Eficacia y seguridad de Molnupiravir para el tratamiento de COVID-19: actualización enero 2022 / Eficacia y seguridad de Molnupiravir para el tratamiento de COVID-19: nueva actualización 2022

INTRODUCCIÓN: El virus SARS-CoV-2, sigue presentando múltiples variantes, el espectro de la enfermedad es amplio e incluye desde cuadros leves y autolimitados hasta neumonía atípica severa y progresiva, falla multiorgánica y muerte. Actualmente, existen vacunas eficaces para prevenir COVID-19, y se están desarrollando otras más nuevas para la prevención del COVID-19 grave, asimismo algunos medicamentos muestran resultados promisorios para prevenir y combatir esta enfermedad. Sin embargo, se carece de fármacos antivirales eficaces para combatir esta enfermedad. Aunque algunos de los medicamentos han recibido recientemente una autorización de uso de emergencia (EUA) para COVID-19, todos estos agentes farmacéuticos deben administrarse en entornos hospitalarios. Este documento fue elaborado para actualizar la evidencia científica disponible respecto a la eficacia y seguridad de Molnupiravir en el tratamiento de COVID-19. OBJETIVO: El objetivo de este documento es actualizar la evidencia científica disponible respecto a la eficacia y seguridad de Molnupiravir en el tratamiento de COVID-19, mejorando los desenlaces de los pacientes, y/o previniendo la enfermedad COVID-19 causada por el virus SARS-CoV-2. MÉTODOS: En la SNT N° 08-2021: E

Eficacia y Seguridad de Molnupiravir para el tratamiento de COVID-19 / Efficacy and Safety of Molnupiravir for the treatment of COVID-19

ANTECEDENTES: El presente informe se realiza a solicitud del Viceministerio de Salud Pública del Ministerio de Salud, y tiene como objetivo identificar la evidencia disponible respecto a la eficacia y seguridad de Molnupiravir en el tratamiento de COVID-19. MÉTODOS: Se realizó una búsqueda en la plataforma Living Overview of the Evidence (L·OVE) de la Fundación Epistemonikos que consulta 10 bases de datos incluyendo Medline, EMBASE, LILACS, medRxiv (un servidor de distribución de manuscritos aún no publicados, sin certificación de revisión por pares) entre otros. La búsqueda se realizó el 13/08/2021. Los detalles de la metodología de búsqueda utilizada por L.OVE se encuentra disponible en: https://app.iloveevidence.com/loves/5e6fdb9669c00e4ac072701d?population=5e7fce7e3d05156b5f5e 032a§ion=methods&classification=all. Adicionalmente se consultó el Registro Cochrane Central de Ensayos Controlados (CENTRAL) y Clinicaltrials.gov de los Institutos de Salud Pública de Estados Unidos (NIH) para identificar los ensayos en curso. La pregunta PICO abordada es: ¿Cuál es la eficacia y seguridad de Molnupiravir para el tratamiento de COVID-19? Ensayos clínicos controlados que reporten la eficacia y seguridad para al menos uno de los desenlaces de interés. Idioma: inglés o español. Se excluyeron estudios preclínicos, series de casos, reportes de casos, reportes breves y cartas al editor. RESULTADOS: La búsqueda sistemática identificó 34 artículos, a la lectura de título y resumen fueron seleccionados 11, solo 3 respondían a la pregunta PICO. Características de los estudios incluidos: Se identificaron 03 estudios que cumplieron con los criterios de selección: 2 ensayos clínicos en fase I y uno en fase II. Dentro de los resultados, 2 de los reportes corresponden a manuscritos no publicados ni certificados por una revisión por pares, lo que implica que éstos podrían modificar sus resultados y/o conclusiones en sucesivas versiones hasta su publicación y no es posible garantizar que respondan satisfactoriamente la revisión por pares y sean finalmente publicados. CONCLUSIONES: Se identificaron 3 estudios, dos ensayos clínicos de fase I y uno de fase II. Dos ensayos evalúan la seguridad y tolerabilidad de una dosis de Molnupiravir comparada con placebo o cuidado estándar para ser usada en otra fase. Los estudios de fase I, reportan la incidencia de eventos adversos evaluados para el uso de Molnupiravir en dosis desde 200 hasta 800 mg vía oral. Sin embargo, recomiendan la dosis de 800 para futuros estudios. Un estudio de fase II, sugiere el uso de Molnupiravir para reducir la replicación del virus en etapas tempranas de la enfermedad, siendo que en el grupo en el que se presentaron mejores resultados fue con la dosis de 800 mg en solo 55 participantes comparado con 62 participantes en el grupo de 400 mg, 23 en el grupo de 200 mg y 62 en el grupo placebo. No existe evidencia sobre la eficacia o efectividad del uso de Molnupiravir para el tratamiento profiláctico, o terapéutico contra COVID-19, pues los ensayos clínicos desarrollados aún se encuentran en fases iniciales para determinar la dosis adecuada con mejores resultados clínicos.

Recomendaciones en el tratamiento actual de la infección crónica por el virus de la hepatitis B / Current recommendations for the treatment of chronic hepatitis B infection

La infección crónica por el virus de la hepatitis B (VHB) se considera un problema de salud pública mundial. Se estima que al menos dos mil millones de personas han estado expuestas al VHB, y a pesar de una vacuna efectiva, 300 millones de personas están infectadas crónicamente a nivel mundial. Aunque el virus no es directamente citopático, la infección puede desencadenar cirrosis hepática y aun, carcinoma hepatocelular (CHC). El ADN circular cerrado covalentemente (ADNccc) en el núcleo de los hepatocitos y la incapacidad del sistema inmunitario para eliminar la infección crónica por el virus son los mecanismos más importantes de la infección por VHB. Las diferentes entidades, como la Asociación Europea para el Estudio del Hígado (EASL) y la Asociación Americana para el Estudio de las Enfermedades Hepáticas (AASLD), ponen a disposición las pautas para el manejo de esta enfermedad. A pesar de los avances en el tratamiento de la infección crónica por el VHB, en particular con el desarrollo de los análogos de los nucleótidos/ nucleósidos, quedan aún muchos interrogantes. Las investigaciones continúan para el desarrollo de nuevas opciones de tratamiento enfocadas principalmente en evitar que la suspensión de la terapia conlleve a un incremento de la carga viral, con el consecuente aumento del riesgo de progresión de la enfermedad hepática, y un eventual CHC.

Chronic hepatitis B virus (HBV) infection is considered a global public health problem. It is estimated that at least two billion people have been exposed to HBV, and despite an effective vaccine, 300 million people are chronically infected worldwide. Although the virus is not directly cytopathic, the infection can trigger liver cirrhosis and even hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) in the nucleus of hepatocytes and the inability of the immune system to eliminate chronic virus infection are the most important mechanisms of chronic HBV infection. Different entities, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), provide guidelines for the management of this disease. Despite advances in the treatment of chronic HBV infection, including the development of nucleotide and nucleoside analogs, many questions remain. Research continues for the development of new treatment options focused mainly on avoiding a relapse on viral load after therapy discontinuation, with an increased risk of liver disease progression, and an eventual CHC.

Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs

We aimed to investigate the influence of regulatory T cells including CD4+CD25+, CD8+CD28- and hepatitis B virus (HBV) genotype on sustained virological response and tolerance of nucleoside drugs. One hundred and thirty-seven patients were enrolled. Lamivudine was administered to 84 patients. Entecavir was administered to the other 53 patients. Before treatment, biochemical tests, HBV DNA load, HBV serum level, HBV genotype, PB CD3+, CD4+, CD8+, CD4+CD25+/CD3+, and CD8+CD28-/CD3+ frequencies were measured. Based on HBV DNA loads after 4 weeks of therapy, patients were divided into response group and suboptimal response group. The lamivudine group received treatment continuously, and then patients were categorized into non-resistance group and resistance group. Compared with the suboptimal response and resistance groups for lamivudine, CD4+CD25+/CD3+ levels were higher in the response and non-resistance groups (t=4.372, P=0.046; t=7.262, P=0.017). In the non-resistance group, CD8+CD28-/CD3+ frequency was lower than in the resistance group (t=5.527, P=0.037). Virus load and hepatitis B E antigen (HBeAg)-positive rate were significantly lower than in the response and resistance group (t=2.164, P=0.038; X2=4.239, P=0.040; t=2.015, P=0.044; X2=16.2, P=0.000). Incidence of drug resistance was high in patients with virogene type C. For the virological response to entecavir, CD8+CD28-/CD3+ level was significantly lower than that of the suboptimal response group (t=6.283, P=0.036). Response and suboptimal response groups were compared in CD3+, CD4+, CD8+, CD4+CD25+/CD3+ and virus genotype, and differences were not statistically significant (P>0.05). Baseline regulatory T cells including CD4+CD25+/CD3+ and CD8+CD28-/CD3+ frequencies have a relationship with the incidence of rapid virological response and the resistance to nucleoside drugs. Patients with HBV genotype C receiving lamivudine more often underwent drug resistance. Antiviral efficacy and the resistance to lamivudine were closely correlated with baseline factors; the same cannot be found for entecavir.

Derivados de lignina de DNA como agentes modificadores no desenvolvimento de sensores voltamétricos / Lignin derivatives and DNA as modificating agents in the development of voltammetric sensors

Neste trabalho, 2 diferentes procedimentosforam utilizados para a extração de lignina a partir do licor negro, caracterizando-se quimicamente as amostras de lignina obtidas em relação a umalignina comercial, visando a aplicação no desenvolvimento de sensores voltamétricos. A análise elementar, espectroscopia na região do infravermelho, análise térmica e caracterização eletroquímica do material mostraram que, tanto a origem da lignina quanto a metodologia de obtenção da mesma, a partir do licor negro, podem fornecer materiais com propriedades químicas distintas, embora possuam comportamento eletroquímico similar. Observou-se, também, que a lignina só pode ser armazenada na forma sólida,devido à oxidação pelo oxigênio dissolvidodurante o tempo em que a solução mãe é armazenada.No entanto, a oxidação dalignina é necessária quando se tem por objetivo o desenvolvimento de sensores voltamétricos, devido a predominância de carbonos sp2na estrutura químicaoxidada, condição em que se obtém maior condutividade. Constatou-se também a necessidade de utilizar um transdutor metálico para o desenvolvimento de eletrodos qumicamente modificados com este material, visto que os eletrodos de carbono modificados com lignina oxidada ou não oxidada não apresentaram atividade eletroquímica. Devido à pequena porcentagem de enxofre existente na estrutura química, a lignina oxidada tende a se organizar pelos grupamentos SH quando na presença de ouro, expondo os grupamentos quinônicos eletroativos. A lignina oxidada ainda foi utilizada no preparo de eletrodo de pasta de carbono com nanopartículas de ouro, na qual a lignina oxidada impregnada no grafite atua como redutor "in-situ" do ouro, permitindo o preparo de um sensor voltamétrico versátil, capaz de realizar a determinação de ácido ascórbico, dopamina, nitrito e iodato. No que tange ao comportamento eletroquímico de fármacos e estudos de interação fármaco-DNA, eletrodos de carbono foram modificados com DNAdupla fita com a finalidade de monitorar a interação DNA-Gemcitabina.O fármaco não apresentou atividade eletroquímica tanto na região positiva quanto na região negativa de potencial. A interação do mesmo com o DNA promove a condensação/agregação das duplas fitas do DNA em uma primeiraetapa, seguida da clivagem do nucleosídeo guanosina, formando guanina livre. O comportamento eletroquímico de leflunomida e sulfasalazina, dois fármacos aplicados ao tratamento da artrite reumatóide, foi estudado e mecanismos de oxidação foram propostos para cada fármaco

The chemical properties of samples of lignin, which were precipitated from black liquor using two different methodologies (precipitation with CO2 and H2SO4), were studied and the results compared to those obtained from a commercial lignin sample in order to prepare voltammetric sensors. The elementary analysis, infrared spectroscopy, thermal analysis and electrochemical characterization of the material demonstrated that both, the source of lignin and the precipitation method from the black liquor, can provide lignin samples with different chemical properties, although the electrochemical behavior of all samples has been the same. Lignin could only be stored in solid form as lignin in the black liquor is slowly and quantitatively oxidized by dissolved oxygen, preventing the extraction procedures. However, the lignin as extracted from black liquor cannot be used to modify solid electrodes due its high resistivity. The previous oxidation of the all material was necessary when the aim was its application on the sensors development. The electrical conductivity in the oxidized lignin was achieved, probably due to the predominance of sp2 hybridized carbon atoms, which improved orbital overlapping in the material. In addition, it was necessary to use a metallic transducer to produce electrodes modified with films of lignin with good electrochemical activity. The films drying time was also important parameter, which suggested a specific organization of lignin macromolecules over the electrode surface. Due to the small percentage of sulfur in the material, the oxidized lignin tended to be organized by the SH groups in the presence of metallic substrates, exposing its electroactive quinone groups. The oxidized lignin was further used to prepare carbon paste electrodes modified with gold nanoparticles, in which the impregnated oxidized lignin on graphite acted as an "in situ" reducing agent towards HAuCl4.The resulting composite allowed the preparation of a versatile voltammetric sensor, capable of detecting ascorbic acid, dopamine, nitrite and iodate. Regarding the electrochemical behavior and drug interaction studies DNA-molecule, carbon electrodes were modified with double strand DNA with the purpose of monitoring Gemcitabine-DNA interaction. The drug showed no electrochemical activity both, in the positive and the negative potential. The Gemcitabine-DNA interaction promoted condensation / aggregation of the double strand DNA in a first step, followed by cleavage of the nucleoside guanosine in the form of free guanine. In addition, the electrochemical behavior of sulfasalazine and leflunomide, two pharmacological compounds applied to the treatment of rheumathoid arthritis, were studied and their oxidation mechanisms were proposed

Simultaneous detection of hepatitis B virus genotypes and mutations associated with resistance to lamivudine, adefovir, and telbivudine by the polymerase chain reaction-ligase detection reaction

OBJECTIVES: Detection of mutations associated to nucleos(t)ide analogs and hepatitis B virus (HBV) genotyping are essential for monitoring treatment of HBV infection. We developed a multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) assay for the rapid detection of HBV genotypes and mutations associated with lamivudine, adefovir, and telbivudine resistance in HBV-infected patients. METHODS: HBV templates were amplified by PCR, followed by LDR and electrophoresis on a sequencer. The assay was evaluated using plasmids that contained wild-type or mutant HBV sequences and 216 clinical samples. RESULTS: The PCR-LDR assay and sequencing gave comparable results for 158 of the 216 samples (73.1 percent) with respect to mutation detection and genotyping. Complete agreement between the two methods was observed for all the samples (100 percent) at codon 180 and codon 204. Concordant results were observed for 99.4 percent of the 158 samples at codon 181 and 98.7 percent at codon 236. The genotyping results were completely concordant between the PCR-LDR assay and sequencing. The PCR-LDR assay could detect a proportion of 1 percent mutant plasmid in a background of wild-type plasmid. CONCLUSION: The PCR-LDR assay is sensitive and specific for detection of HBV genotypes and drug resistance mutations, and could be helpful for decision making in the treatment of HBV infection.

Cost-effectiveness of telbivudine versus lamivudine for chronic hepatitis B

BACKGROUND AND AIM: Chronic hepatitis B is a highly prevalent disease worldwide, leading to serious consequences if not properly treated. Six treatment options for chronic hepatitis B are currently provided by the Brazilian public health system. Telbivudine is a nucleoside analogue that is neither included in the Brazilian clinical protocol nor in the therapeutic guidelines for chronic hepatitis B. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of telbivudine for the viewpoint of the Brazilian public system, comparing it to lamivudine. METHODS: A Markov model was used to project lifetime complications and costs of treatment with lamivudine or telbivudine for chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. To evaluate disease progression, probabilities and utilities of virologic response, virologic resistance, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, treatment, interruption of treatment, death and seroconversion were collected in systematic reviews. Costs were collected in DATASUS, ABC da Saúde and scientific literature. RESULTS: Higher rate of virologic response and seroconversion was obtained with telbivudine, and also higher values of quality adjusted life years. However lamivudine is associated with lower costs and also lower cost-effectiveness values. The incremental cost-effectiveness ratios for telbivudine, when compared with lamivudine, were US$ 30,575 and US$ 40,457, respectively for HBeAg-positive and HBeAg-negative patients. CONCLUSION: In chronic hepatitis B lamivudine is a more cost-effective or even cost-saving strategy when compared with telbivudine.

Eficácia do adefovir dipivoxil, entecavir e telbivudina para o tratamento da hepatite crônica B: revisão sistemática / The efficacy of adefovir dipivoxil, entecavir and telbivudine for chronic hepatitis B treatment: a systematic review

INTRODUÇÃO: A hepatite crônica B é uma das doenças infecciosas mais frequentes no mundo e constitui um grave problema de saúde pública MÉTODOS: Para avaliar a eficácia dos análogos de núcleosídeo/nucletídeo utilizados no seu tratamento (adefovir dipivoxil, entecavir e telbivudina) foi conduzida uma revisão sistemática de ensaios clínicos randomizados. Foram consultadas, dentre outras, as bases de dados PubMed e LILACS RESULTADOS: Foram selecionados 29 artigos entre os publicados de janeiro/1970 até dezembro/2009 CONCLUSÕES: Todos os análogos de núcleosídeo/nucletídeo apresentam eficácia superior ou similar à lamivudina. O entecavir pode ser indicado para o tratamento da hepatite B crônica como alternativa à lamivudina em pacientes HBeAg positivo e negativo virgens de tratamento, considerando seu baixo potencial de resistência viral. A adição de adefovir à lamivudina apresentou bons resultados em pacientes resistentes à lamivudina. O uso de entecavir e telbivudina nesses pacientes apresenta risco de resistência cruzada. Telbivudina é um dos mais recentes antivirais disponíveis, mas resistência antiviral já documentada representa limitação ao seu uso como opção terapêutica à lamivudina. Eventos adversos aos análogos de núcleosídeo/nucletídeo foram similares em características, gravidade e incidência quando comparados à lamivudina e placebo.

INTRODUCTION: Chronic hepatitis B is one of the most frequent infectious disease in the world and represents a serious problem of public health METHODS: A systematic review of randomized clinical trials was conducted to evaluate the efficacy of the nucleoside/nucleotide analogues (adefovir, entecavir and telbivudine) used for the treatment of chronic hepatitis B. The databases PubMed and LILACS were consulted, among others RESULTS: Twenty nine articles published between January/1970 to December/2009 were selected CONCLUSIONS: All nucleoside/nucleotide analogues demonstrate upper or similar efficacy to lamivudine. The entecavir can be appropriate for patients with chronic hepatitis B, HBeAg positive and negative treatment-naive as alternative to lamivudine, considering its low potential of viral resistance. The addition of adefovir to lamivudine presented good results in lamivudine resistant patients. The use of entecavir and telbivudine in those patients presents risk of crossed resistance. TBV is one of the most recent antivirals available, but antiviral resistance already documented represents limitation to its use as therapeutic option to LAM. Adverse events of nucleoside/nucleotide analogues were similar in characteristics, gravity and incidence when compared to the lamivudina and placebo.

Selection and characterization of brivudin resistant bovine herpesvirus type 5

Bovine herpesvirus type 5 (BoHV-5) is the agent of meningoencephalitis, an important disease of cattle in South America. The neuropathogenesis of BoHV-5 infection is poorly understood and most previous research focused on the role of envelope glicoproteins in neurovirulence. Thymidine kinase (TK) is a viral enzyme necessary for virus replication in neurons and, therefore, represents a potential target for virus attenuation. The selection and characterization of BoHV-5 variants resistant to the nucleoside analog brivudin (BVDU), which selects TK-defective viruses is here described. Several BVDU-resistant clones were obtained after multiple passages in tissue culture in the presence of BVDU and one clone (BoHV-5/R-27) was further characterized. The selected clone replicated to similar titers and produced plaques with similar size and morphology to those of wild-type virus (SV507/99). The genetic stability of the resistant virus was demonstrated after ten passages in cell culture in the absence of the drug. Moreover, the drug-resistant virus showed reduced virulence in a rabbit model: virus inoculation in four rabbits did not result in disease, in contrast with 75 percent morbidity (3/4) and 50 percent mortality (2/2) among rabbits inoculated with the parental virus. These results demonstrate that BoHV-5 is sensitive to BVDU and that drug-resistant mutants can be readily selected upon BVDU treatment. BVDU-resistant mutants, likely defective in TK, retained their ability to replicate in tissue culture yet were attenuated for rabbits. This strategy to obtain TK-defective BoHV-5 may be useful to study the role of TK in BoHV-5 neuropathogenesis and for vaccine development.

Hepatitis crónica viral / Chronic viral hepatitis

Los Virus Hepatitis B (VHB) y Hepatitis C (VHC) en la actualidad son infecciones frecuentes en el hombre, afectando a una proporción significativa de la población mundial. Estos son causa frecuente de hepatitis aguda y crónica, cirrosis hepática, hepatocarcinoma y trasplante hepático. En 105 últimos años ha habido un gran progreso en el conocimiento de la epidemiología e historia natural de la infección con el VHB y VHC. Además, se han logrado grandes avances en su tratamiento y con numerosas drogas actualmente en evaluación.

Hepatitis B (HBV) and Hepatitis C (HCV) virus are common viral infections, affecting at a large worldwide population. These viruses are frequent cause of acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver transplantation. In the last few years, the knowledge of the epidemiology and natural history of HBV and HCV infections have markedly improved. Furthermore, considerable progress have been achieved in the efficacy of treatment and several new drugs are currently under evaluation.

Efectividad de efavirenz versus lopinavir/ritonavir asociado a dos análogos nucleósidos como tratamiento de inicio en pacientes VIH positivos / Effectiveness of efavirenz versus lopinavir / ritonavir associated with two nucleoside analogues as initial therapy for HIV patients

Comparar la efectividad virológica e inmunológica, de dos esquemas, uno basado en efavirenz y el otro en lopinavir/ritonavir, ambos combinados con dos análogos nucleósidos, en pacientes con infección avanzada por VIH, sin tratamiento previo. Estudio observacional de cohorte. Falla virológica definida como carga viral >50 copias/mL en los intervalos 3 a 9, 10 a 16 y 22 a 28 meses después del inicio. Se determinó la variación de CD4+. Se realizó análisis univariado de variables asociadas falla virológica. Se aplicaron Chi², Sum Rank Testy Log Rank Test. 189 pacientes iniciaron tratamiento entre diciembre 2000 y abril 2004, 114 con efavirenz y 45 con lopinavir/ritonavir, combinados con dos análogos nucleósidos. Los grupos fueron comparables en características basales: edad en años (36,5 en efavirenz vs 36,9 en lopinavir/ritonavir, (P=0,78); CD4+ basal (183,3 en efavirenz vs. 143,7 en lopinavir/ritonavir, (P=0,14); carga viral basal (203,696 cop/mL en efavirenz vs 217,772 cop/mL en lopinavir/ritonavir, P=0,77). Para la cohorte completa 87 por ciento obtuvo valores de carga viral indetectable a los 6 meses, 58 por ciento al año y 48 por ciento a los 28 meses. El cambio en el valor de CD4+/mes (+10,5 en efavirenz vs + 9,5 en lopinavir/ritonavir, P=0,77) y el porcentaje de indetectabilidad fueron similares en ambos grupos, tomando en cuenta los pacientes que pudieron seguirse durante el período de observación, cuyo número fue disminuyendo a partir de la muestra inicial. Ambos esquemas fueron comparables en su efectividad en esta cohorte de pacientes en términos de variación de CD4+ y porcentaje de indetectabilidad de carga viral.

Lesões em DNA promovidas por produtos de oxidação do ß-caroteno: possivéis implicações biológicas / Lesions in DNA promoted by oxidation of products the ß-carotene: possible biological implications

Apesar de diversos estudos in vitro e em populações indicarem um efeito protetor do ß-caroteno em sistemas biológicos, estudos epidemiológicos como o "The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study"(ATBC) e o "The Beta-Carotene and Retinol Efficacy Trial"(CARET) mostraram um aumento na incidência de câncer pulmonar em indivíduos fumantes suplementados com ß-caroteno. Essa ação contraditória tem sido chamada na literatura de "Paradoxo do ß-Caroteno". Sabe-se que este carotenóide sob altas pressões de oxigênio ou na presença de peróxidos pode sofrer oxidação e levar a formação de compostos como aldeídos, epóxidos, etc, que são capazes de se adicionarem covalentemente ao DNA. Estudos, in vitro e in vivo têm demonstrado a possibilidade de os metabólicos do ß-caroteno agirem como agentes pró-carcinogênicos. Estes agentes quando ativados quimicamente podem levar à formação de adutos de DNA. Já se sabe que alguns desses adutos encontram-se em níveis aumentados em diversas situações de risco de câncer. Diversos grupos incluindo o nosso, têm demonstrado a formação de lesões em DNA a partir de aldeídos e epóxidos exógenos ou gerados endogenamente...

Actividad antifúngica in vitro de los análogos nucleósidos de los inhibidores no-nucleósidos de la transcriptasa reversa / Antifungal activities in vitro of the nucleoside analogous and of the monocleouside reverse transcriptase inhibitors

Venezuela, es endémica para la mayoría de las micosis profundas. Algunos pacientes con VIH+ o SIDA, no reciben profilaxis antifúngica ya sea por conteos CD4+ >100, o porque asisten a la primera consulta ya en un estado muy avanzado de enfermedad o por falta de recursos económicos. Sin embargo, nosotros hemos observado que nuestros pacientes de la Fundación Amigos por la Vida, ham experimentado una disminución en la aparición de infecciones fúngicas oportunistas (IFO) a pesar de que todavía no se ha evidenciado una evolución en el número de células CD4+. Estos pacientes reciben principalmente tratamiento antiretroviral a base de los inhibidores de la transcriptasa reversa análogos de nucleósidos (ITRN) (Zidovudina, Lamivudina, Stavudina) y al inhibidor de transcriptasa reversa no-análogo de nucleósidos (ITRNN) como es el Efavirenz. Por tal motivo se decide evaluar la suceptibilidad antifúngica "in vitro" de estas drogas. Se observa una actividad antifúngica de Efavirenz contra Cryptococcus neoformans, C. glabrata y C. krusei. En contraste encontramos que C. albicans, C. tropicalis y C. parapsilosis presentan un asensibilidad antifúngica ante Zidovudina, Lamivudina y Stavudina, y poco o ninguna sensibilidad ante Efavirenz. En base a estos hallazgos, nosotros pensamos que las drogas estudiadas pudieran inducir un efecto directo adicional contra Cryptococcus o Candida spp., independiente de la reconstitución inmunológica en individuos VIH positivos. El mecanismo de acción de las mismas no lo podemos explicar. A la luz de nuestros conocimientos esta sería la primera vez que se reporta en la literatura este hallazgo

Diagnosis, antiretroviral therapy, and emergence of resistance to antiretroviral agents in HIV-2 infection: a review

Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are the causative agents of AIDS. HIV-2 is prevalent at moderate to high rates in West African countries, such as Senegal, Guinea, Gambia, and Cape Verde. Diagnosis of HIV-2 is made with a positive HIV-1/HIV-2 ELISA or simple/rapid assay, followed by one or two confirmatory tests specific for HIV-2. Following CD4+ T cell counts, HIV-2 viral burden and clinical signs and symptoms of immunodeficiency are beneficial in monitoring HIV-2 disease progression. Although non-nucleoside reverse transcriptase inhibitors are ineffective in treating HIV-2, nucleoside reverse transcriptase inhibitors and protease inhibitors can be effective in dual and triple antiretroviral regimens. Their use can decrease HIV-2 viral load, increase CD4+ T cell counts and improve AIDS-related symptoms. HIV-2 resistance to various nucleoside reverse transcriptase inhibitors and protease inhibitors, including zidovudine, lamivudine, ritonavir and indinavir, has been identified in some HIV-2 infected patients on antiretroviral therapy. The knowledge of HIV-2 peculiarities, when compared to HIV-1, is crucial to helping diagnose and guide the clinician in the choice of the initial antiretroviral regimen and for monitoring therapy success

Tratamiento antirretroviral / Antiretroviral therapy

En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos.

Procedures to characterize and study P2Z/P2X7 purinoceptor: flow cytometry as a promising practical, reliable tool

The expression of P2Z/P2X7 purinoceptor in different cell types is well established. This receptor is a member of the ionotropic P2X receptor family, which is composed by seven cloned receptor subtypes (P2X1 - P2X7). Interestingly, the P2Z/P2X7 has a unique feature of being linked to a non-selective pore which allows the passage of molecules up to 900 Da depending on the cell type. Early studies of P2Z/P2X7 purinoceptor were exclusively based on classical pharmacological studies but the recent tools of molecular biology have enriched the analysis of the receptor expression. The majority of assays and techniques chosen so far to study the expression of P2Z/P2X7 receptor explore directly or indirectly the effects of the opening of P2Z/P2X7 linked pore. In this review we describe the main techniques used to study the expression and functionality of P2Z/P2X7 receptor. Additionally, the increasing need and importance of a multifunctional analysis of P2Z/P2X7 expression based on flow cytometry technology is discussed, as well as the adoption of a more complete analysis of P2Z/P2X7 expression involving different techniques.

Tratamento de hepatites crônicas virais: uma atualização / Chronic viral hepatitis: an update

O autor realiza uma revisão da literatura sobre o tratamento atual das hepatites virais. Salienta, no caso da hepatite crônica pelo vírus B, a importância da vacinação, já que essa é uma doença que pode ser evitada. No seu tratamento, a droga mais aceita é o Interferon, a despeito da baixa eficácia. O papel dos análogos nucleosídios (lamivudina) ainda não está definido, restringindo-se o seu uso a protocolos, salvo em pacientes em programa de transplante hepático. No que tange ao tratamento da hepatite crônica pelo vírus C, a droga a ser ofertada também é o Inteferon. No entanto, pela baixa resposta terapêutica alcançada, abre-se uma perspectiva em sua associação com a Ribavirina