Eficacia y seguridad del uso de maraviroc para el tratamiento de VIH-1 con tropismo ccr5 positivo, en pacientes multidrogorresistentes en estadio sida / Efficacy and safety of the use of maraviroc for the treatment of HIV-1 with ccr5 positive tropism in multidrug-resistant patients in AIDS stage

INTRODUCCIÓN: Antecedentes: El presente dictamen presenta la evaluación de tecnología de la eficacia y seguridad de maraviroc para el tratamiento de pacientes infectados con VIH01 con tropismo CCR5 positivo, multidrogorresistentes, en estadio SIDA. Aspectos Generales: Hacia el final de 2014, alrededor de 36.9 millones de personas en el mundo vivian con VIH. De estas, aproximadamente 1.2 millones murieron por causas relacionadas al VIH ese mismo año. Las terapias antirretrovirales han permitido reducir el número de muertes en un 42% desde el 2004. Tecnología Sanitaria de Interés: Maraviroc es un antagonista del receptor de quimoquina C-Ctipo 5 (CCR5 por sus siglas en inglés) en las membranas de los linfocitos CD4. El receptor CCR5, junto con el receptor de quimioterapina C-X-C tipo 4 (CXCR4 por sus siglas en inglés), son los co´receptores más relevantes en la infección con VIH-1, ya que permiten la fusión de las membranas celular y viral, y la consecuente entrada del ARN viral al citoplasma. METODOLOGIA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de maraviroc para el tratamiento de VIH-1 con tropismo CCR5 positivo, en pacientes multidrogorresistentes en las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de gruposdedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE) y The USA Department of human and health services (DHHS); y especializados en VIH como The British HIV Association (BHIVA), The International \r\nAntiviral Society (IAS), The British Columbia Centre for Excellence in HIV/AIDS (BC-CfE) y The European AIDS Clinical Society. RESULTADOS: Sinopsis de la Evidencia: se llevó a cabo una búsqueda de evidencia científica relacionada al uso de maraviroc como tratamiento de pacientes infectados con VIH-1 con tropismo CCR5, multidrogorresistentes y en estadio SIDA. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: A la fecha (Mayo 2016) no existe evidencia de ensayos clínicos en fase III que \r\ncomparen directamente la eficacia y seguridad de maraviroc vs enfuvirtide en la población de pacientes con SIDA, multidrogorresistentes e infectados con VIH-1 con tropismo CCR5 positivo. Sin embargo, se toma como evidencia indirecta dos ensayos clínicos multicéntricos de fase III que evaluaron la eficacia y seguridad de maraviroc en comparación con placebo, y un posterior análisis de sub-grupo de los mismos, así como estudios sobre los eventos adversos relacionados al uso de enfuvirtide. El Instituto de Evaluación de Tecnologías Sanitarias-IETSI, aprueba por el periodo de 2 años a partir de la fecha de publicación del presente \r\nFiesT Es. dictamen preliminar, el uso de maraviroc para el tratamiento de pacientes infectados con VIH-1 con tropismo CCR5 positivo, multidrogorresistentes y en estadio SIDA, ya que se ha demostrado su eficacia en dicha sub-población de pacientes con VIH-1, y representa un beneficio para la calidad de vida de estos pacientes y un menor costo para la institución.

Newer targeted therapies in psoriasis.

Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted due to chronicity of the disease and frequent remissions and relapses. Many available systemic therapies, however, are unsuitable for chronic administration due to the risk of cumulative toxicity. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. These include approaches targeting antigen presentation and co-stimulation, T-cell activation and leukocyte adhesion, action on pro-inflammatory mediators, and modulating the cytokine balance. Although only preliminary data are available so far and there is limited data supporting their use, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis.

Newer targeted therapies in psoriasis.

Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted due to chronicity of the disease and frequent remissions and relapses. Many available systemic therapies, however, are unsuitable for chronic administration due to the risk of cumulative toxicity. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. These include approaches targeting antigen presentation and co-stimulation, T-cell activation and leukocyte adhesion, action on pro-inflammatory mediators, and modulating the cytokine balance. Although only preliminary data are available so far and there is limited data supporting their use, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis.

Emerging Drugs in the Treatment of Inflammatory Bowel Disease: Beyond Anti-TNF-alpha / 대한소화기학회지

Understanding of the pathophysiology of inflammatory bowel disease (IBD) is constantly evolving and, recently, a number of biologic agents have been developed. They selectively target specific molecule or pathways and correct the imbalance of the gut immune system. Among them, antibody to tumor necrosis factor (anti-TNF-alpha) is the first developed drugs, and it dramatically improved the IBD management. However, more than one-third of the patients do not respond to the drugs due to antibody formation. To increase treatment efficacy, enormous effort to develop novel anti-cytokines which can be an alternative to anti-TNF-alpha has been made. They are anti CD4+ T cell cytokine including interleukin (IL)-12/23 and IL-17 blockers, selective anti-adhesion molecule known as natalizumab, vedolizumab and alicaforsen, T-cell proliferation inhibitor, anti-inflammatory cytokine, immune stimulator, growth factor, and mitogen-activated protein kinase inhibitor. The efficacy and safety of each drugs are under investigation. Some drugs reported very promising data, however, others showed disappointing and different results. In addition, most of the trials were done in a very small number of patients, and there is no trial comparing to anti-TNF-alpha. The present paper reviews the action mechanism, short or long term efficacy and safety of variable drugs other than anti-TNF-alpha in IBD.

New therapies for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease [COPD] is a major global health problem which is increasing throughout the world and a major cause of death. However, current therapies fail to prevent disease progression or mortality. The mainstay of current drug therapy are long-acting bronchodilators; several longer-acting inhaled beta 2-agonists and muscarinic antagonists [and combinations] are now in development. No treatments have so far been shown to suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new targets have been identified. Several mediator antagonists tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment may be more promising. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, NF-[K] B kinase and phosphoinositide 3 kinase-gamma and-delta, but side effects will be a major limitation so that inhaled delivery may be necessary. Perhaps the most promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by theophylline-like drugs, phosphoinositide 3 kinase-delta inhibitors, more effective antioxidants and non-antibiotic macrolides

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

Effect of lecithin with vitamin-B complex and tocopheryl acetate on long-term effect of ethanol induced immunomodulatory activities.

The alcoholic liver disease usually causes overall immunological alterations which might be attributed to hepatic disease, to ethanol action, and/or to malnourishment. In the present study, efficacy of lecithin with vitamin-B complex to treat ethanol induced immunomodulatory activity was compared with the effect of lecithin alone and tocopheryl acetate (vitamin E). Ethanol (1.6 g/kg body wt/day for 12 weeks) exposure increased thiobarbituric acid reactive substance (TBARS) level, while decreased superoxide dismutase (SOD) activity and reduced glutathione (GSH) content in whole blood hemolysate of 8-10 week-old male BALB/c mice (weighing 20-30 g). The activities of transaminase (AST and ALT) enzymes, interleukin (IL)-10 and gamma interferon (IFN-gamma) elevated, while IL-2 and IL-4 reduced in mice serum due to ethanol exposure. These suggested that oxidative stress and immunomodulatory activities were interdependent and associated with ethanol induced liver damage. Lecithin treatment significantly reduced AST (32.44%), ALT (32.09%), IL-10 (25.63%) activities and TBARS content (12.76%) compared to ethanol treated group. However, lecithin with vitamin-B complex treatment, significantly reduced AST (62.83%); ALT (61.96%); IL-10 (35.88%); IFN-gamma (22.55%) activities and TBARS content (31.58%), while significantly elevated GSH content (36.49%) and SOD activity (61.21%). Tocopheryl acetate treatment significantly reduced AST (62.83%); ALT (61.54%); IL-10 (36.35%): IFN-gamma (23.28%) activities and TBARS content (35.84%). while significantly elevated GSH content (28.76%) and SOD activity (62.42%) compared to ethanol treated group. These findings persuasively argued that lecithin with vitamin-B complex was a new promising therapeutic approach in controlling ethanol induced immunomodulatory activities involving liver damage processes. Prevention of oxidative stress with correction of nutritional deficiency caused alteration in the ethanol-induced immunomodulatory activities and associated liver diseases.

Uso de corticosteróides em cirurgia / Use of corticosteroids in surgery

Introdução: o efeito antinflamatório dosglicocorticóides tem implicações clínicas que interferem de forma decisiva na evolução de pacientes submetidosa procedimentos cirúrgicos. Objetivos: realizar uma revisão sobre o uso adequado de corticosteróides emcirurgia. Métodos: Foram coletados e analisados artigos referentes ao emprego de corticoterapia em pacientescríticos, bem como pacientes submetidos a procedimentos eletivos. Todos os artigos foram extraídos do banco de dados Medline.Discussão: Apesar de seusinúmeros efeitos colaterais, é clara na literatura a participação dos corticosteróides na modulação doprocesso inflamatório sistêmico durante uma situação de estresse. A administração de tais drogas durante oprocedimento cirúrgico deriva do seu emprego prévio em pacientes em sepse e cujo prognóstico sofreuconsiderado impacto após sua indicação em maior escala. Conclusões: Concluímos que o uso de corticosteróides nas doses e intervalos definidos promove benefícios a homeostasia dos pacientes submetidos aprocedimento cirúrgicos, bem como, evolução pósoperatória com menor morbidade .

Background: the anti-inflamatory effect of the glicocorticoids have clinical implication in the evolution of patients that go under surgical procedures. Objective: Review the appropriate use of glucocorticoids in surgery.Methods: articles focused in corticotherapy in critically illpatients as well as corticotherapy in patients that go under elective procedures were selected and analyzed. All the articles were selected from Medline data base. Discussion:Despite of its large number of collateral effect, it’s well defined in the literature the use of corticosteroids in themodulation of the systemic inflammatory process along a situation of stress. The administration of this drugs alongthe surgical procedure comes from its usage in patients with sepsis which prognosis suffered important impact after its indication in large scale. Conclusions: we concluded that the use of corticosteroids in doses and defined period of time has benefits in the homeo stasis of patients submitted to surgical procedures as well as a less morbidityin the postoperative time .

Inmunoglobulinas en sepsis y shock septico / Immunoglobulins in sepsis and septic shock

La eficacia clinica de las inmunoglobulinas poliespecificas o anticuerpos monoclonales para tratar pacientes con sepsis severa o shock septico es un motivo de controversia despues de haberse desarrollado numerosos ensayos clinicos. Solo algunos de ellos han podido demostrar un beneficio directo para reducir la mortalidad o este efecto es evidente tras un meta-analisis. La evidencia sostiene que las inmunoglobulinas G poliespecificas reducen la mortalidad en estos pacientes, siendo este efecto mayor para las inmunoglobulinas enriquecidas con IgM. Las mejores indicaciones son sepsis postquirurgicas o pacientes en shock septico precoz con altos títulos de endotoxinemia. Se recomienda tambien indicar inmunoglobulinas intravenosas en el tratamiento de pacientes con shock toxico estreptococcico, evidencia establecida a traves de estudios caso-control y un ensayo clinico randomizado que mostro una clara tendencia al beneficio. La evidencia no apoya a un impacto favorable en mortalidad para anticuerpos monoclonales dirigidos contra lipopolisacaridos bacterianos, otros antigenos bacterianos o contra FNT-alfa. Mas aun, la infusion de antagonistas del receptor recombinante de IL-1 o receptores solubles de FNT-alfa que pudieran atenuar la respuesta inflamatoria, no han demostrado utilidad despues de numerosos ensayos clinicos. Estas herramientas terapeuticas se caracterizan por un alto costo de adquisicion y aun no se han realizado analisis costo-efectividad

Biological agents in rheumatoid arthritis.

Rheumatoid arthritis (RA) is the commonest inflammatory joint disease with considerable morbidity and mortality. Conventional disease-modifying antirheumatic drugs like methotrexate form the cornerstone of therapy. However, they have several limitations in terms of slow onset of action, adverse effects and modest remission and retention rates. Several cytokines are involved in the pathogenesis of RA. Biological agents that specifically inhibit the effects of tumour necrosis factor-a (TNF-a) or Interleukin-1 (IL-1) represent a major advancement in the treatment of RA. By targeting molecules that are directly involved in the pathogenesis of RA, these therapies are proving to be efficacious, highly specific and better tolerated than standard therapies. The use of these agents needs to be monitored carefully for possible side-effects, including the development of infections. Additional anti-cytokine agents for the treatment of RA are under further development.

Níveis de citocinas proinflamatórias e seus antagonistas em pacientes com insuficiência aórtica crônica importante / Proninflamatory cytokine and antagonists levels with chronic severe aortic regurgitation

Realizamos estudo transversal com um grupo homogêneo constituído de 90 pacientes com insuficiência aórtica crônica importante, de etiologia reumática. Foram realizadas dosagens plasmáticas de citocinas proninfmamatórias a saber : Fator de necrose tumoral alfa( TNF ), receptores solúveis de TNF tipo I e II ( sTNFRI e sTNFRII ), interleucina 6 ( IL-6 ) e seu receptor solúvel ( IL-6R ), inteleucina 1-beta ( IL-1B ), antagonista do receptor de IL-1 ( IL1-RA ) e endotelina-1. Realizado o polimorfismo –308 do gene do TNF. Observamos níveis aumentados de TNF, IL-6 e sTNFRI em relação a indivíduos normais. Pacientes sintomáticos e assintomáticos tiveram níveis semelhantes de citocinas. O polimorfismo TNF 1/2 foi mais frequente em indivíduos assintomáticos. O aumento dos diâmetros ventriculares correlacionou-se a diminuição dos níveis de sTNFR II. /We made a transversal study in a homogeneous group of rheumatic patients with chronic severe aortic regurgitation. We determined plasma levels of the following proinflamatory cytokines : Tumor necrosis factor-alpha ( TNF ) and its soluble receptors type I and II ( sTNFR I and sTNFR II ), Interleukin-6 ( IL-6 ) and its soluble receptor ( IL-6R ), interleukin-1 beta ( IL-1 beta ), antagonist of the IL-1 receptor ( IL1-RA ) and endothelin-1. The -308 genetic polimorphism os the TNF gene was made. Plasma levels of TNF, IL-6 and sTNFRI were increased in asymptomatic and symptomatic in relation to controls. There were similar levels of cytokines in asymptromatic and symptomatic patients. The polimorphism TNF 1/2 was more frequent in asymptomatic patients. Increase of ventricular diameters was correlated to decrease...

Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic beta-cell damage

Cytokines produced by immune cells infiltrating pancreatic islets have been implicated as one of the important mediators of beta-cell destruction in insulin-dependent diabetes mellitus. In this study, the protective effects of epigallocatechin gallate (EGCG) on cytokine-induced beta-cell destruction were investigated. EGCG effectively protected IL-1beta and IFN-g-mediated cytotoxicity in insulinoma cell line (RINm5F). EGCG induced a significant reduction in IL-1b and IFN-gamma-induced nitric oxide (NO) production and reduced levels of the inducible form of NO synthase (iNOS) mRNA and protein levels on RINm5F cells. The molecular mechanism by which EGCG inhibited iNOS gene expression appeared to involve the inhibition of NF-kB activation. These findings revealed EGCG as a possible therapeutic agent for the prevention of diabetes mellitus progression.

Role of interleukin-10 as an immuno modulatory cytokine in rheumatoid arthritis

Interleukin-10 [IL-10] levels were measured by specific enzyme linked immunosorbent assay in the serum of rheumatoid arthritis [RA] [n = 52 patients] and in a group of control subjects, including carefully matched 20 healthy volunteers and another 20 patients with osteoarthritis [O A]. IL-10 levles were also, measured in synovial fluid [SF] spicements extracted from 20 patients within the RA group and from all patients within the OA group. From the results obtained it was concluded that IL-10 production is increased in RA with highest values in the more severe cases. It may play a role in B-lymphocyte hyperactivity with subsequent increase in RF and autoantibody production in RA