preservação da Fertilidade/métodos , Fertilização In Vitro/métodos , Oócitos/fisiologia , Taxa de Gravidez , Superovulação , Vitrificação/efeitos dos fármacos , Animais , Criopreservação , Transferência Embrionária , Feminino , Depuradores de Radicais Livres/administração & dosagem , Técnicas de Maturação in Vitro de Oócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oócitos/citologia , Gravidez
11.
Arq Gastroenterol ; 56(2): 184-190, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31460584

RESUMO

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.


Assuntos
Acetilcisteína/administração & dosagem , Metformina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Ursodesoxicólico/administração & dosagem , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
12.
Nat Commun ; 10(1): 3533, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387997

RESUMO

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.


Assuntos
Aneurisma Dissecante/prevenção & controle , Aneurisma da Aorta Torácica/prevenção & controle , Cobamidas/administração & dosagem , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Depuradores de Radicais Livres/administração & dosagem , Acetilcisteína/administração & dosagem , Aneurisma Dissecante/genética , Aneurisma Dissecante/patologia , Animais , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Feminino , Mutação com Ganho de Função , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Camundongos , Camundongos Transgênicos , Miócitos de Músculo Liso , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Cultura Primária de Células
13.
Cardiovasc Intervent Radiol ; 42(12): 1777-1785, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392490

RESUMO

PURPOSE: Contrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired acute kidney injury due to the use of iodinated contrast media in various interventional procedures like endovascular aneurysm repair. Its pathophysiology remains mostly unclear. The purpose of the present study was to comparatively study the possible protective role of direct intra-arterial administration of mannitol and acetylcysteine and per os administration of simvastatin in a histopathological level. MATERIALS AND METHODS: In the present study, we administered iopromide directly in the infrarenal aorta of 24 New Zealand white rabbits after laparotomy. Animals were divided in four groups of six: G1 received iopromide with no protection, G2 iopromide with mannitol, G3 iopromide with acetylcysteine, and G4 iopromide with simvastatin. Renal function blood parameters were assessed prior to the administration, and in 48 h; histopathological evaluation of the kidneys was performed. RESULTS: CIN was evident only in the no protection group G1. Moreover, G1 demonstrated significantly more severe lesions than groups G2, G3, and G4 regarding histopathological findings in glomeruli, vacuolization of tubular epithelial cells, tubular proteinaceous casts, and tubular necrosis. According to our results, intra-arterial administration of mannitol seems to be effective in protection against tubular necrosis. CONCLUSION: In general, all three agents demonstrated a protective role in preventing the development of CIN, although it seems that there are various pathways that remain to be investigated further.


Assuntos
Acetilcisteína/uso terapêutico , Lesão Renal Aguda/tratamento farmacológico , Meios de Contraste/efeitos adversos , Manitol/uso terapêutico , Sinvastatina/farmacologia , Acetilcisteína/administração & dosagem , Lesão Renal Aguda/induzido quimicamente , Administração Oral , Animais , Modelos Animais de Doenças , Diuréticos Osmóticos/administração & dosagem , Diuréticos Osmóticos/uso terapêutico , Humanos , Infusões Intra-Arteriais , Iohexol/efeitos adversos , Iohexol/análogos & derivados , Masculino , Manitol/administração & dosagem , Coelhos
14.
Ann Saudi Med ; 39(4): 251-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31381364

RESUMO

BACKGROUND: Colon surgery can cause systemic inflammatory response syndrome (SIRS). There is a recent trend towards the use of antioxidant agents in the prevention or alleviation of the severity of postoperative SIRS, but its use is controversial as studies have shown conflicting results. OBJECTIVES: Investigate the efficacy and tolerability of perioperative intravenous administration of N-acetylcysteine (NAC) as an antioxidant and anti-inflammatory agent in patients undergoing colon surgery. DESIGN: Randomized, double-blinded, and controlled clinical trial. SETTING: Surgical critical care unit in Egypt. PATIENTS AND METHODS: Sixty patients who required admission to the ICU following colon surgery were enrolled in the study between July 2015 and October 2016. Eligibility included the need for parenteral nutrition for at least 5 days due to failure of or contraindication to enteral nutrition. Patients were randomly allocated using a computer-generated list to a loading dose of NAC followed by continuous infusion started one hour prior to induction, and continued over 48 hours, or to the control group, who received the same volume of dextrose 5%. Allocation was concealed using opaque, sealed envelopes under pharmacy control. The researcher, the anesthesiologist, the surgeon, and patients were blinded to the treatment allocation. MAIN OUTCOME MEASURES: Clinical and laboratory evaluation for manifestations of SIRS, serum levels of tumor necrosis factor alpha and malondialdehyde, and occurrence of side effects in the study group. SAMPLE SIZE: 60 patients with mean (SD) ages of 56 (15.1) years in the study group (n=30) and 57.7 (12.3) years in the control group (n=30). RESULTS: There was a significant difference in the mean serum level of ALT (22.6 (9.9) U/L in the study group vs. 31.1 (17.8) U/L in the control group, P=.028) after treatment with NAC, but differences between the groups in the serum level of tumor necrosis factor alpha and malondialdehyde after treatment were not significant. Serum levels of malondialdehyde increased in both groups after treatment P<.001. There was no statistically significant difference from baseline or between the groups after treatment in other clinical data and laboratory parameters following NAC administration, and only 6.6% of the patients in the study group experienced mild side effects. CONCLUSIONS: Preoperative administration of NAC is safe, but its efficacy as an antioxidant and anti-inflammatory agent was not statistically significant and requires further investigation in a larger sample. LIMITATIONS: Single-center study, small sample size, and short duration of NAC administration. CLINICAL TRIALS REGISTRY: NCT03589495. CONFLICT OF INTEREST: None.


Assuntos
Acetilcisteína/administração & dosagem , Antioxidantes/administração & dosagem , Doenças do Colo/cirurgia , Dipeptídeos/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Acetilcisteína/efeitos adversos , Administração Intravenosa , Adulto , Idoso , Antioxidantes/efeitos adversos , Dipeptídeos/efeitos adversos , Método Duplo-Cego , Egito , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Síndrome de Resposta Inflamatória Sistêmica/epidemiologia
15.
Lakartidningen ; 1162019 Jul 29.
Artigo em Sueco | MEDLINE | ID: mdl-31361324

RESUMO

Toxicological analysis is an important part of the acute treatment of various intoxications. Rapid laboratory responses are important for the patient to be assessed and treated correctly, and also to exclude poisoning and thus avoid unjustified and costly overtreatment. In Sweden, paracetamol (acetaminophen) is one of the most common pharmaceuticals in drug poisoning. Paracetamol overdose can cause severe liver damage unless treated early with the antidote acetylcysteine. A nation-wide initiative for improved laboratory measurement of paracetamol in plasma/serum samples has resulted in a marked reduction in the inter-laboratory coefficient of variation to generally below 10%. The introduction of a harmonized national reporting range for plasma/serum paracetamol covering at least 50-5 000 µmol/l was also recommended. This initiative will hopefully contribute to better healthcare from both a patient and health resource perspective in cases of paracetamol poisoning.


Assuntos
Acetaminofen , Analgésicos não Entorpecentes , Serviços de Laboratório Clínico/normas , Acetaminofen/sangue , Acetaminofen/envenenamento , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Analgésicos não Entorpecentes/sangue , Analgésicos não Entorpecentes/envenenamento , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Overdose de Drogas/diagnóstico , Overdose de Drogas/tratamento farmacológico , Humanos , Envenenamento/diagnóstico , Envenenamento/tratamento farmacológico , Guias de Prática Clínica como Assunto , Suécia , Fatores de Tempo
16.
Dtsch Med Wochenschr ; 144(15): 1009-1013, 2019 08.
Artigo em Alemão | MEDLINE | ID: mdl-31350739

RESUMO

Acute kidney injury (AKI) episodes after iodine radiocontrast application are decreasing since non-ionic agents are routinely used. Retrospective studies (in total comprising more than 100 000 patients) DO NOT show increased AKI rates after CT scans with the application of radiocontrast (vs. uncontrasted CT scans). AKI rates are generally higher after intra-arterial (i. a.) compared with intra-venous (i. v.) radiocontrast application - cholesterol embolism due to catheter manipulation does play a role in this setting. Because of the multifactorial pathogenesis the term "contrast-associated AKI" (CA-AKI) should be used preferentially. The AMACING trial, which prospectively evaluated the use of i. v. volume administration before contrast application to prevent CA-AKI, DID NOT show a benefit for volume therapy. Instead, the trial found a significant increase in symptomatic heart failure episodes in patients after volume administrastion. "Hydration" before (emergency) contrasted CT scans therefore can put patients at risk through both volume overload and diagnostic delay. The PRESERVE trial prospectively evaluated the use of volume administration and N-acetyl cysteine (NAC) before i. a. contrast application to prevent CA-AKI. While NAC, which was placebo controlled, did not show any benefit (and therefore should not be used anymore), all patients in the PRESERVE trial received i. v. volume (either sodium chloride or sodium bicarbonate). Interestingly, the incidence of CA-AKI in both groups was below 5 % and hence almost half of what was expected based on previous trials. If the baseline volume status is checked in order to avoid overload, volume administration in patients with i. a. contrast application can be safely performed until definitive data are available. The type of solution can be pragmatically guided by the patient's acid base status. While preventive measures to avoid CA-AKI are limited, the clinical relevance of (any) AKI remains - new data showing increased morbidity and mortality with creatinine increments of onl 0.3 mg/dl. In order to distinguish CA-AKI from other, potentially treatably forms of AKI (e. g. pre- or post-renal AKI), early consultation of a nephrologist seems favorable.


Assuntos
Lesão Renal Aguda , Meios de Contraste/efeitos adversos , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/prevenção & controle , Ensaios Clínicos como Assunto , Estudos Epidemiológicos , Humanos , Tomografia Computadorizada por Raios X/efeitos adversos
17.
Eur Heart J Acute Cardiovasc Care ; 8(5): 443-456, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172789

RESUMO

There is a need to find interventions able to reduce the extent of injury in reperfused ST-segment elevation myocardial infarction (STEMI) beyond timely reperfusion. In this review, we summarise the clinical impact of STEMI from epidemiological, clinical and biological perspectives. We also revise the pathophysiology underlying the ischaemia/reperfusion syndrome occurring in reperfused STEMI, including the several players involved in this syndrome, such as cardiomyocytes, microcirculation and circulating cells. Interventions aimed to reduce the resultant infarct size, known as cardioprotective therapies, are extensively discussed, putting the focus on both mechanical interventions (i.e. ischaemic conditioning) and promising pharmacological therapies, such as early intravenous metoprolol, exenatide and other glucose modulators, N-acetylcysteine as well as on some other classic therapies which have failed to be translated to the clinical arena. Novel targets for evolving therapeutic interventions to ameliorate ischaemia/reperfusion injury are also discussed. Finally, we highlight the necessity to improve the study design of future randomised clinical trials in the field, as well as to select patients better who can most likely benefit from cardioprotective interventions.


Assuntos
Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Doença Aguda , Administração Intravenosa , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Cardiotônicos/uso terapêutico , Exenatida/administração & dosagem , Exenatida/uso terapêutico , Depuradores de Radicais Livres/administração & dosagem , Depuradores de Radicais Livres/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Incidência , Metoprolol/administração & dosagem , Metoprolol/uso terapêutico , Camundongos , Camundongos Transgênicos , Microcirculação/fisiologia , Modelos Animais , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/epidemiologia , Miócitos Cardíacos/patologia , Intervenção Coronária Percutânea/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia
18.
J Dairy Sci ; 102(8): 6920-6922, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178194

RESUMO

The present study investigated the effects of N-acetylcysteine (NAC) on ß-lactam antibacterial activity against 20 methicillin-resistant Staphylococcus aureus (MRSA) isolates from bovine mastitis. Minimum inhibitory concentrations (MIC) were determined by the E-test method. The presence of 10 mM NAC reduced the MIC of penicillin, ampicillin, oxacillin, cefoxitin, ceftazidime, and cefotaxime to MRSA. Importantly, the MIC of cefoxitin in MRSA in the presence of NAC was lower than the susceptible breakpoint of cefoxitin. The results provide a new way to use current ß-lactam antibiotics combined with NAC against MRSA.


Assuntos
Acetilcisteína/farmacologia , Antibacterianos/farmacologia , Mastite Bovina/microbiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , beta-Lactamas/farmacologia , Acetilcisteína/administração & dosagem , Ampicilina/farmacologia , Animais , Bovinos , Cefoxitina/farmacologia , Feminino , Testes de Sensibilidade Microbiana , Oxacilina/farmacologia , Penicilina G/farmacologia
19.
Expert Opin Investig Drugs ; 28(7): 593-603, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31185180

RESUMO

INTRODUCTION: Oxidative stress toxicity (OST) has been implicated in almost all pathological conditions. Despite the widespread use of natural antioxidants, no pharmaceutical antioxidants have yet been developed or prescribed in medical practise. Antioxidant drugs such as Deferiprone and N-acetylcysteine can target essential pathways of OST in many pathological conditions. The pharmacological parameters required by antioxidant drugs in relation to the OST target characteristics include the determination of the therapeutic index, ADMET and drug interactions. Antioxidant drug development efforts are currently targeting the treatment of severe diseases with no proven effective therapies. AREAS COVERED: This article addresses the damaging effects of OST, prospects for the development of pharmaceutical antioxidants and clinical studies using other drugs with antioxidant potential. EXPERT OPINION: Effective antioxidant therapeutic strategies should include the design of protocols for the inhibition of OST through iron chelation, administration of synthetic and natural antioxidants and enhancement of the antioxidant defences by increasing the production of endogenous antioxidants and activation of antioxidant mechanisms. Different therapeutic strategies apply in the use of antioxidant drugs for one or more targets, for prevention, treatment, or of post-treatment effects and for systematic, long-term or short-term applications. The design of new antioxidant drugs and effective protocols which can include Deferiprone and N-acetylcysteine combinations, could lead to the development of a new class of therapeutics for clinical use.


Assuntos
Antioxidantes/farmacologia , Depuradores de Radicais Livres/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Animais , Antioxidantes/administração & dosagem , Deferiprona/administração & dosagem , Deferiprona/farmacologia , Desenho de Fármacos , Desenvolvimento de Medicamentos/métodos , Depuradores de Radicais Livres/administração & dosagem , Radicais Livres , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacologia , Terapia de Alvo Molecular
20.
Clin Pharmacol Ther ; 106(4): 884-890, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31206613

RESUMO

This study assessed the biological and clinical effects in patients with Parkinson's disease (PD) of N-acetyl-cysteine (NAC), the prodrug to l-cysteine, a precursor to the natural biological antioxidant glutathione. Forty-two patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for 3 months or standard of care only. Participants received prebrain and postbrain imaging with ioflupane (DaTscan) to measure dopamine transporter (DAT) binding. In the NAC group, significantly increased DAT binding was found in the caudate and putamen (mean increase from 3.4% to 8.3%) compared with controls (P < 0.05), along with significantly improved PD symptoms (P < 0.0001). The results suggest NAC may positively affect the dopaminergic system in patients with PD, with corresponding positive clinical effects. Larger scale studies are warranted.


Assuntos
Acetilcisteína , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson , Putamen , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacocinética , Administração Oral , Idoso , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Neuroimagem Funcional/métodos , Humanos , Infusões Intravenosas , Masculino , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Putamen/diagnóstico por imagem , Putamen/metabolismo , Avaliação de Sintomas/métodos , Resultado do Tratamento
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