Uso de fármacos anticorpos monoclonais, imunomoduladores e anti-inflamatórios no tratamento da infecção por COVID-19 / Use of monoclonal antibodies, immunomodulators, and anti-inflammatory drugs in the treatment of COVID-19

O objetivo deste estudo foi realizar o levantamento bibliográfico de artigos científicos e ensaios clínicos sobre a utilização de anticorpos monoclonais, imunomoduladores e anti-inflamatórios como possíveis alternativas terapêuticas para uso em pacientes com COVID-19, com ênfase nos mecanismos de ação e resultados de ensaios clínicos. Foram analisados artigos obtidos na base de dados MEDLINE® e ensaios clínicos disponíveis no site ClinicalTrials no período de 6 de abril a 6 de maio de 2020. Os ensaios realizados com os fármacos apresentados nesta revisão bibliográfica sugerem a viabilidade de uso de algumas dessas drogas como alternativas para tratamento da COVID-19. No entanto, observou-se que, em função do número reduzido de participantes dos estudos disponíveis, é indispensável a continuidade de pesquisas e dos ensaios clínicos com esses medicamentos, para estimar a eficácia dessas drogas no tratamento do SARS-CoV-2, contra o qual ainda não há terapia específica

The objective of this study was to carry out a bibliographic survey of scientific articles and current clinical trials on the use of monoclonal antibodies, immunomodulators, and anti-inflammatories as possible therapeutic alternatives for use in patients with COVID-19, highlighting their mechanisms of action and results of clinical trials. Articles from the MEDLINE® database and clinical trials available on the ClinicalTrials website were analyzedThe tests performed with the drugs presented in this bibliographic review suggest the feasibility of using some of these drugs as treatment alternatives for COVID-19. However, it was observed that the small samples evaluated in these tests make it imperative to proceed with research and clinical trials with these drugs to provide greater evidence of the effectiveness of these drugs in the treatment of the disease caused by SARS-CoV-2, for which there is no specific therapy so far.

Identidade do homem resiliente no contexto de adoecer por câncer de próstata: uma perspectiva cultural / Identity of the resilient man in the context of ill with prostate cancer: a cultural perspective / Identidad del hombre resiliente en el contexto al enfermar por cáncer de próstata: una perspectiva cultural

O estudo objetivou conhecer o contexto do homem resiliente ao adoecer por câncer de próstata. Trata-se de um estudo de caso etnográfico realizado com dois homens sobreviventes ao câncer de próstata, com alto grau de resiliência. Os dados foram coletados no domicílio, no período de abril e maio de 2012, por meio da entrevista semiestruturada em profundidade, de observação participante e do ecomapa. Pela análise dos dados construíram-se duas unidades de sentido: "Identidade do homem resiliente: contextualizando os informantes" e "O homem resiliente descobrindo-se doente". Apreende-se que a identidade de ser homem resiliente, para estes informantes, foi marcada pela diferença histórica e cultural que permeou as suas ações, no processo de adoecimento por câncer de próstata. Considera-se importante que os enfermeiros atentem para os aspectos culturais da saúde do homem, para que este possa sentir-se parte integrante do processo de cura, tornando-se sujeito ativo frente à própria saúde.

The study aimed to understand the context of resilient man when ill with prostate cancer. This is an ethnographic case study conducted with two prostate cancer survival men with a high degree of resilience. The data was collected on their places, in 2012 April and May, using semi-structured in-depth interviews, participant observation and ecomap. For the data analysis, it was built two units of meaning: "Identity of the resilient man: contextualizing the informants" and "The resilient man finding himself ill". It was noticed that the identity of being a resilient man, to these informants, was marked by historical and cultural difference which permeated their actions in the process of being ill with prostate cancer. It is important that nurses pay attention to the cultural aspects of human health, so that they can feel part of the healing process, becoming an active subject facing their own health.

El estudio enfocó conocer el contexto del hombre resiliente al enfermar por cáncer de próstata. Se trata de un estudio de caso etnográfico realizado con dos hombres sobrevivientes al cáncer de próstata con alto grado de resiliencia. Los datos fueron recogidos en el domicilio, en el período de abril y mayo de 2012, por medio de entrevista semiestructurada en profundidad, observación participante y ecomapa. Por el análisis de los datos, se construyeron dos unidades de sentido: "Identidad del hombre resiliente: contextualizando a los informantes" y "El hombre resiliente descubriéndose enfermo". Se comprende que la identidad de ser hombre resiliente, para estos informantes, fue marcada por la diferencia histórica y cultural que hicieron permeables sus acciones en el proceso de enfermar por cáncer de próstata. Se considera importante que los enfermeros estén atentos a los aspectos culturales de la salud del hombre, para que este se pueda sentir parte integrante del proceso de cura, tornándose sujeto activo frente a la propia salud.

Avanços recentes no emprego de imunobiológicos nas doenças alérgicas / Recent advances in the use of biologicals in allergic diseases

O uso de imunobiológicos, já consagrados como importantes avanços terapêuticos na Reumatologia, para o tratamento de pacientes com doenças autoimunes do tecido conjuntivo, e na Gastroenterologia, no manejo de pacientes com doenças intestinais inflamatórias, inicia uma trajetória também muito promissora no controle mais eficaz de várias condições em Alergia-Imunologia, incluindo asma grave eosinofílica, urticária crônica espontânea, dermatite atópica, e esofagite eosinofílica. É possível que futuramente, tal como na Oncologia, possam ser empregadas várias combinações de drogas visando um melhor controle da alergia, baseado sempre que possível na caracterização dos diversos endótipos e fenótipos estabelecidos. No presente artigo, é feita uma revisão objetiva e atualizada de vários agentes imunobiológicos em Alergia: omalizumabe (anti-IgE), anti-IL-5 (mepolizumabe, reslizumabe e benralizumabe), dupilumabe (anti-subunidade alfa do receptor de IL-4), quilizumabe (anti-receptor M1 prime de membrana da IgE nas células-alvo), anti-TSLP (AMG 157), e lebrikizumabe (anti-IL-13). Futuramente, novos agentes imunoterapêuticos poderão surgir, com potencial de melhorar as atuais estratégias para tratamento das doenças alérgicas mais complexas e graves, de difícil controle...

The use of biologicals, currently recognized as an important therapeutic advance in the fields of rheumatology – in the treatment of patients with autoimmune connective tissue disorders – and gastroenterology – in the management of patients with inflammatory bowel disease – has also shown promising results in terms of a more effective control of different conditions in the field of allergy and immunology, including severe eosinophilic asthma, chronic spontaneous urticaria, atopic dermatitis and eosinophilic esophagitis. Similarly to what has been seen in oncology, it is possible that, in the future, several drug combinations can be used with the aim of better controlling atopic conditions, whenever possible based on the characterization of established endotypes and phenotypes. This article presents an objective, up-to-date review of the use of different biologicals in allergy, namely, omalizumab (anti-IgE), anti-IL-5 (mepolizumab, reslizumab,and benralizumab), dupilumab (anti-alpha subunit of the IL-4 receptor), quilizumab (anti-M1 prime membrane receptor of IgE in target cells), anti-TSLP (AMG 157), and lebrikizumab (anti-IL-13). In the future, other biological agents may be developed, with the potential to improve the treatment strategies currently available for more severe, complex, difficult-to-control allergic diseases...

Respostas fisiológicas e de desempenho de leitões suplementados com B-glucanos e desafiados imunologicamente / Phisiologial responses and growth performance of immune challenged piglets supplemented with B-glucans

O estudo buscou avaliar as respostas fisiológicas e de desempenho à adição de diferentes níveis de β-glucanos na dieta de leitões recém-desmamados. Foram utilizados 30 machos de linhagem comercial, com 34 dias de idade e peso de 10,9±0,63kg, alojados em gaiolas individuais, durante 14 dias. Os tratamentos variaram somente nos níveis de β-glucanos que foram de 35, 70, 140 e 280g/T. No final desse período, em metade dos animais foram injetados 2,7mg de lipopolissacarídeo (LPS) em 1mL de solução (PBS)/leitão, e nos demais 1mL/leitão de PBS. Foram avaliadas temperatura retal (TR), frequência respiratória (FR), perfil bioquímico sanguíneo e sinais clínicos aos 30, 90, 120 e 390 minutos seguintes à injeção. As respostas de desempenho não foram afetadas pelos níveis de β-glucanos. Foi observado o aumento de TR, tanto em função do LPS como em função da hora em que a temperatura foi medida. No entanto, os animais LPS-injetados, que receberam 280g/T de β-glucanos, tiveram a mesma TR daqueles LPS-não injetados. Os sinais clínicos foram compatíveis com um quadro de inflamação aguda e foram observados, nos animais LPS-injetados, vômito, prostração e diarreia, sendo que a inclusão de β-glucanos não conseguiu reverter esses sintomas. O uso de β-glucanos por 14 dias na dieta de leitões recém-desmamados mostrou um efeito anti-inflamatório em situação de desafio agudo. Para reverter o desafio imunológico utilizado, o nível de 280g/T de β-glucanos mostrou-se o mais recomendado.

This study was done to evaluate immunological responses and performance of weaning piglets receiving diets with different levels of β-glucans. Thirty males from a commercial line with 34 days of age and 10.9±0,6kg initial weight were housed in individual metabolic cages during 14 days. The treatments only differed in β-glucans levels: 35; 70; 140 and 280g/T. On the 14th day, half of the pigs were inoculated with 2.7mg LPS (lipopolysaccharide)/mL of solution (PBS)/pig and the other half received 1mL PBS/pig. Rectal temperature (RT), respiratory frequency (RF), biochemical profile and animal behavior (120 and 390 minutes after LPS inoculation) were evaluated. As the experiment was conducted, performance was not affected by β-glucans. An RT increase was observed due to LPS and time of temperature measurement. LPS-injected animals receiving 280g/T of β-glucans had the same RT as the LPS- non injected group. Clinical signs were near the expectation for acute inflammation. LPS-injected presented prostration, diarrhea and vomit and the β-glucans did not reverse this situation. The use of β-glucans in weaning pigs for fourteen days showed an anti-inflammatory action. To revert the immunologic challenge, the level of 280g/T of β-glucans was the most recommended.

A reconstituted HDL containing V156K or R173C apoA-I exhibited anti-inflammatory activity in apo-E deficient mice and showed resistance to myeloperoxidase-mediated oxidation

It has been hypothesized that blood infusion of reconstituted HDL (rHDL) is a possible therapeutic strategy for the treatment of coronary artery disese. To compare short-term anti-inflammatory activity of wildtype (WT) apoA-I and point mutants, each rHDL containing WT, V156K, or R173C was infused into apo-E deficient atherosclerotic mice. Each rHDL was injected via the tail vein at a dosage of 120 mg/kg of body weight in 0.4 ml of tris-buffered saline (TBS), and blood was then collected at 24 and 48 h post-injection. Although regression activity was observed in each of the rHDL infused groups, a 30% reduction in the lipid-stained area of the aortic sinus was observed in the V156K and R173C-rHDL groups when compared to that of the WT-rHDL group, and this reduction was well correlated with an approximately 60% reduction in the accumulation of macrophages in the lesion area. Additionally, the groups that received the V156K and R173C-rHDL treatments showed smaller increases in the GOT, GPT, interleukin-6, myeloperoxidase (MPO) and lipid hydroperoxide (LPO) serum levels than those that received the WT-rHDL treatment. In addition, the strongest serum paraoxonase and ferric reducing ability was observed in the V156K and R173C-rHDL groups. In vitro nitration and chlorination of apoA-I by MPO treatment revealed that V156K-rHDL and R173C-rHDL were less susceptible to chlorination. Furthermore, rHDL treatment inhibited cellular uptake of oxidized LDL by macrophage cells and the production of proatherogenic species in culture media. In conclusion, blood infusions of the rHDLs exerted in vivo regression activity with anti-inflammatory and antioxidant activity in apo-E deficient mice and THP-1 cells, especially in those that were treated with V156K and R173C apoA-I.

Effect of sildenafil citrate on interleukin-1beta-induced nitric oxide synthesis and iNOS expression in SW982 cells

The purpose of this study was to identify the effect of sildenafil citrate on IL-1 beta induced nitric oxide (NO) synthesis and iNOS expression in human synovial sarcoma SW982 cells. IL-1 beta stimulated the cells to generate NO in both dose- and time-dependent manners. The IL-1 beta -induced NO synthesis was inhibited by guanylate cyclase (GC) inhibitor, LY83583. When the cells were treated with 8-bromo-cGMP, a hydrolyzable analog of cGMP, NO synthesis was increased upto 5-fold without IL-1 beta treatment suggesting that cGMP is an essential component for increasing the NO synthesis. Synoviocytes and chondrocytes contain strong cGMP phosphodiesterase (PDE) activity, which has biochemical features of PDE5. When SW982 cells were pretreated with sildenafil citrate (Viagra), a PDE5 specific inhibitor, sildenafil citrate significantly inhibited IL-1 beta -induced NO synthesis and iNOS expressions. From this result, we noticed that PDE5 activity is required for IL-1 beta -induced NO synthesis and iNOS expressions in human synovial sarcoma cells, and sildenafil citrate may be able to suppress an inflammatory reaction of synovium through inhibition of NO synthesis and iNOS expression by cytokines.

Reversión del eclipse inmunológico y vacunación terapéutica contra el cáncer en un modelo experimental / Reversion of the immunological eclipse and therapeutic vaccination against cancer in an experimental model

Aunque existen vacunas para prevenir la aparición de tumores en animales de experimentación, la mayoría de los intentos por aplicar aquellas vacunas con fines terapéuticos contra tumores establecidos no han sido exitosos. Para comprender la naturaleza de esta refractariedad, estudiamos un tumor de ratón fuertemente inmunogénico inducido por el carcinógeno químico metilcolantreno. En nuestro modelo, el inicio de esta refractariedad coincidió con el comienzo de un estado de inmunosupresión conocido como "eclipse inmunológico" caracterizado por una pérdida o bloqueo de la respuesta inmune antitumoral después que el tumor ha superado cierto tamaño crítico. Este eclipse inmunológico fue acompañado por un proceso de inflamación sistémica en el organismo. El tratamiento de los ratones portadores de tumor con una única dosis del corticoide sintético dexametasona (DX) redujo los parámetros de inflamación sistémica e indujo la reversión del eclipse. Esta reversión no fue por sí misma curativa pero permitió que un tratamiento inmunológico basado en células dendríticas estimuladas con antígenos tumorales, que por sí solo era absolutamente ineficaz, pudiera ejercer un significativo efecto inhibidor sobre un tumor en crecimiento. El esquema de dos pasos que comprende, primero, un tratamiento antiinflamatorio para revertir el eclipse y segundo, una estrategia de vacunación basada en células dendríticas destinada a estimular la respuesta inmune antitumoral, podría servir, eventualmente, como un modelo de inmunoterapia contra tumores en animales y seres humanos.

Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the anti-tumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors.