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1.
s.l; CONETEC; 17 mar. 2022.
Non-conventional in Spanish | LILACS, BRISA | ID: biblio-1363177

ABSTRACT

INTRODUCCIÓN: El nirmatrelvir es un inhibidor de la proteasa que se administra por vía oral, que demostró ser activo frente a MPRO, una proteasa viral que desempeña un papel esencial en la replicación viral al escindir las 2 poliproteínas virales. 15 Además, ha demostrado actividad antiviral frente a todos los coronavirus que se sabe que infectan a los humanos. 16 El nirmatrelvir es empaquetado con ritonavir (como Paxlovid), un inhibidor del citocromo P450 (CYP) 3A4 y agente potenciador farmacocinético, que se ha utilizado para potenciar los inhibidores de la proteasa del virus de la inmunodeficiencia humana (VIH). La coadministración tiene como objetivo aumentar las concentraciones de nirmatrelvir al rango terapéutico objetivo. El 22 de diciembre de 2021, la Administración de Alimentos y Medicamentos (FDA, su siglas en inglés Food and Drug Administration) emitió una autorización de uso de emergencia para nirmatrelvir potenciado con ritonavir para el tratamiento de pacientes con COVID-19 leve a moderado de ≥12 años y un peso de ≥ 40 kg que están dentro de los 5 días de inicio de los síntomas y con alto riesgo de progresar a enfermedad grave. 17,18 Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) aún no ha autorizado la comercialización del medicamento para este fin. OBJETIVO: El objetivo del presente informe es evaluar parámetros de eficacia, seguridad, conveniencia y recomendaciones disponibles acerca del empleo de nirmatrelvir-ritonavir para el tratamiento de pacientes con COVID-19 en Argentina. MÉTODOS: Teniendo en cuenta la velocidad con la que la información relacionada con la pandemia aparece y se modifica (link), se desarrolló un protocolo sustentado en proyectos que resume activamente la evidencia científica a medida que la misma se hace disponible. Con este fin se utilizó la plataforma L- ove de Epistemonikos para identificar revisiones sistemáticas "vivas". Se seleccionaron aquellas con una calidad metodológica apropiada evaluada a través de la herramienta AMSTAR-2, y que a su vez llevaran un proceso de actualización frecuente.19 De cada una de las revisiones sistemáticas identificadas se extractaron los efectos de la intervención sobre los desenlaces priorizados como importantes o críticos y la certeza en dichos efectos. Para la priorización de los desenlaces se adoptó una perspectiva desde el paciente considerando sus potenciales preferencias. La selección se realizó por consenso entre los autores y supervisores del informe considerando los resultados de múltiples ejercicios de priorización publicados, realizados en el marco del desarrollo de distintas guías de práctica clínica.20­23 Se seleccionaron "mortalidad", "ingreso en asistencia ventilatoria mecánica", "tiempo hasta resolución de síntomas", "hospitalización", "eventos adversos graves" como desenlaces críticos. Adicionalmente, se extractaron datos relacionados con efectos de subgrupo potencialmente relevantes para la toma de decisión, con especial énfasis en el tiempo de evolución, la severidad de la enfermedad y el estado de vacunación. En los casos en que no fue reportado por las revisiones sistemáticas incluidas, se calculó el efecto absoluto de las intervenciones en pacientes vacunados, tomando el riesgo basal reportado para pacientes no vacunados multiplicado por un riesgo relativo de 0,1 según el efecto de la vacunación observado en distintos estudios y sistemas de vigilancia.24­26 Para confeccionar las conclusiones en el efecto de las intervenciones evaluadas sobre los desenlaces priorizados, utilizamos lineamientos publicados, específicamente desarrollados a tal fin. RESULTADOS: Se identificaron dos sistemáticas que cumplieron con los criterios de inclusión del presente informe y reportaron resultados: Se identificó un ECA que incluyó 2.085 pacientes en los que nirmatrelvir-ritonavir se comparó con el tratamiento estándar en pacientes con COVID-19. Se describen los efectos absolutos y la certeza en dichos efectos de nirmatrelvir-ritonavir para pacientes con COVID-19. Los pacientes incluidos en el estudio no habían recibido un esquema completo de vacunación, por lo que no se realizó un análisis de subgrupos según el estado de vacunación. Sin embargo, un análisis de subgrupo según la presencia o no de anticuerpos anti SARS-CoV-2 en suero al momento de ingresar al estudio sugiere que los beneficios observados podrían ser mayores, o incluso limitarse, para aquellos pacientes que no posean inmunidad previa. Luego de la aprobación de emergencia por la FDA de nirmatrelvir-ritonavir (Paxlovir), el Departamento de Salud de los Estados Unidos estimó que tendrá distribuidos para el mes de marzo de 2022, a través del Organismo de Emergencia Pública en Salud, un total de 513.830 dosis a un costo unitario de 520 USD por 5 días de tratamiento; llevando a un gasto total de más de 266 millones de dólares (266.760 000 USD).32,33 La tecnología no está autorizada aún para su comercialización en Argentina para su uso en personas con COVID-19. La vía de administración oral podría asociarse con mayor facilidad de uso; sin embargo, no se conoce la disponibilidad del laboratorio para responder a la demanda sin afectar la equidad en la distribución en nuestro país. CONCLUSIONES: El cuerpo de la evidencia muestra que nirmatrelvir-ritonavir tiene un efecto incierto sobre la mortalidad en pacientes con COVID-19 leve o moderada de reciente comienzo, con factores de riesgo para progresar a enfermedad grave que no han sido vacunados. En esta población, probablemente disminuya la necesidad de hospitalización sin aumentar los eventos adversos severos. Esta tecnología no ha sido probada en personas vacunadas ni en otros escenarios. La tecnología no está autorizada para su comercialización por la Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) de nuestro país. Aunque la forma de administración oral es simple, la experiencia en otros países muestra que el costo comparativo estimado es elevado, la población objetivo es muy alta y podrían existir además problemas de suministro y distribución que afecten la disponibilidad y la equidad en la distribución. Las guías de práctica clínica de alta calidad metodológica actualizadas entregan recomendaciones discordantes en cuanto a su uso. Aquellas que recomiendan en forma condicional a favor se basan en el beneficio observado en personas de muy alto riesgo, no vacunadas, con enfermedad de reciente comienzo, y su facilidad de administración. Las que entregan recomendaciones en contra se basan en el costo comparativo muy elevado, para una población objetivo muy amplia y la baja certeza en su efecto sobre la mortalidad.


Subject(s)
Humans , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , COVID-19/drug therapy , Argentina , Efficacy , Cost-Benefit Analysis/economics , Ritonavir/therapeutic use
2.
Protein & Cell ; (12): 877-888, 2021.
Article in English | WPRIM | ID: wpr-922482

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M


Subject(s)
Antiviral Agents/therapeutic use , Binding Sites , COVID-19/virology , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , High-Throughput Screening Assays/methods , Humans , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/therapeutic use , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification
3.
Rev. Hosp. Clin. Univ. Chile ; 32(2): 159-167, 2021.
Article in Spanish | LILACS | ID: biblio-1283537

ABSTRACT

The main treatment for patients with severe Covid-19 is to maintain adequate ventilatory support and monitor the possible progression of the disease. Therapeutic strategies such as High Flow Nasal Cannula, awake prone position, antithrombotic prophylaxis and the use of dexamethasone. There have improved the probability of not presenting complications and not requiring invasive mechanical ventilation. The use of convalescent plasma is still under investigation and is currently only recommended in clinical trials. Finding antivirals that allow treating the infection and clinically improving patients has led to mounting studies with different methodologies, and currently there are specific and limited indications for their routine use, as in the case of Remdesivir, which has been approved by the FDA as emergency treatment in severe cases. Immunomodulatory treatments are still under study. An example of this is Tocilizumab and Anakinra, which have shown promising results for the management of seriously ill patients. It should be noted that there are many therapies that are being tested and that every day the information about the results obtained is changing. (AU)


Subject(s)
Humans , Male , Female , COVID-19/therapy , Antiviral Agents/therapeutic use , Protease Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use
4.
Article in English | WPRIM | ID: wpr-880736

ABSTRACT

The aim of this study was to evaluate the safety of an antiviral regimen of protease inhibitors combined with Arbidol (umifenovir) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients. The genomic sequence of SARS-CoV-2 is highly homologous to that of SARS-CoV (Zhou et al., 2020). Previously published basic and clinical research on anti-SARS-CoV treatment found that lopinavir/ritonavir (LPV/r) could improve the prognosis of SARS patients (Chan et al., 2003; Chu et al., 2004). Darunavir (DRV) is another protease inhibitor that blocks the binding of SARS-CoV-2 to human angiotensin-converting enzyme 2 (Omotuyi et al., 2020). The broad-spectrum antiviral drug Arbidol (umifenovir) also shows in vitro anti-SARS-CoV activity (Khamitov et al., 2008).


Subject(s)
Adult , COVID-19/drug therapy , China , Darunavir , Drug Combinations , Female , Humans , Indoles/therapeutic use , Lipid Metabolism , Lopinavir , Male , Middle Aged , Protease Inhibitors/therapeutic use , Retrospective Studies , Ritonavir , SARS-CoV-2/genetics
5.
Evid. actual. práct. ambul ; 23(2): e002053, 2020.
Article in Spanish | LILACS | ID: biblio-1103669

ABSTRACT

En este artículo, el autor reflexiona sobre las expectativas de los profesionales de la salud acerca de la evidencia para recomendar tratamiento farmacológico a los pacientes con COVID-19. (AU)


In this article, the author reflects on the expectations of health professionals regarding the evidence to recommend pharmacological treatment to patients with COVID-19. (AU)


Subject(s)
Humans , Pneumonia, Viral/drug therapy , Health Communication , Protease Inhibitors/therapeutic use , Coronavirus Infections/drug therapy , Azithromycin/therapeutic use , Risk Assessment , Ritonavir/therapeutic use , Evidence-Based Medicine/trends , Coronaviridae/drug effects , Information Dissemination , Pandemics , Lopinavir/therapeutic use , Betacoronavirus/drug effects , Hydroxychloroquine/therapeutic use
6.
Rev. chil. infectol ; 36(4): 475-489, ago. 2019. tab
Article in Spanish | LILACS | ID: biblio-1042665

ABSTRACT

Resumen Introducción: La farmacocinética de los anti-retrovirales (ARVs) puede ser modificada por otros medicamentos de uso concomitante. Es oportuno actualizar las interacciones entre nuevos ARVs y fármacos de uso crónico para mantener un éxito terapéutico. Objetivo: Actualizar información sobre interacciones medicamentosas en pacientes con infección por VIH/SIDA en terapia antiretroviral. Método: Revisión estructurada en MEDLINE/ PubMed utilizando los términos Mesh: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions, entre enero de 2015 y junio de 2017. Fueron seleccionadas publicaciones sobre interacciones medicamentosas en humanos, en inglés o español y con acceso a texto completo. Además, se incluyeron referencias de artículos considerados relevantes. La inclusión de los artículos fue evaluada por tres investigadores independientes y, en caso de requerirlo, por consenso entre ellos. La relevancia clínica se estableció, acorde con la gravedad y probabilidad de ocurrencia de la interacción. Resultados: Se identificaron 466 artículos, se accedió a texto completo a 444. De éstos, 164 aportaron interacciones, lo que permitió identificar un total de 534 parejas de interacciones medicamentosas. Las interacciones que presentaron un mayor riesgo de generar problemas de seguridad y efectividad fueron 308 (57,7%) de nivel 2 y 35 (6,6%) de nivel 1. Conclusiones: Se identifican 534 parejas nuevas de interacciones medicamentosas, de ellas 308 (64,2%) de mayor relevancia clínica.


Background: The pharmacokinetics of anti-retrovirals (ARVs) can be modified by other concomitant medicinal products. It is timely to update the interactions between new ARVs and drugs of chronic use to maintain therapeutic success. Aim: To update information about drug interactions in patients with HIV/AIDS on antiretroviral therapy. Methods: Comprehensive literature review in MEDLINE/PubMed database from January of 2015 to June of 2017, using the Mesh terms: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full text were retrieved. Additionally, citation lists from identified articles were reviewed. The study inclusion was assessed by three independent researchers and by consensus among them when was necessary. Clinical relevance of drug interaction was grouped into levels according to seriously and probability of occurrence. Results: 466 articles were identified; full text was accessed in 444. Of these, 164 provided interactions, which allowed the identification of a total of 534 pairs of drug interactions. The interactions that presented a higher risk of generating safety and effectiveness problems were 308 (57.7%) of level 2 and 35 (6.6%) of level 1. Conclusions: We identify 534 new pairs of drug interactions, of which 308 (64.2%) are the most clinically relevant.


Subject(s)
Humans , Protease Inhibitors/pharmacology , HIV Infections/drug therapy , Anti-HIV Agents/pharmacology , Drug Interactions , Protease Inhibitors/therapeutic use , Risk Factors , Anti-HIV Agents/therapeutic use
8.
Rev. ciênc. farm. básica apl ; 3901/01/2018. tab, ilus
Article in English | LILACS | ID: biblio-1100213

ABSTRACT

The combination of Inhibitors of protease boceprevir (BOC) or telaprevir (TLV) concomitantly with peginterferon (PEG) and ribavirin (RBV) constitute the triple therapy (TT) for Hepatitis C treatment. Objective: To describe the experience of the TT treatment of chronic hepatitis C patients, besides discussing safety issues, in real life. Methods: Observational and retrospective study with 180 patients attended in a specialized center, between July 2014 and December 2015. Were evaluated variables as gender, age, access to drugs, pattern of alcohol consumption, pathway of contamination reported by the patient, previous treatment, degree of fibrosis, treatment regimen, treatment interruption and reason and Sustained Viral Response (SVR). Adverse Drug Reactions (ADRs) were collect through monthly self-report by the patient to the pharmacist. Results: 65 patients used BOC and 115 TLV, and the mean age was 54.20 (BOC) and 53.92 (TLV) years. End of treatment rate was 52.3% (BOC) and 53.3% (TLV). ADRs occurred in 18.5% of the patients (BOC) and 13.9% (TLV), being more frequent the severe anemia. Erythropoietin (EPO) used in 45.4% (BOC) and 58.2% (TLV). SVR rate calculated by intention to treat was 38.5% (BOC) e 50.4% (TLV). Conclusion: This study has shown that the effectiveness of TT is not significantly higher than double therapy and is lower than the reported in clinical trials. High dropout rates due to ADRs have been demonstrated, as well as a lower SVR found in clinical trials.(AU)


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Protease Inhibitors/therapeutic use , Ribavirin/therapeutic use , Hepatitis C, Chronic/drug therapy , Interferon alpha-2/therapeutic use , Brazil , Treatment Outcome , Drug-Related Side Effects and Adverse Reactions
9.
Actual. SIDA. infectol ; 25(96): 80-83, 20170000.
Article in Spanish | LILACS, BINACIS | ID: biblio-1355240

ABSTRACT

El ergotismo es una complicación bien conocida, aunque poco fre-cuente, asociada a la ingesta de derivados de la ergotamina en dosis habitualmente más altas de las recomendadas. No obstante, también puede presentarse luego del uso de bajas dosis cuando se adminis-tran concomitantemente drogas que inhiben su metabolismo, entre ellas los inhibidores de proteasa (IP), ampliamente utilizados en el tra-tamiento de pacientes con infección por el virus de la inmunodeficien-cia humana (VIH). A pesar de esta interacción predecible se siguen observando en la práctica clínica diaria casos de ergotismo, probable-mente debido a que se trata de una droga de uso frecuente, bajo cos-to y que no requiere prescripción médica, sumado a la falta de conoci-miento del paciente de las potenciales interacciones. Se describen las características, diagnóstico, tratamiento y evolución de cuatro pacien-tes con infección por VIH en tratamiento antirretroviral (TARV), basa-do en IP, que presentaron un cuadro de ergotismo


Ergotism is a well-known but rare complication associated with the intake of ergotamine derivatives at doses usually higher than recommended. However, it may also occur after low doses of ergotamine when it is co-administered with drugs that inhibit its metabolism, such as protease inhibitors (PIs), widely used in the treatment of patients with human immunodeficiency virus. Despite this predictable interaction, cases of ergotism are still being observed in daily clinical practice, probably because it is a frequently used, low cost drug that does not require medical prescription, in addition to the patient's lack of knowledge of the potential interactions. We describe here the characteristics, diagnosis, treatment and evolution of four HIV-infected patients on PI-based antiretroviral treatment who presented a clinical picture of ergotism


Subject(s)
Humans , Male , Female , Protease Inhibitors/therapeutic use , Self Medication , HIV Infections/immunology , Ergotism , Antiretroviral Therapy, Highly Active , Ergotamine/administration & dosage , Prescription Drug Misuse
10.
Ann. hepatol ; 16(3): 366-374, May.-Jun. 2017. tab, graf
Article in English | LILACS | ID: biblio-887248

ABSTRACT

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.


Subject(s)
Humans , Protease Inhibitors/economics , Protease Inhibitors/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/economics , Hepatitis C, Chronic/drug therapy , Simeprevir/economics , Simeprevir/therapeutic use , Sofosbuvir/economics , Sofosbuvir/therapeutic use , Outpatient Clinics, Hospital/economics , Protease Inhibitors/adverse effects , Remission Induction , Colorado , Treatment Outcome , Cost-Benefit Analysis , Hepacivirus/enzymology , Hepacivirus/genetics , Models, Economic , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/virology , Drug Therapy, Combination , Simeprevir/adverse effects , Sofosbuvir/adverse effects , Sustained Virologic Response , Genotype
11.
Medicina (B.Aires) ; 76(6): 390-398, dic. 2016. ilus, graf, tab
Article in Spanish | LILACS | ID: biblio-841617

ABSTRACT

La hepatitis crónica por el virus de la hepatitis C (HCV) es un problema de salud mundial. En el mundo, 170 millones de personas están infectadas. En Latinoamérica la prevalencia se estima entre 1.0 y 2.3% y en Argentina es en promedio 1.0 a 1.5%. La eficacia del tratamiento de esta enfermedad ha mejorado sustancialmente en los últimos 2 a 3 años. Con los nuevos antivirales de acción directa (AAD) disponibles actualmente, pueden lograrse tasas de respuesta viral sostenida (RVS) mayores al 90-95% prácticamente con pocos efectos adversos. Para poder acceder a estos tratamientos con una alta tasa de curación, y así lograr reducir la carga de la enfermedad en la salud pública, es necesario aumentar el número de pacientes diagnosticados y que estos accedan a un cuidado adecuado. El rol de los médicos de atención primaria es fundamental: deben sospechar la infección, diagnosticarla y complementar su atención con la derivación al especialista. El trabajo conjunto de generalistas y especialistas optimizará el manejo de los recursos disponibles, permitiendo que cada vez más personas infectadas con el HCV sean diagnosticadas y tratadas adecuadamente.


Chronic hepatitis C (HCV) is a global health problem. Worldwide, 170 million people are chronically infected. In Latin America its prevalence is estimated between 1.0 and 2.3%, and in Argentina between 1.0 and 1.5%. Treatment efficacy has considerably improved in the last 2 or 3 years. Sustained virological response (SVR) rates around 90-95% can be achieved with the new direct acting antiviral agents (DAAs) currently available, with few side effects. It is necessary to increase the number of diagnosed patients, linking them to adequate management and treatment. Raising treatment rates will increase the percentage of cured patients, reducing the burden of disease. Primary care physicians´ role is essential to achieve this goal. They must identify persons at risk, diagnose them and work with specialists to continue their medical care. Team working of generalists and specialists will permit that more HCV infected people can access to adequate care and treatment.


Subject(s)
Humans , Male , Female , Adult , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Antiviral Agents/therapeutic use , Argentina/epidemiology , Protease Inhibitors/therapeutic use , Time Factors , Prevalence , Risk Factors , Treatment Outcome , Viral Nonstructural Proteins/antagonists & inhibitors , Hepatitis C, Chronic/epidemiology
13.
Article in Korean | WPRIM | ID: wpr-202464

ABSTRACT

Acute pancreatitis is common but remains a condition with significant morbidity and mortality. Despite a better understanding of the pathophysiology of acute pancreatitis achieved during the past few decades, there is no specific pharmacologic entity available. Therefore, supportive care is still the mainstay of treatment. Recently, novel interventions for increasing survival and minimizing morbidity have been investigated, which are highlighted in this review.


Subject(s)
Acute Disease , Antioxidants/therapeutic use , Bacteremia/complications , Cholangiopancreatography, Endoscopic Retrograde , Fluid Therapy , Gallstones/complications , Humans , Necrosis , Pancreatitis/mortality , Protease Inhibitors/therapeutic use , Renal Dialysis
14.
J. bras. med ; 102(1)jan.-fev. 2014. graf, ilus, tab
Article in Portuguese | LILACS | ID: lil-712210

ABSTRACT

A infecção pelo vírus da hepatite C (HCV) é importante causa de hepatite crônica, cirrose e carcinoma hepatocelular, sendo razão para a indicação de transplante hepático no mundo industrializado (Sherlock, 1995). Várias estratégias de tratamento da hepatite C foram empregadas ao longo dos últimos anos. O interferon peguilado em monoterapia ou combinado à ribavirina tornou-se tratamento padrão. Em 2011, foram introduzidos os inibidores de protease. Em dezembro de 2013, uma nova geração de drogas tem conferido resultados auspiciosos à terapia.


The hepatitis C virus infection (HCV) is an important cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, which leads indication for liver transplantation in the industrialized world (Sherlock, 1995). Many treatment strategies for hepatitis C were used for the latest years. Pegylated interferon monotherapy or combined to the ribavirin became a standard treatment. In 2011, protease inhibitors were introduced. In December 2013, a new generation drugs have been presented auspicious results to the therapy.


Subject(s)
Humans , Male , Female , Hepacivirus , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Protease Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Protease Inhibitors/administration & dosage , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Proline/analogs & derivatives , Ribavirin/administration & dosage , Ribavirin/therapeutic use
15.
Gut and Liver ; : 471-479, 2014.
Article in English | WPRIM | ID: wpr-108135

ABSTRACT

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.


Subject(s)
Antiviral Agents/therapeutic use , Drug Therapy, Combination , Hepacivirus/drug effects , Hepatitis C/drug therapy , Humans , Protease Inhibitors/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects
16.
Indian J Biochem Biophys ; 2013 Oct; 50(5): 363-376
Article in English | IMSEAR | ID: sea-150246

ABSTRACT

Leishmaniasis is a deadly protozoan parasitic disease affecting millions of people worldwide. The treatment strategy of Leishmania infection depends exclusively on chemotherapy till date. But the treatment of the disease is greatly hampered due to high cost, toxicity of the available drugs and more importantly emergence of drug resistance. Hence the potential new drugs are highly needed to combat this disease. The first and foremost step of the drug discovery process is to search and select the putative target in a specific biological pathway in the parasite that should be either unambiguously absent in the host or considerably different from the host homolog. Importantly, Leishmania genome sequences enrich our knowledge about Leishmania and simultaneously reinforce us to identify the ideal drug targets that distinctly exist in the parasite as well as to develop the effective drugs for leishmaniasis. Though the leishmanial research has significantly progressed during the past two decades, the identification of suitable drug targets or development of effective drugs to combat leishmaniasis is far from satisfactory. Enzymatic systems of Leishmania metabolic and biochemical pathways are essential for their survival and infection. Concurrently, it is noteworthy that Leishmania proteases, especially the cysteine proteases, metalloproteases and serine proteases have been extensively investigated and found to be indispensable for the survival of the parasites and disease pathogenesis. Herein, we have discussed the importance of few enzymes, particularly the Leishmania proteases and their inhibitors as promising candidates for potential development of anti-leishmanial drugs.


Subject(s)
Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Drug Discovery/methods , Leishmania/drug effects , Leishmania/physiology , Leishmaniasis/drug therapy , Molecular Targeted Therapy , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use
17.
J. pediatr. (Rio J.) ; 89(1): 91-99, jan.-fev. 2013. tab
Article in Portuguese | LILACS | ID: lil-668831

ABSTRACT

OBJETIVO: Descrever a densidade mineral óssea (DMO) e conteúdo mineral ósseo (CMO) de crianças e adolescentes que vivem com o vírus da imunodeficiência humana e comparar com os dados do National Health and Nutrition Examination Survey IV (NHANES IV). MÉTODO: Participaram do estudo48 crianças e adolescentes (sete a 17 anos de idade) com infecção pelo vírus da imunodeficiência humana adquirida por transmissão vertical. A DMO e o CMO foram mensurados pela absorciometria por dupla emissão de raios-X, calculando-se escores-z com base nos dados do NHANES IV. Nos prontuários médicos foram obtidas as informações dos parâmetros clínicos e laboratoriais da infecção pelo vírus da imunodeficiência humana. Foram ainda avaliada a atividade física, a ingestão de cálcio e a maturação esquelética. Utilizaram-se procedimentos da estatística descritiva e inferencial, estabelecendo níveis de significância de 5%. RESULTADOS :Os pacientes soropositivos demonstraram valores inferiores comparados aos dados do NHANES IV em todos os escores-z da massa óssea (média = -0,52 a -1,22, dp = 0,91 e 0,84, respectivamente). Com base no z-DMOsubtotal, há uma prevalência de 16,7% de crianças e adolescentes com massa óssea reduzida para a idade. Indivíduos que utilizaram inibidores de protease apresentaram um z-DMOtotal inferior, comparado ao grupo que não utilizou (-1,31 vs. -0,79; p = 0,02). Não foram encontradas diferenças na massa óssea em relação ao nível de atividade física e ingestão de cálcio. CONCLUSÕES: Na presente amostra, crianças e adolescentes que vivem com o vírus da imuno deficiência humana possuem baixa massa óssea para idade, e o uso de inibidores de protease parece estar relacionado a tais reduções.


OBJECTIVE: To describe bone mineral density (BMD) and bone mineral content (BMC) in children and adolescents infected with the human immunodeficiency virus (HIV), and to compare them with data from the National Health and Nutrition Examination Survey IV (NHANES IV). METHOD: The study included 48 children and adolescents (7 to 17 years old) infected with HIV through vertical transmission. BMC and BMD were measured by dual energy absorptiometry X-ray, by calculating z-scores based on data from NHANES IV. The information on clinical and laboratory parameters of infection by HIV was obtained from medical records. Physical activity, calcium intake, and skeletal maturation were also assessed. Descriptive and inferential statistical procedures were used, with levels of significance set at 5%. RESULTS: Seropositive patients presented lower values compared to data from NHANES IV in all z-scores of bone mass (mean = -0.52 to -1.22, SD = 0.91 and 0.84, respectively). Based on the subtotal z-BMD, there was a prevalence of 16.7% of children and adolescents with low bone mass for age. Individuals using protease inhibitors presented a lower total z-BMD when compared to the group that did not use (-1.31 vs. -0.79, p = 0.02). There were no bone mass differences in relation to physical activity and calcium intake. CONCLUSIONS: In the present sample children and adolescents living with HIV have low bone mass for age, and the use of protease inhibitors appears to be related to such decreases.


Subject(s)
Adolescent , Child , Female , Humans , Male , Bone Density/physiology , HIV Infections/physiopathology , Protease Inhibitors/therapeutic use , Absorptiometry, Photon/methods , Body Size , Case-Control Studies , Chi-Square Distribution , Calcium, Dietary/administration & dosage , Eating , Exercise , HIV Infections/drug therapy , HIV Infections/transmission , Infectious Disease Transmission, Vertical , Sex Distribution , Sex Factors , Socioeconomic Factors
18.
Mem. Inst. Oswaldo Cruz ; 107(4): 450-457, June 2012.
Article in English | LILACS | ID: lil-626436

ABSTRACT

Determining the prevalence and type of antiretroviral (ARV) resistance among ARV-naïve individuals is important to assess the potential responses of these individuals to first-line regimens. The prevalence of primary resistance and the occurrence of recent infections among individuals with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) were identified among recently diagnosed patients at five sexually transmitted disease/AIDS testing and counselling centres in the metropolitan region of Recife (RMR), Pernambuco, Brazil, between 2007-2009. One-hundred and eight samples were analysed using the Calypte® BED assay. Males predominated (56%), as did patients aged 31-50 years. Twenty-three percent presented evidence of a recent HIV infection. The median CD4+ T lymphocyte count was 408 cells/mm³ and the median viral load was 3.683 copies/mL. The prevalence of primary resistance was 4.6% (confidence interval 95% = 1-8.2%) based on criteria that excluded common polymorphisms in accordance with the surveillance drug resistance mutation criteria. The prevalence of resistance to non-nucleoside reverse transcriptase, nucleoside/nucleotide reverse transcriptase and protease inhibitors were 3.8%, 1.5% and 0.8%, respectively. Fifty-seven percent of strains were from clade B, 37.7% were clade F and 3.1% were clade C; there were no statistically significant differences with respect to resistance between clades. Recent infection tended to be more common in men (p = 0.06) and in municipalities in the south of the RMR (Jaboatão dos Guararapes and Cabo de Santo Agostinho) (p = 0.046). The high prevalence of recent infection and the high prevalence of non-B strains in this poor Brazilian region merit further attention.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Drug Resistance, Viral/genetics , HIV Infections/virology , HIV Protease/genetics , HIV Reverse Transcriptase/genetics , HIV-1 , Mutation/genetics , Anti-HIV Agents/therapeutic use , Genotype , HIV Infections/drug therapy , HIV Infections/epidemiology , HIV-1 , Prevalence , Protease Inhibitors/therapeutic use , RNA, Viral/genetics , Reverse Transcriptase Inhibitors/therapeutic use , Socioeconomic Factors , Urban Population , Viral Load
19.
Article in English | WPRIM | ID: wpr-181896

ABSTRACT

Pegylated interferon and ribavirin combination therapy is accepted as the standard antiviral treatment for chronic hepatitis C regardless of HCV genotype. This combination therapy achieves higher response rates than previous therapy, but, nevertheless, a large proportion of patients suffer from treatment failure or adverse events. Recent clinical studies of viral kinetics during antiviral treatment have led to the introduction of response-guided therapy, the concept of 'customized therapy depending on viral response', which focuses on modulation of the treatment period depending on the viral response to create a sustained viral response without unnecessary medication and costs. New upcoming direct-acting antivirals (DAAs) maximize response rate, and triple therapy including DAAs along with pegylated interferon and ribavirin combination therapy could soon be the standard therapy. In this article, we reviewed the factors affecting treatment, response guided treatment, retreatment after failure of standard treatment, management of adverse events during treatment, and new treatment options.


Subject(s)
Anemia, Hemolytic/drug therapy , Antiviral Agents/adverse effects , Erythropoietin/therapeutic use , Hepatitis C, Chronic/drug therapy , Humans , Precision Medicine , Interferon-alpha/adverse effects , Polyethylene Glycols/adverse effects , Protease Inhibitors/therapeutic use , RNA, Viral/analysis , Recombinant Proteins/adverse effects , Ribavirin/adverse effects
20.
Rio de Janeiro; s.n; 2012. 112 p. ilus.
Thesis in Portuguese | LILACS | ID: lil-665411

ABSTRACT

Leishmanioses são um grupo de doenças com um largo espectro de manifestações clínicas, as quais variam desde lesões cutâneas até o envolvimento visceral severo, podendo levar ao ótibo. A leishmaniose é, ainda hoje, uma doença negligenciada, estando entre os agravos prioritários do programa de pesquisa sobre doenças da pobreza da Organização Mundial da Saúde (OMS). Além de não haver vacinas disponíveis, a terapia é baseada em medicamentos injetáveis que causam sérios efeitos colaterais, tornando o tratamento inviável para muitos países endêmicos. Drogas derivadas de metal representam um novo arsenal terapêutico antimicrobiano e anti-câncer. Os inibidores de peptidase/agentes quelantes tais como 1,10-fenantrolina e seus derivados, no estado livre de metal ou como ligantes com metais de transição, interferem com a função de vários sistemas biológicos. Em trabalhos anteriores, nosso grupo descreveu que o parasito L. braziliensis produziu moléculas gp63 sensíveis a 1,10-fenantrolina. No presente trabalho, demonstramos a distribuição celular da molécula gp63 em uma cepa virulenta de L. braziliensis por meio de análises bioquímicas e imuno-histoquímica. Depois disso, relatamos os efeitos inibitórios de três compostos derivados da 1,10-fenantrolina, 1,10-fenantrolina-5,6-dioma (phendio), [Cu(phendio)2] e [Ag(phendio)2], nas atividades metalopeptidases celulares e extracelulares produzidas por promastigotas de L. braziliensis, bem como as suas ações sobre a viabilidade do parasita e na interação com as células de macrófagos murinos. As moléculas gp63 foram detectadas em compartimentos de parasitos, incluindo membrana citoplasmatica e bolsa flagelar. O tratamento de promastigotas de L. braziliensis durante 1 hora com 1,10-fenantrolina e seus derivados resultou numa inibição significativa da viabilidade celular e mostrou um mecanismo de ação irreversível. Estes inibidores de metalopeptidases induziram apoptose em promastigotas de L. braziliensis, demonstrada através ...


Leishmaniasis is a group of diseases with a wide spectrum of clinical manifestations, which range from self-limited skin lesions to severe visceral involvement that can lead to death. Leishmaniasis is still a neglected disease, and it is among the priorities of the research program on diseases of poverty of World Health Organization (TDR/WHO). There is no available vaccine and the treatment is based on drugs that cause serious side effects, and are unaffordable in several endemic countries. Metal-based drugs represent a novel antimicrobial and anti-cancer therapeutics arsenal. Peptidase inhibitors/chelating agents such as 1,10-phenanthroline and its substituted derivatives, either the metal-free state or as ligands coordinated to transition metals, interfere with crucial functions of several biological systems. In previous works, our group described that L. braziliensis produced gp63 molecules sensible to 1,10-phenanthroline. Herein, we initially studied the cellular distribution of gp63 in a virulent strain of L. braziliensis by biochemical and immunocytochemical analyses. After that, we reported the inhibitory effects of three 1,10-phenanthroline derivative compounds, 1,10-phenanthroloine-5,6-dione (phendio), [Cu(phendio)2] and [Ag(phendio)2], on both cellular and extracellular metallopeptidase activities produced by L. braziliensis promastigotes as well as their actions on the parasite viability and on the interaction with murine macrophage cells. The gp63 molecules were detected in several parasite compartments, including cytoplasm, membrane lining the cell body and flagellum, and flagellar pocket. The treatment of L. braziliensis promastigotes for 1 hour with 1,10-phenanthroline and its derivatives resulted in a significant inhibition of cell viability and showed an irreversible mechanism of action. These metallopeptidase inhibitors induced apoptosis in L. braziliensis promastigotes as judged by annexin/propidium iodide staining and TUNEL assays ...


Subject(s)
Animals , Male , Female , Rats , Phenanthrolines/administration & dosage , Phenanthrolines/therapeutic use , Protease Inhibitors/therapeutic use , Leishmania braziliensis , Leishmania braziliensis/enzymology , Antiprotozoal Agents/therapeutic use , Leishmaniasis/drug therapy , Metals/chemistry , Metalloproteases/antagonists & inhibitors , Chelating Agents/administration & dosage
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