Résumé
SUMMARY: An association between certain food additives and chronic diseases is reported. Current study determined whether administering toxic doses of the food additive monosodium glutamate (MSG) into rats can induce aortopathy in association with the oxidative stress and inflammatory biomarkers upregulation and whether the effects of MSG overdose can be inhibited by vitamin E. MSG at a dose of (4 mg/kg; orally) that exceeds the average human daily consumption by 1000x was administered daily for 7 days to the rats in the model group. Whereas, rats treated with vitamin E were divided into two groups and given daily doses of MSG plus 100 mg/ kg vitamin E or MSG plus 300 mg/kg vitamin E. On the eighth day, all rats were culled. Using light and electron microscopy examinations, a profound aortic injury in the model group was observed demonstrated by damaged endothelial layer, degenerated smooth muscle cells (SMC) with vacuoles and condensed nuclei, vacuolated cytoplasm, disrupted plasma membrane, interrupted internal elastic lamina, clumped chromatin, and damaged actin and myosin filaments. Vitamin E significantly protected aorta tissue and cells as well as inhibited MSG-induced tissue malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). The highest used vitamin E dosage was more effective. Additionally, a significant correlation was observed between the aortic injury degree and tissue MDA, TNF-α, IL-6, and superoxide dismutase (SOD) levels (p=0.001). Vitamin E effectively protects against aortopathy induced by toxic doses of MSG in rats and inhibits oxidative stress and inflammation.
RESUMEN: Se reporta una asociación entre ciertos aditivos alimentarios y enfermedades crónicas. El objetivo de este estudio fue determinar si la administración de dosis tóxicas del aditivo alimentario glutamato monosódico (MSG) en ratas puede inducir aortopatía en asociación con el estrés oxidativo y la regulación positiva de los biomarcadores inflamatorios y si el efecto de una sobredosis de MSG se puede inhibir con vitamina E. Se administró MSG diariamente durante 7 días una dosis de (4 g/kg; por vía oral) que excede el consumo diario humano promedio, en 1000x a las ratas del grupo modelo. Mientras que las ratas tratadas con vitamina E se dividieron en dos grupos y se administraron dosis diarias de MSG más 100 mg/kg de vitamina E o MSG más 300 mg/kg de vitamina E. Todas las ratas fueron sacrificadas en el octavo día. Usando exámenes de microscopía óptica y electrónica, se observó una lesión aórtica profunda en el grupo modelo demostrada por una capa endotelial dañada, células musculares lisas degeneradas (SMC) con vacuolas y núcleos condensados, citoplasma vacuolado, membrana plasmática rota, lámina elástica interna interrumpida, cromatina agrupada y filamentos de actina y miosina dañados. La vitamina E protegió significativamente el tejido y las células de la aorta, además de inhibir el malondialdehído tisular (MDA) inducido por MSG, la interleucina-6 (IL-6) y el factor de necrosis tumoral alfa (TNF-α). La dosis más alta de vitamina E utilizada fue más efectiva. Además, se observó una correlación significativa entre el grado de lesión aórtica y los niveles tisulares de MDA, TNF-α, IL-6 y superóxido dismutasa (SOD) (p=0,001). La vitamina E efectivamente protege contra la aortopatía inducida por dosis tóxicas de MSG en ratas e inhibe el estrés oxidativo y la inflamación.
Sujets)
Animaux , Rats , Aorte/effets des médicaments et des substances chimiques , Maladies de l'aorte/induit chimiquement , Glutamate de sodium/toxicité , Vitamine E/pharmacologie , Aorte/anatomopathologie , Glutamate de sodium/administration et posologie , Vitamine E/administration et posologie , Microscopie électronique , Interleukine-6/antagonistes et inhibiteurs , Facteur de nécrose tumorale alpha/antagonistes et inhibiteurs , Rat Sprague-Dawley , Stress oxydatif/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Malonaldéhyde/antagonistes et inhibiteursRésumé
Resumen Desde la notificación de la pandemia por SARS-CoV-2, agente patógeno responsable del COVID-19, muchos de los tratamientos dirigidos a su manejo han estado sometidos a estudios de manera constante, con el fin de comprobar su eficacia y seguridad. El conocimiento de su virología y etiopatogenia posibilitaría objetivar los pasos moleculares específicos que puedan ser blancos terapéuticos de variados fármacos actualmente disponibles. Esta experiencia proviene principalmente de las infecciones por SARS-CoV y MERS-CoV, con resultados variados 'in vitro' en el SARS-CoV-2, sin evidencia clínica que demuestre efectividad y seguridad de dichos tratamientos. A la fecha, no se ha podido concretar con claridad un esquema de tratamiento específico, debido a que la evidencia surgida ha puesto en jaque cada uno de los fármacos propuestos. Esto ha motivado a continuar en la búsqueda de una estrategia efectiva que permita manejar esta pandemia con la seguridad y eficacia necesaria para que el beneficio terapéutico esté por sobre los posibles efectos adversos que estos esquemas farmacológicos pudiesen presentar. La siguiente revisión pretende mostrar la evidencia disponible a la fecha, definiendo la actividad de cada fármaco en función de su mecanismo de acción.
Since the beginning of the pandemic by SARS-CoV-2, the pathogen responsible for COVID-19, many of the therapeutic options for its management have been under constant revision, in order to verify their safety and efficiency. Knowledge of the viral structure and pathogenesis make it possible to determine the molecular pathways that may be targeted with current available drugs. The experience with these drugs comes mainly from infections caused by SARS-CoV and MERS-CoV, in vitro studies with SARS-CoV-2 that yield variable results, and clinical experience that does not ensure effectiveness and safety of such drugs. To date, it has not been possible to elucidate a specific treatment scheme, because of the constant release of evidence that challenges the usefulness of the proposed drugs. This has motived us to continue seeking for an effective strategy that allows to manage this pandemic in a safe and efficient manner, so that therapeutic benefit surpasses the related adverse drug reactions that can occur. The following review aims to showcase the evidence available to date by defining the activity of each drug based on its mechanism of action.
Sujets)
Humains , Antiviraux/administration et posologie , SARS-CoV-2/effets des médicaments et des substances chimiques , COVID-19/traitement médicamenteux , Plasma sanguin , Ivermectine/administration et posologie , AMP/analogues et dérivés , Chloroquine/administration et posologie , Interleukine-6/antagonistes et inhibiteurs , Interleukine-1/antagonistes et inhibiteurs , Interféron bêta/administration et posologie , Hormones corticosurrénaliennes/administration et posologie , Ritonavir/administration et posologie , Alanine/analogues et dérivés , Lopinavir/administration et posologie , Anticoagulants/administration et posologieRésumé
RESUMO Introdução: Os marcadores pró-inflamatórios desempenham papel importante na severidade de pacientes com COVID-19. Assim, terapêuticas anti-inflamatórias são agentes interessantes para potencialmente combater a cascata inflamatória descontrolada em tais pacientes. Delineamos um ensaio para testar tocilizumabe em comparação com o tratamento padrão, tendo como objetivo melhorar os desfechos por meio da inibição da interleucina 6, um importante mediador inflamatório na COVID-19. Métodos e análises: Este será um estudo aberto multicêntrico, randomizado e controlado, que comparará os desfechos de pacientes tratados com tocilizumabe mais tratamento padrão com o tratamento padrão isoladamente em pacientes com COVID-19 moderada a grave. Como critérios de inclusão, serão exigidos dois dos quatro critérios a seguir: dosagens de dímero D acima de 1.000ng/mL, proteína C-reativa acima de 5mg/dL, ferritina acima de 300mg/dL e desidrogenase lática acima do limite superior do normal. O objetivo primário será comparar a condição clínica no dia 15, conforme avaliação por meio de escala ordinal de 7 pontos aplicada nos estudos de COVID-19 em todo o mundo. O desfecho primário será avaliado por regressão logística ordinal assumindo razões de propensão proporcionais ajustadas pelas variáveis de estratificação (idade e sexo). Ética e disseminação: O TOCIBRAS foi aprovado pelos comitês de ética locais e central (nacional) do Brasil em conformidade com as atuais diretrizes e orientações nacionais e internacionais. Cada centro participante obteve aprovação do estudo por parte de seu comitê de ética em pesquisa, antes de iniciar as inscrições no protocolo. Os dados derivados deste ensaio serão publicados independentemente de seus resultados. Se tiver sua efetividade comprovada, esta estratégia terapêutica poderá aliviar as consequências da resposta inflamatória na COVID-19 e melhorar os resultados clínicos.
ABSTRACT Introduction: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19. Methods and analysis: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex). Ethics and dissemination: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.
Sujets)
Humains , Pneumopathie virale/traitement médicamenteux , Infections à coronavirus/traitement médicamenteux , Anticorps monoclonaux humanisés/usage thérapeutique , Anti-inflammatoires/usage thérapeutique , Pneumopathie virale/physiopathologie , Indice de gravité de la maladie , Brésil , Interleukine-6/antagonistes et inhibiteurs , Pandémies , Anticorps monoclonaux humanisés/pharmacologie , COVID-19 , Anti-inflammatoires/pharmacologieSujets)
Pneumopathie virale/traitement médicamenteux , Infections à coronavirus/traitement médicamenteux , Betacoronavirus/effets des médicaments et des substances chimiques , Acide ascorbique/usage thérapeutique , Évaluation de la technologie biomédicale , Inhibiteurs de l'enzyme de conversion de l'angiotensine/usage thérapeutique , Inhibiteurs des canaux calciques/usage thérapeutique , Héparine/usage thérapeutique , Vancomycine/usage thérapeutique , Mémantine/usage thérapeutique , Chloroquine/usage thérapeutique , Études transversales/instrumentation , Études de cohortes , Interleukine-6/antagonistes et inhibiteurs , Hormones corticosurrénaliennes/usage thérapeutique , Énoxaparine/usage thérapeutique , Azithromycine/usage thérapeutique , Ritonavir/usage thérapeutique , Oséltamivir/usage thérapeutique , Lopinavir/usage thérapeutique , Atorvastatine/usage thérapeutique , Méropénème/usage thérapeutique , Hydroxychloroquine/usage thérapeutique , Antibactériens/usage thérapeutiqueSujets)
Humains , Pneumopathie virale/traitement médicamenteux , Infections à coronavirus/traitement médicamenteux , Betacoronavirus/effets des médicaments et des substances chimiques , Méthylprednisolone/usage thérapeutique , Chloroquine/usage thérapeutique , Interleukine-6/antagonistes et inhibiteurs , Ritonavir/usage thérapeutique , Oséltamivir/usage thérapeutique , Lopinavir/usage thérapeutique , Hydroxychloroquine/usage thérapeutiqueRésumé
Preeclampsia is one of the most frequent and difficult illnesses in pregnancy, which jeopardizes both mother and fetus. There are several diagnostic criteria for preeclampsia. However, the preeclampsia-associated myocardial damage has not been described. In this study, we employed reduced uterine perfusion pressure (RUPP) to generate a rat model of preeclampsia for the evaluation of myocardial damage in late-gestation rats. The expressions of cardiac injury markers were analyzed by immunohistochemistry and ELISA. The arterial pressure and myocardial tissue velocities were also measured. The role of interleukin (IL)-6 in RUPP-associated myocardial damage was further explored. The results showed that RUPP rats had significant myocardial damage, as demonstrated by the high expressions of myoglobin, creatine kinase isoenzyme, cardiac troponin I, and brain natriuretic peptide. In addition, RUPP increased the mean arterial pressure and the early transmitral flow velocity to mitral annulus early diastolic velocity ratio (E/Ea). Furthermore, IL-6 deteriorated these abnormalities, whereas inhibition of IL-6 significantly relieved them. In conclusion, our study demonstrated that RUPP rats displayed myocardial damage in an IL-6-dependent manner.
Sujets)
Animaux , Femelle , Grossesse , Pré-éclampsie/métabolisme , Interleukine-6/métabolisme , Cardiomyopathies/étiologie , Myocarde/métabolisme , Perfusion , Pré-éclampsie/étiologie , Répartition aléatoire , Interleukine-6/antagonistes et inhibiteurs , Rat Sprague-Dawley , Échocardiographie-doppler couleur , Troponine I/métabolisme , Peptide natriurétique cérébral/métabolisme , Modèles animaux de maladie humaine , MB Creatine kinase/métabolisme , Anticorps monoclonaux humanisés/administration et posologie , Anticorps monoclonaux humanisés/métabolisme , Pression artérielle , Coeur/effets des médicaments et des substances chimiques , Coeur/imagerie diagnostique , Cardiomyopathies/métabolisme , Cardiomyopathies/anatomopathologie , Myoglobine/métabolismeRésumé
OBJECTIVES: Several compounds characterized by an olefin linkage conjugated to a carbonyl group have anti-inflammatory properties. The diuretic ethacrynic acid (EA) is a compound of this type. Herein, we tested the hypothesis that ethacrynic acid can modulate the development of ileus after bowel manipulation. METHODS: Groups (n=9) of male C57Bl/6 mice underwent surgical manipulation of the small intestine using a pair of cotton-tipped applicators (MAN). Control animals (CONT) did not undergo any surgical intervention or receive treatment. MAN mice were pre- and post-treated with four intraperitoneal doses of phosphate buffered saline (PBS), EA1 (1mg/kg per dose), or EA10 (10mg/kg per dose). Gastrointestinal transit of non-absorbable FITC-labeled dextran was assessed by gavaging the mice with the tracer 24h after operation and assessing FD70 concentration 120 min later in the bowel contents from the stomach, 10 equally long segments of small intestine, cecum, and two equally long segments of colon. The geometric center for the tracer was calculated for each animal. Expression of interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) transcripts in the ileal muscularis propria was assessed using semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: In control animals, the mean (±SE) geometric center for the transit marker was 9.89±0.47, whereas it was 4.59±0.59 for PBS-treated animals (p<0.05 vs CONT). The geometric center for pre- post treatment with low (1mg/kg) and high (10mg/kg) doses of ethacrynic acid were 7.23±0.97 and 5.15±0.57, respectively. Compared to PBS, treatment with ethacrynic acid (1mg/kg) significantly decreased manipulation-induced IL-6 and iNOS mRNA expression in the wall of the small bowel. CONCLUSIONS: Pre- and post-treatment with ethacrynic acid ameliorates ileus and modulates inflammation in the gut wall induced by bowel manipulation.
Sujets)
Animaux , Mâle , Souris , Transit gastrointestinal/effets des médicaments et des substances chimiques , Interleukine-6/antagonistes et inhibiteurs , Médiateurs de l'inflammation/antagonistes et inhibiteurs , Iléus/anatomopathologie , Nitric oxide synthase type II/antagonistes et inhibiteurs , Acide étacrynique/pharmacologie , Intestin grêle/effets des médicaments et des substances chimiques , Complications postopératoires , RT-PCR , Iléus/chirurgie , Modèles animaux de maladie humaine , Intestin grêle/anatomopathologie , Souris de lignée C57BLRésumé
A circulação extracorpórea (CEC) propicia o desenvolvimento de uma Síndrome de Resposta Inflamatória Sistêmica, com liberação de citocinas responsáveis por várias manifestações clínicas. OBJETIVO: Observar a liberação das citocinas Fator de Necrose Tumoral Alfa (TNF) e Interleucina 6 (IL-6) e verificar as alterações clínicas produzidas em pacientes submetidos à revascularização do miocárdio com CEC, utilizando ou não corticóide. CASUÍSTICA E MÉTODOS: Foram estudados 30 pacientes, sendo 15 (Grupo I) com uso de corticóide (Metilprednisolona, 30 mg/kg) e 15 (Grupo II) sem uso de corticóide. Amostras sangüíneas seriadas foram colhidas, sendo analisadas a liberação de TNF alfa e IL-6, contagem de leucócitos, VHS e glicemia. Foram comparadas a pressão arterial, freqüência cardíaca, temperatura, sangramento pós-operatório, tempo de intubação orotraqueal e necessidade de drogas vasoativas. Na análise estatística foram considerados significativos valores de p 0,05. RESULTADOS: No Grupo I o TNF não foi detectado e a IL-6 foi detectada em 13 pacientes, com níveis variando de 8,6 a 101,8 pg/ml. No Grupo II o TNF foi detectado em 13 pacientes, com níveis entre 5,4 e 231,0 pg/ml. A IL-6 neste grupo foi detectada nos 15 pacientes, sendo seus níveis mais elevados que aqueles encontrados no Grupo I, variando entre 5,5 e 2569,0 pg/ml. Os pacientes do Grupo I apresentaram pressão arterial média mais elevada (7,9 / 0,5 vs 7,3 / 0,4 mmHg), menor necessidade de drogas vasoativas (5 vs 11). Evoluíram com menos taquicardia (105,6 / 5,9 vs 109,3 / 7,2 bpm), temperatura menos elevada (36,5 / 0,2 vs 37,3 / 0,2 C), menor sangramento pós-operatório (576,6 / 119,5 vs 810,0 / 176,2 ml), menor tempo de intubação orotraqueal (11,0 / 2,0 vs 14,6 / 2,9 h) e leucocitose menos acentuada. Os níveis de glicemia só foram significativos (Grupo I > Grupo II) nas amostras colhidas no PO imediato e 1º PO. O VHS não apresentou diferença estatisticamente significativa entre os dois grupos. CONCLUSÕES: A metilprednisolona inibiu significantemente a liberação de citocinas pró-inflamatórias principalmente o TNF. Os efeitos sistêmicos adversos decorrentes da reação inflamatória pós-CEC foram atenuados com o uso do corticóide
Sujets)
Humains , Femelle , Sujet âgé , Syndrome SAPHO , Hormones corticosurrénaliennes/pharmacologie , Circulation extracorporelle/effets indésirables , Interleukine-6/antagonistes et inhibiteurs , Revascularisation myocardique , Syndrome de réponse inflammatoire généralisée/étiologie , Facteur de nécrose tumorale alpha/antagonistes et inhibiteurs , Sujet âgé de 80 ans ou plus , Études prospectivesRésumé
Las infecciones por bacterias gram negativas son una de las primeras causas de muerte en el recién nacido. La depuración de bacterias es deficiente en el neonato, situación que aumenta la susceptibilidad a las infecciones. En este estudio se logró mejorar el patrón de depuración de Klebsiella pneumoniae en ratas wistar recién nacidas inoculadas por vía IP con 800mg/k de fosfatidilcolina de soya (FC), en contraste con el grupo testigo inyectado con PBS(p<0.05). La sobrevida de los animales aumentó (p<0.05), y los cambios leucocitarios se caracterizaron por una mayor leucocitosis y neutrofilia durante el pico de bacteremia en los animales tratados con FC. Los niveles circulantes de interleucina-6 fueron mayores en el grupo de FC, observándose además hematopoyesis extramedular de las series granulocíticas (p<0.05) y de megacariocitos (p<0.01) en el bazo de las ratas del grupo de FC. No se observaron cambios significativos en los depósitos de granulocitos en la médula ósea de ambos grupos. La mejoría de la sobrevida, los cambios leucocitarios y los focos de hematopoyesis extramedular, parecen asociarse al aumento en la producción de IL-6. Los resultados sugieren que la IL-6 participa en el mecanismo de protección; y que la FC induce en este modelo a septicemia experimental. La FC parece comportarse como un inmunomodulador inespecífico de la respuesta aguda a la infección bacteriana