RESUMO
Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.
Assuntos
Comprimidos/análise , Zidovudina/agonistas , HIV/patogenicidade , Lamivudina/agonistas , Pacientes/classificação , Gestão da Qualidade Total/organização & administração , Honorários e Preços/estatística & dados numéricos , Laboratórios/classificação , Manufaturas/provisão & distribuiçãoRESUMO
A reversed-phase high performance liquid chromatography (RP-HPLC) method with ultraviolet detection was developed and validated for the simultaneous quantification of antiretroviral drugs lamivudine (3TC), stavudine (d4T), and zidovudine (AZT) in perfusate samples obtained from the Single-Pass Intestinal Perfusion studies. The chromatographic analysis was performed using a Gemini C18 column and didanosine as internal standard (IS). The following parameters were considered for the validation procedure: system suitability, accuracy, precision, linearity and selectivity. The limits of detection were 0.32 µg/mL for 3TC, 0.11 µg/mL for d4T and 0.45 µg/mL for AZT and the limits of quantification were 1.06 µg/mL for 3TC, 0.38 µg/mL for d4T and 1.51 µg/mL for AZT. Repeatability and intermediate precision ranged from 1.05 to 1.31 and 1.50 to 1.87, respectively, and are expressed as percent of relative standard deviation (RSD). Based on these results, the developed and validated RP-HPLC method can be used for simultaneous determination of 3TC, d4T, and AZT in perfusate samples. Furthermore, this method is simple and adequate for measurements of the antiretroviral drugs in the same sample, since those compounds are mostly co-administered. Besides, this work can be used as an initial base for the development of similar methods in the same conditions presented in our study.
Assuntos
Zidovudina/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Lamivudina/farmacologia , Estudo de Validação , Antirretrovirais/farmacologia , Perfusão/instrumentação , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Limite de DetecçãoRESUMO
ABSTRACT Antiretroviral therapy (ART) has modified the outcome of patients with HIV infection, providing virological control and reducing mortality. However, there are several reasons as to why patients may discontinue their antiretroviral therapy, with adverse events being one of the main reasons reported in the literature. This is a case-control nested in a cohort of people living with HIV/AIDS, conducted to identify the incidence of ART modification due to adverse events and the associated factors, in two referral services in Recife, Brazil, between 2011 and 2014. Of the modifications occurred in the first year of ART, 25.7% were driven by adverse events. The median time elapsed between initiating ART and the first modification due to adverse events was 70.5 days (95% CI: 26-161 days). The main adverse events were dermatological, neuropsychiatric and gastrointestinal. Dermatological events were the earliest to appear after initiating ART. Efavirenz was the most prescribed and most modified drug during the study period. The group of participants who used zidovudine, lamivudine, and efavirenz had a 2-fold greater chance (adjusted OR: 2.16 95% CI: 1.28-3.65) of switching ART due to adverse events when compared to the group that used tenofovir with lamivudine and efavirenz.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fatores de Tempo , Brasil , Zidovudina/efeitos adversos , Modelos Logísticos , Fatores de Risco , Síndrome da Imunodeficiência Adquirida/mortalidade , Ritonavir/efeitos adversos , Lamivudina/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/efeitos adversos , Combinação de Medicamentos , Estimativa de Kaplan-Meier , Lopinavir/efeitos adversos , Tenofovir/efeitos adversosRESUMO
Background/objective: The World Health Organization (WHO) recommends routine assessment of antiretroviral treatment outcomes to detect treatment failure early and prevent the development of drug resistance. The aim of this study was to describe treatment outcomes of antiretroviral therapy (ART) over 2 years in children living with the human immune deficiency virus enrolled in the paediatric HIV clinic at the Lagos UniversityTeaching Hospital (LUTH). Materials and methods: This was a retrospective study of antiretroviral treatment outcomes in 278 children receiving antiretroviral therapy at the paediatric HIV clinic of LUTH. Demographic, clinical and laboratory data were retrospectively collected from clinical records of pediatric patients who received antiretroviral therapy for 2 years ( from November 2015 to December 2017) . Virological failure was defined as viral load > 400 copies/ml and immunological failure was defined as a CD4 count <100 cells/mm3 or CD4 % <15% after receiving antiretroviral agents for 12 months. Data was analysed using graph pad prism version 5.0.Results: After 12 months on antiretroviral therapy (ART), 101 (36%) had virological failure while 14 (5%) and 36 (13%) failed immunologically [CD4 count <100 cells/mn3 and CD4 <15% respectively]. Virological blips were observed at 24 months in 6.1% of patients while immunovirological discordance occurred in 30% of patients (poor virological clearance despite good immunological recovery) . High baseline viral load (>5000 copies/ml), poor adherence (<95%) and low baseline CD4 counts (101-249 cells/mn3) were significantly associated with virological failure, while low baseline CD4 counts (<350 cells/mn3) and poor adherence (<95%) were significantly associated with immunologic failure.Conclusion: The treatment outcomes observed in this study are similar to those reported in earlier studies. At 1 and 2 years of antiretroviral therapy , there was immune restoration however 101 (36%) and 87 (31%) respectively had virological failure despite good adherence to therapy and good Immunological restoration. This calls for early initiation and switch to second and third line drugs
Assuntos
Lagos , Lamivudina , Nevirapina , Nigéria , ZidovudinaRESUMO
Objetivo: Generar recomendaciones basadas en la mejor evidencia disponible acerca de la prevención y tratamiento de la infección por VIH en niños expuestos al VIH y niños con VIH/SIDA. Escenario: Recién nacidos expuestos al VIH y niños con VIH/SIDA. Tipo de pacientes y escenario clínico: Recién nacidos expuestos al VIH/SIDA. Usuarios de la guía: Todos los profesionales de salud que realizan la atención de niños expuestos al VIH y niños con VIH/SIDA: médicos, enfermeras, matronas, psicólogos, químicos farmacéuticos, trabajadores sociales, entre otros Metodología: Las recomendaciones de esta Guía fueron elaboradas de acuerdo con el sistema "Grading of Recommendations Assessment, Development, and Evaluation" (GRADE). Luego de priorizadas las preguntas a responder, se realizó la búsqueda y la síntesis de evidencia, para finalmente generar las recomendaciones a través del juicio del Panel de Expertos. La búsqueda y selección de la evidencia de esta Guía se basó en un método sistemático, transparente y reproducible. Una vez seleccionada la evidencia, se resumió en un formato claro y conciso que permitiera al Grupo Elaborador realizar los juicios respecto a la calidad de dicha evidencia, el balance entre los riesgos y beneficios asociados a la intervención o calidad de una prueba, un tratamiento, los valores y preferencias de los pacientes, y los costos derivados de su implementación.
Assuntos
Pediatria , Recém-Nascido , Zidovudina , Criança , Síndrome da Imunodeficiência Adquirida , Síndrome da Imunodeficiência Adquirida/prevenção & controle , HIV , Guia de Prática Clínica , ChileRESUMO
O objetivo deste artigo é destacar características e atravessamentos dos movimentos LGBTI brasileiros, da aids, do HIV e de coberturas jornalísticas da síndrome que surgiu publicamente no início dos anos 1980. Resgatamos dimensões históricas e questões atuais como desafiadoras para as ciências, a medicina, governos e militantes com o intuito de refletir sobre disputas que estiveram e estão em curso, principalmente aquelas que se relacionam com a LGBTIfobia e outras opressões sociais. A pesquisa foi realizada por meio de levantamento bibliográfico acerca das políticas do movimento LGBTI, do HIV e da aids, bem como do uso de resultados de pesquisa anteriormente realizada sobre homofobia e narrativas jornalísticas. Observou-se uma conexão complexa entre as relações engendradas no surgimento da síndrome, próxima aos primeiros passos do movimento LGBTI no Brasil, como a produção ambivalente de visibilidades, assim como a manutenção de preconceitos históricos que ainda reverberam no tecido social.
The aim of this article is to highlight the characteristics and crossings of Brazilian LGBTI, AIDS, HIV movements and of journalistic coverage of the syndrome that emerged publicly in the early 1980s. We brought up historical dimensions and current issues as challenging for the sciences, medicine, governments and militants in order to reflect on ongoing disputes, especially those that are related to LGBTIphobia and others social oppressions. The research was carried out through a bibliographical survey about policies of the LGBTI, HIV and AIDS movements, as well as the use of previously conducted research results on homophobia and journalistic narratives. It was observed a complex connection between the relations generated in the beginning of the syndrome, close to the first steps of the LGBTI movement in Brazil, as the ambivalent production of visibility, as well as the maintenance of historical prejudices that still reverberate in social world.
El objetivo de este artículo es subrayar puntos y atravesamientos de los movimientos LGBTI brasileños, del Sida, del VIH y de las coberturas periodísticas del síndrome que surgió en público en el principio de los años 1980. Rescatamos dimensiones históricas y cuestiones actuales desafiantes para las ciencias, la medicina, los gobiernos y militantes con el propósito de reflexionar sobre disputas que estuvieron y están en curso, principalmente aquellas que se relacionan con la LGBTIfobia y otras opresiones sociales. La investigación fue realizada por medio de levantamiento bibliográfico acerca de las políticas del movimiento LGBTI, del VIH y del Sida, así como del uso de resultados de investigación previamente realizada sobre homofobia y narrativas periodísticas. Se observó una conexión compleja entre las relaciones engendradas en el surgimiento del síndrome, próxima a los primeros pasos del movimiento LGBTI en Brasil, como la producción ambivalente de visibilidades, así como el mantenimiento de prejuicios históricos que aún reverberan en el tejido social.
Assuntos
Humanos , Brasil , Síndrome da Imunodeficiência Adquirida , HIV , Jornalismo , Minorias Sexuais e de Gênero , Doenças Virais Sexualmente Transmissíveis , Zidovudina , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Cultura , Rede Social , Profilaxia Pré-Exposição , Opressão SocialRESUMO
OBJECTIVE: The present literature review aims to highlight gaps in the treatment of preventative mother-to-child HIV transmission and the risk factors in Brazil. METHODS: Among the 425 articles identified in SciELO and PubMed searches, 59 articles published between 1994 and 2016 were selected for reading and data extraction, and 33 articles were included in the present review. RESULTS: The rates of vertical HIV transmission described in the studies varied widely, from 1.8% to 27.8%, with a significant reduction over the years. However, recent rates were also found to be variable in different regions of Brazil, and despite the significant reduction in mother-to-child transmission, many gaps remain in prevention services. A failure to attend prenatal care is the main factor associated with the increased risk of vertical transmission of HIV, hindering early maternal diagnosis and the completion of preventative measures during the prenatal period and, often, the peripartum and postnatal periods. A small number of studies discussed the sociodemographic factors, including a low level of education for pregnant women and the inadequacies of health services, such as difficulties scheduling appointments and undertrained staff, associated with vertical transmission. As such, the current challenge is to better define the sociodemographic and infrastructural factors that increase the risk of mother-to-child transmission of HIV to provide the necessary investments to promote an earlier inclusion of these populations in prevention services. CONCLUSIONS: This review may serve as a guide for future programs to focus efforts on the prevention of vertical HIV transmission.
Assuntos
Humanos , Feminino , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Cuidado Pré-Natal , Brasil , Zidovudina/uso terapêutico , Infecções por HIV/prevenção & controle , Fatores de Risco , Quimioterapia CombinadaRESUMO
Cell replacement therapy using neural progenitor cells (NPCs) following ischemic stroke is a promising potential therapeutic strategy, but lacks efficacy for human central nervous system (CNS) therapeutics. In a previous in vitro study, we reported that the overexpression of human arginine decarboxylase (ADC) genes by a retroviral plasmid vector promoted the neuronal differentiation of mouse NPCs. In the present study, we focused on the cellular mechanism underlying cell proliferation and differentiation following ischemic injury, and the therapeutic feasibility of NPCs overexpressing ADC genes (ADC-NPCs) following ischemic stroke. To mimic cerebral ischemia in vitro , we subjected the NPCs to oxygen-glucose deprivation (OGD). The overexpressing ADC-NPCs were differentiated by neural lineage, which was related to excessive intracellular calcium-mediated cell cycle arrest and phosphorylation in the ERK1/2, CREB, and STAT1 signaling cascade following ischemic injury. Moreover, the ADC-NPCs were able to resist mitochondrial membrane potential collapse in the increasingly excessive intracellular calcium environment. Subsequently, transplanted ADC-NPCs suppressed infarct volume, and promoted neural differentiation, synapse formation, and motor behavior performance in an in vivo tMCAO rat model. The results suggest that ADC-NPCs are potentially useful for cell replacement therapy following ischemic stroke.
Assuntos
Animais , Humanos , Camundongos , Arginina , Isquemia Encefálica , Cálcio , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Sistema Nervoso Central , Técnicas In Vitro , Potencial da Membrana Mitocondrial , Modelos Animais , Neurônios , Fosforilação , Plasmídeos , Células-Tronco , Acidente Vascular Cerebral , Sinapses , ZidovudinaRESUMO
BACKGROUND AND OBJECTIVES: Several recent studies have claimed that cancer cells can be reprogrammed into induced pluripotent stem cells (iPSCs). However, in most cases, cancer cells seem to be resistant to cellular reprogramming. Furthermore, the underlying mechanisms of limited reprogramming in cancer cells are largely unknown. Here, we identified the candidate barrier genes and their target genes at the early stage of reprogramming for investigating cancer reprogramming.METHODS: We tried induction of pluripotency in normal human fibroblasts (BJ) and both human benign (MCF10A) and malignant (MCF7) breast cancer cell lines using a classical retroviral reprogramming method. We conducted RNA-sequencing analysis to compare the transcriptome of the three cell lines at early stage of reprogramming.RESULTS: We could generate iPSCs from BJ, whereas we were unable to obtain iPSCs from cancer cell lines. To address the underlying mechanism of limited reprogramming in cancer cells, we identified 29 the candidate barrier genes based on RNA-sequencing data. In addition, we found 40 their target genes using Cytoscape software.CONCLUSIONS: Our data suggest that these genes might one of the roadblock for cancer cell reprogramming. Furthermore, we provide new insights into application of iPSCs technology in cancer cell field for therapeutic purposes.
Assuntos
Humanos , Neoplasias da Mama , Linhagem Celular , Reprogramação Celular , Fibroblastos , Células-Tronco Pluripotentes Induzidas , Métodos , Transcriptoma , ZidovudinaRESUMO
With the advent of the antiretroviral therapy (ART), people infected with HIV are experiencing a significant increase in life expectancy. However, as this population ages, the morbidity and mortality due to events not related to HIV infection and/or treatment become increasingly clear. Cardiovascular diseases are among the major causes of death, and, thus, understanding the factors that trigger this situation is necessary. This review article will assess how the intrinsic and extrinsic factors related to HIV, ART and the associated risk factors can aid the epidemiological transition of mortality in this population. Moreover, we will present the studies on the epidemiology and pathogenesis of each clinical condition related to HIV-infected individuals, in addition to introducing the major markers of cardiovascular disease in this population. Finally, we will point the main issues to be addressed by health professionals for an adequate prognosis
Assuntos
Humanos , Masculino , Feminino , Síndrome da Imunodeficiência Adquirida , Terapia Antirretroviral de Alta Atividade , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , HIV , Síndrome Retroviral Aguda , Fatores Etários , Diabetes Mellitus , Dislipidemias , Hipertensão/complicações , Síndrome Metabólica , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Fatores de Risco , Fatores Sexuais , Drogas Ilícitas/efeitos adversos , Tabagismo/complicações , Zidovudina/uso terapêuticoRESUMO
Introducción: el embarazo controlado y la supresión del amamantamiento son estrategias para disminuir la transmisión vertical (TMI) del virus de inmunodeficiencia humana (VIH). La profilaxis al neonato con zidovudina o zidovudina con nevirapina se utiliza según el riesgo de TMI. Objetivo: describir la TMI entre los años 2012 y 2014 en el Centro Hospitalario Pereira Rossell (CHPR), su relación con la carga viral materna y el cumplimiento de la recomendación AZT-NVP al neonato. Material y método: estudio descriptivo en el Centro de Referencia Obstétrico - Pediátrico VIH-Sida desde 1° de setiembre de 2012 al 31de diciembre 2014. Se incluyeron los recién nacidos de mujeres con carga viral detectable o indetectable al momento del parto. Se registró la administración de zidovudina-nevirapina. Se determinó la transmisión vertical. Resultados: se incluyeron 162 mujeres, 86 con carga viral detectable o desconocida y 76 indetectable. Las primeras tuvieron 88 hijos y las segundas 76. La TMI global fue de 4,9%; 9% en el primer grupo y 0% en el segundo. Se registró asociación entre TMI y CV materna (p <0,05). La administración de AZT-NVP se indicó en 46,5% de los niños. De los ocho niños infectados, la TMI fue intraútero en cinco. En los tres restantes, dos recibieron AZT y otro ninguna profilaxis. Discusión y conclusiones: la mitad de las mujeres no controló bien su embarazo. La TMI promedio fue de 4,9%. De los ocho infectados, cinco fueron intraútero; solo un diagnóstico y tratamiento precoces lo hubiesen evitado. El protocolo AZT-NVP no se utiliza en forma adecuada. Quizá su aplicación en los tres niños restantes hubiera evitado la infección.
Introduction: controlled pregnancy and interruption of breastfeeding are strategies used to reduce vertical transmission of the immunodeficiency virus (HIV). Neonates are subject to prophylactic treatment of zidovudine or combination therapy with zidovudine and nevirapine based on the mother-to-child transmission risk. Objective: to describe mother-to-child transmission from 2012 to 2014 at the Pereira Rossell Hospital Center, its relationship with the maternal viral load and the observation of the AZT-NVP prophylactic treatment recommended for neonates. Method: descriptive study, at the Obstetric Pediatrix HIV-Aids Reference Center from September 1, 2012 until December, 31, 2014. The newborns to mother with detectable or undetectable viral loads at the time of delivery. Administration of zidovudine-nevirapine was recorded. Vertical transmission was defined. Results: 162 women were included in the study, 86 of them with a detectable or unknown viral load and 76 women with a detectable load. The first group gave birth to 88 children and the second one to 76. Global mother-to-child transmission rate was 4.9%, 9% in the first group and 0% in the second one. The association between mother-to-child transmission and maternal load was recorded (P<0.05). Administration of AZT-NVP was indicated in 45.5% of children. Intrauterine mother-to child transmission was 5 for the 8 infected children. As to the other three children: 2 received AZT and another one received no prophylactic therapy. Discussion and conclusions: fifty per cent of the women's pregnancies were not dully controlled. Average mother-to-child transmission was 4.9%. Out of the 8 infected cases, 5 happened in the uterus, only an early diagnosis and treatment would have prevented it from happening. The AZT-NVP protocol is not applied in the right way. Its application on the other 3 children may have avoided the infection.
Introdução: o controle da gravidez e a supressão do aleitamento materno são estratégias para diminuir a transmissão vertical (TMI) do Vírus da Imunodeficiência Humana (VIH). No neonato, a profilaxia com zidovudina ou zidovudina com nevirapina é utilizada de acordo com o risco de TMI. Objetivo: descrever a TMI no período 2012-2014 no CHPR, sua relação com a carga viral materna e o cumprimento da recomendação AZT-NVP no neonato. Material e métodos: estudo descritivo, realizado no Centro de Referencia Obstétrico- Pediátrico VIH-Sida no período 1° de setembro de 2012 31 de dezembro de 2014. Foram incluídos os recém-nascidos de mulheres com carga viral (CV) detectável ou indetectável no momento do parto. A administração de zidovudina nevirapina e a transmissão vertical foram registradas. Resultados: foram incluídas 162 mulheres, 86 com carga viral detectável ou desconhecida e 76 indetectável. As primeiras tiveram 88 filhos e as segundas 76. A TMI global foi de 4,9%, 9% no primeiro grupo e 0% no segundo. A associação entre TMI e CV materna (P<0.05) foi registrada. A administração de AZT-NVP foi indicada em 46.5% das crianças. Nas 8 crianças infectadas, a TMI foi intrauterina em 5 . Nas 3 restantes, duas receberam AZT e a restante não recebeu nenhum tipo de profilaxia. Discussão e conclusões: a metade das mulheres não controlou sua gravidez adequadamente. A TMI média foi de 4.9%. Das 8 infectadas, 5 foram intrauterinas; somente o diagnóstico e tratamento precoces poderiam ter evitado. O protocolo AZT-NVP, não foi utilizado de forma adequada. É possível que sua aplicação nas 3 crianças restantes tivesse evitado a infecção.
Assuntos
Gravidez , Infecções por HIV/terapia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Nevirapina/uso terapêutico , Zidovudina/uso terapêuticoRESUMO
O uso de ferramentas estatísticas no ciclo de vida de um produto farmacêutico permite verificar e controlar o processo tendo como objetivo a sua melhoria contínua. No presente estudo foi avaliada a estabilidade e a capacidade estatística do processo de fabricação dos comprimidos revestidos de lamivudina 3TC e zidovudina AZT (150 + 300 mg) fabricados pela Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP). Esse medicamento, distribuido gratuitamente pelo programa DST/AIDS do Ministério da Saúde, e fabricado por compressão direta, processo rápido que permite a implementação futura da tecnologia analítica de processo (Process Analytical Technology - PAT). No Capítulo I foi realizada avaliação retrospectiva da variabilidade de atributos criticos da qualidade de 529 lotes dos comprimidos fabricados de acordo com a RDC ANVISA 17/2010 e as monografias oficiais, sendo tais atributos: peso médio, uniformidade de dose unitária e % m/v de fármaco dissolvido, antes e após o revestimento. O objetivo foi identificar eventuais causas especiais de variabilidade dos processos que permitam melhorias contínuas. No Capitulo II foi desenvolvida metodologia analítica empregando a espectroscopia no infravermelho próximo com transformada de Fourier para a avaliação da homogeneidade da mistura dos pós. Nesse estudo foram analisadas amostras de misturas dos fármacos lamivudina 3TC e zidovudina AZT e mistura excipiente, empregando como método de referência a CLAE, para a quantificação desses dois fármacos. No Capitulo I, a avaliação do processo para o peso médio revelou a necessidade de investigação das causa especiais de variabilidade, evidenciada por meio das cartas de controle. Os resultados do ano de 2015 indicaram necessidade de centralização e de consistência do processo, com redução de probabilidade de falha. As cartas de controle para uniformidade de dose unitária, no ano de 2013, revelaram menor variabilidade do processo. Porem, nesse ano, a análise estatística para a dissolução revelou processo descentralizado e sem consistência, com maior evidência para o fármaco 3TC que demonstrou menor desempenho, Cpk<1,0. A avaliação da estabilidade e da capacidade do processo de fabricação de comprimidos de lamivudina + zidovudina (150+300 mg), no período de 2012 a 2015, permitiu o maior entendimento de suas fontes de variação. Foi possível detectar e determinar o grau dessa variação e seu impacto no processo e nos atributos críticos de qualidade do produto com evidentes oportunidades de melhoria do processo, reduzindo os riscos para o paciente. No capítulo II, no desenvolvimento do método, as estatísticas de validação revelaram que os menores valores de BIAS foram observados para a 3TC, 0,000116 e 0,0021, respectivamente para validação cruzada e validação. Os valores de BIAS próximos a zero indicaram reduzida porcentagem de variabilidade do método. O presente estudo demonstrou a viabilidade do uso do modelo desenvolvido para a quantificação da 3TC e AZT por FT-NIR apos ajustes que contribuam para a elevação de R, R2 e RPD para valores aceitáveis. Valores de RPD acima de 5,0 que permitem o uso do modelo para uso em controle de qualidade
The use of statistical tools in the life cycle of a pharmaceutical product allows verifying and controlling the process aiming at its continuous improvement. In the present study, the stability and statistical capacity of the lamivudine coated tablets 3TC and zidovudine AZT (150 + 300 mg) manufactured by the Chopin Tavares de Lima Foundation (FURP) were evaluated. This drug, distributed free of charge by the Ministry of Health's DST/AIDS program, is manufactured by direct compression, a rapid process that allows the future implementation of Process Analytical Technology (PAT). In Chapter I, a retrospective evaluation of the variability of critical quality attributes of 529 batches of tablets manufactured was carried out, such attributes being: mean weight, unit dose uniformity and % m/v of dissolved drug substances, before and after coating. The objective was to identify possible special causes of variability of the processes that allow continuous improvements. In Chapter II an analytical methodology was developed employing the near infrared spectroscopy with Fourier transform for the evaluation of the homogeneity of the powder mixture. In this study, samples of mixtures of the drugs lamivudine 3TC and zidovudine AZT and excipient mixture were analyzed, using as reference method the HPLC, for the quantification of these two drugs. In Chapter I, the evaluation of the process for the mean weight revealed the need to investigate the special cause of variability, as evidenced by the charts. The results of the year 2015 indicated the need for centralization and process consistency, with a reduction in the probability of failure. The control charts for unit dose uniformity, in the year 2013, revealed less process variability. However, in that year, the statistical analysis for dissolution revealed a decentralized process with no consistency, with greater evidence for the 3TC drug that showed lower performance, Cpk<1.0. The evaluation of the stability and capacity of the lamivudine + zidovudine tablet manufacturing process (150 + 300 mg) in the period from 2012 to 2015 allowed a better understanding of its sources of variation. It was possible to detect and determine the degree of this variation and its impact on the process and the critical quality attributes of the product with evident opportunities to improve the process, reducing risks for the patient. In Chapter II, in the development of the method, the validation revealed that the lowest values of BIAS were observed for 3TC, 0.000116 and 0.0021, respectively for cross validation and validation. BIAS values close to zero indicated a reduced percentage of variability of the method. The present study demonstrated the feasibility of using the model developed for the quantification of 3TC and AZT by FT-NIR after adjustments that contribute to the elevation of R, R2 and RPD to acceptable values. RPD values above 5.0 that allow the use of the model for use in quality control
Assuntos
Comprimidos/análise , Zidovudina/análise , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Lamivudina/análise , Estudo de Validação , Composição de Medicamentos/instrumentaçãoRESUMO
Introducción: El Virus de la Inmunodeficiencia Adquirida (VIH) se presenta actualmente como uno de los problemas más serios de salud pública a nivel mundial debido a la alta tasa de casos nuevos. En Paraguay, según los últimos informes del PRONASIDA, en el 2017, el 23,92% del total de mujeres que ingresaron al programa fueron embarazadas. Objetivos: Caracterizar a las embarazadas portadoras de VIH en el Hospital Regional de Coronel Oviedo, periodo 2007 - 2017. Materiales y método: Estudio observacional descriptivo de corte transversal. Fueron incluidas todas las embarazadas portadoras de VIH que acudieron al Hospital Regional de Coronel Oviedo, 2007 - 2017 con fichas clínicas completas según los datos de interés para este trabajo. Resultados: Ingresaron al estudio 73 embarazadas portadoras de VIH. La mediana de edad fue de 23 años y la mitad de la población estuvo entre 19 a 28 años. La mayor cantidad de ingresos fueron en los años 2012 y 2014. El 93,15% de las embarazadas procedieron del departamento de Caaguazú y la mayoría fueron captadas en el Hospital Regional de Coronel Oviedo; siendo el rango del primer contacto con el servicio entre las 6 y 39 semanas de gestación. El 69,86% de las gestantes fueron diagnosticadas portadoras del virus antes del embarazo, el 61,64% y el 83,56% utilizó antirretrovirales (ARV) antes y durante del embarazo, respectivamente. El nacimiento se produjo entre las 35 y 40 semanas de gestación, el 93,15% fue por cesárea y el 95,89% de las gestantes recibieron Zidovudina (AZT) endovenoso durante el parto. Conclusión: En este servicio no se encontró ningún caso de transmisión materno-infantil del VIH, por más de que en algunas pacientes el diagnóstico y tratamiento fue a una edad gestacional muy avanzada.
Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Adolescente , Adulto , Adulto Jovem , Infecções por HIV/prevenção & controle , Infecções por HIV/epidemiologia , Paraguai/epidemiologia , Fatores Socioeconômicos , Aleitamento Materno , Zidovudina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Estudos Transversais , Fatores de Risco , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Idade Gestacional , Distribuição por Idade , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêuticoRESUMO
Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.
Resumen Introducción: El tratamiento inicial de la infección por VIH se basa en el uso de tres medicamentos, dos de ellos inhibidores de transcriptasa reversa análogos de nucleósido. Existen tres combinaciones de estos medicamentos aprobadas por diferentes guías, con resultados divergentes en cuanto a eficacia y seguridad. Objetivo: Comparar la eficacia y seguridad de las 3 combinaciones Métodos: Revisión sistemática y metanálisis en red de ensayos clínicos con asignación aleatoria comparando dosis fijas de Tenofovir Disoproxil Fumarato/Emtricitabina (TDF/FTC), Abacavir/Lamivudina (ABC/3TC) y Zidovudina/Lamivudina (ZDV/3TC). Resultados: Siete ensayos clínicos cumplieron los criterios de elegibilidad. Los resultados sugirieron mayor eficacia con TDF/FTC vs ABC/3TC a 96 semanas y vs. ZDV/3TC a 48 semanas. Sin embargo, existe heterogeneidad clínica y estadística. Se realizó análisis de subgrupos por tercer medicamento y por nivel de carga viral previa al tratamiento, sin encontrar diferencias en control virológico. Se pudo realizar metanálisis en red con TDF/FTC vs ZDV/3TC y proporción de pacientes con respuesta virológica, sin diferencias a las 48 semanas ni 96 semanas. Las comparaciones directas evidenciaron mayor riesgo de supresión de médula ósea de ZDV/3TC vs TDF/FTC y de reacciones de hipersensibilidad de ABC/3TC vs ZDV/3TC. Conclusión: Los resultados no demostraron diferencias en efectividad entre las intervenciones; sin embargo, debido a heterogeneidad en cuanto al tercer medicamento y el tiempo de seguimiento entre los estudios incluidos, dicho resultado no es definitivo. Los resultados plantean la necesidad de realizar nuevos estudios que ayuden a mejorar las recomendaciones de tratamiento en los pacientes infectados por el VIH.
Assuntos
Humanos , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/efeitos adversos , Zidovudina/administração & dosagem , Zidovudina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Fármacos Anti-HIV/efeitos adversos , Combinação de Medicamentos , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/administração & dosagem , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/efeitos adversos , Metanálise em RedeRESUMO
Abstract Background: Adult T-cell leukemia/lymphoma is a peripheral disease associated with human T-cell lymphotropic virus type 1. Treatment is carried out according to clinical type with watchful waiting being recommended for less aggressive types. Aggressive adult T-cell leukemia/lymphoma is generally treated with chemotherapy and/or antivirals. The objective of this study was to correlate the survival of patients diagnosed in Bahia, Brazil, with the therapeutic approaches employed and to evaluate what issues existed in their treatment processes. Methods: Eighty-three adult T-cell leukemia/lymphoma patients (26 smoldering, 23 chronic, 16 acute, 13 lymphoma and five primary cutaneous tumoral) with available data were included in this study. Results: Complete response was achieved in seven smoldering patients with symptomatic treatment, in two with chronic disease using antivirals/chemotherapy, in one with acute disease using antivirals and in one lymphoma using the LSG15 regimen [vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP); doxorubicin, ranimustine, and prednisolone (AMP); and vindesine, etoposide, carboplatin, and prednisolone (VECP)]. Smoldering patients who received symptomatic treatment presented longer survival. Favorable chronic patients treated with antivirals presented longer survival compared to the unfavorable subtype. However, for the acute form, first-line chemotherapy was better, albeit without significance, than antivirals. Only one of the patients with lymphoma and primary cutaneous tumors responded. Conclusions: Watchful waiting associated with phototherapy represents the best option for smoldering adult T-cell leukemia/lymphoma with survival in Bahia being superior to that described in Japan. There was a trend of better results with zidovudine/interferon-alpha in favorable chronic disease. Excellent results were achieved in the lymphoma type treated with the LSG15 protocol. Patients are diagnosed late probably due to lack of knowledge of adult T-cell leukemia/lymphoma by primary healthcare doctors and a Brazilian treatment protocol needs to be established.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Vírus Linfotrópico T Tipo 1 Humano , Infecções por HTLV-I , Leucemia-Linfoma de Células T do Adulto , Zidovudina , Leucemia , Linfoma de Células T PeriféricoRESUMO
A zidovudina (AZT), fármaco antirretroviral utilizado no tratamento da AIDS, apresenta biodisponibilidade oral em torno de 60% e seu uso prolongado pode ocasionar efeitos tóxicos e tolerância ao tratamento. A lamivudina (3TC), apesar de demonstrar menor citotoxicidade e menor resistência viral, é considerada também menos potente. A associação entre os dois fármacos é recomendável em função da boa resposta terapêutica e maior adesão ao tratamento. As nanopartículas são uma alternativa para melhorar a biodisponibilidade e o transporte de fármacos sobretudo através da BHE. Nesse sentido, as nanopartículas poliméricas de poli (n-butil cianoacrilato) (PBCA) apresentam grande potencial para melhoria das características farmacêuticas, além de possibilitar resultados terapêuticos mais eficazes por meio da modificação de sua superfície, direcionando o fármaco ao sítio alvo. Diante do exposto, foram desenvolvidas nanopartículas de PBCA contendo a associação lamivudina e zidovudina (3TC/AZT) revestidas com polissorbato 80 (Ps80). As nanopartículas obtidas foram caracterizadas e apresentaram resultados coerentes aos encontrados na literatura. Após a encapsulação dos fármacos e o revestimento com Ps80, notou-se um aumento no diâmetro médio e o potencial Zeta foi próximo de zero. Esses resultados juntamente com a análise de SAXS comprovam o revestimento das nanopartículas de PBCA. Os dados de DSC e TG/DTG mostram que a encapsulação foi eficiente para a estabilização térmica dos fármacos. Foi desenvolvido e validado o método analítico por CLAE, a fim de determinar a eficiência de encapsulação. A validação do método analítico para quantificação simultânea do 3TC e AZT, tanto nas nanopartículas de PBCA quanto nas nanopartículas revestidas, apresentou linearidade, especificidade, precisão e exatidão adequadas de acordo com as normativas. A porcentagem de encapsulação dos fármacos foi igual a 44,45% e 30,44%. As nanopartículas de PBCA e PBCAPs80, em concentrações abaixo de 100 µg/mL, apresentaram viabilidade celular superior a 70% em células Caco-2, comprovando que o sistema apresenta baixa citotoxicidade, o que representa uma alternativa promissora para a encapsulação de fármacos antirretrovirais e consequente progresso no tratamento da AIDS
Zidovudine (AZT), which is an anti-retroviral drug used in the treatment of AIDS, has oral bioavailability around 60% and its prolonged use can cause toxic effects and tolerance to the treatment. Lamivudine (3TC), although it has lower cytotoxicity and lower viral resistance, is also considered less potent. The association between these two drugs is recommended based on the good therapeutic response and greater adherence to treatment. Nanoparticles are an alternative to improve the bioavailability and the transport of drugs, particularly through the BBB. Thus, the polymeric nanoparticles of poly (n-butyl cyanoacrylate) (PBCA) have great potential for improving the pharmaceutical characteristics, besides enabling more effective therapeutic results through the modification of its surface, directing the drug to the target site. That being said, PBCA nanoparticles were developed containing the association of lamivudine and zidovudine (3TC/AZT) coated with polysorbate 80 (Ps80). Nanoparticles obtained were characterized and presented coherent results when compared to those found in the literature. After the encapsulation of pharmaceuticals and Ps80 coating, it was noted an increase in the average diameter and Zeta potential was close to zero. These results along with the SAXS analysis proved the coating of the PBCA nanoparticles. The data of DSC and TG/DTG show that encapsulation was efficient for thermal stabilization of pharmaceuticals. An analytical method by HPLC was developed and validated to determine the efficiency of encapsulation. The validation of the analytical method for simultaneous quantification of 3TC and AZT, in both the PBCA nanoparticles and coated nanoparticles, presented as in linearity, specificity, precision and accuracy according to the regulations. The percentage of drug encapsulation was equal to 44.45% and 30.44%. The nanoparticles of PBCA and PBCA-Ps80, at concentrations below 100 µg/ml, presented cell viability greater than 70% in Caco-2 cells, proving that the system has low cytotoxicity, which represents a promising alternative for the encapsulation of antiretroviral drugs and consequent progress in AIDS treatment
Assuntos
Zidovudina/farmacologia , Lamivudina/farmacologia , Nanopartículas/análise , Polissorbatos/farmacologia , Síndrome da Imunodeficiência Adquirida/prevenção & controleRESUMO
BACKGROUND/AIMS: Cancer is known to be a disease by many factors. However, specific results of reprogramming by pluripotency-related transcription factors remain to be scarcely reported. Here, we verified potential effects of pluripotent-related genes in hepatocellular carcinoma cancer cells. METHODS: To better understand reprogramming of cancer cells in different genetic backgrounds, we used four liver cancer cell lines representing different states of p53 (HepG2, Hep3B, Huh7 and PLC). Retroviral-mediated introduction of reprogramming related genes (KLF4, Oct4, Sox2, and Myc) was used to induce the expression of proteins related to a pluripotent status in liver cancer cells. RESULTS: Hep3B cells (null p53) exhibited a higher efficiency of reprogramming in comparison to the other liver cancer cell lines. The reprogrammed Hep3B cells acquired similar characteristics to pluripotent stem cells. However, loss of stemness in Hep3B-iPCs was detected during continual passage. CONCLUSIONS: We demonstrated that reprogramming was achieved in tumor cells through retroviral induction of genes associated with reprogramming. Interestingly, the reprogrammed pluripotent cancer cells (iPCs) were very different from original cancer cells in terms of colony shape and expressed markers. The induction of pluripotency of liver cancer cells correlated with the status of p53, suggesting that different expression level of p53 in cancer cells may affect their reprogramming.
Assuntos
Carcinoma Hepatocelular , Linhagem Celular , Patrimônio Genético , Células-Tronco Pluripotentes Induzidas , Neoplasias Hepáticas , Células-Tronco Pluripotentes , Fatores de Transcrição , ZidovudinaRESUMO
CXCR5⁺ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of Foxp3+ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in Foxp3⁺ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.
Assuntos
Humanos , Transferência Adotiva , Formação de Anticorpos , Doenças Autoimunes , Linfócitos B , Centro Germinativo , Linfócitos T , Linfócitos T Reguladores , ZidovudinaRESUMO
In spite of frequent usage of primary human foreskin keratinocytes (HFKs) in the study of skin biology, senescence-induced blockage of in vitro proliferation has been a big hurdle for their effective utilization. In order to overcome this passage limitation, we first isolated ten HFK lines from circumcision patients and successfully immortalized four of them via a retroviral transduction of high-risk human papillomavirus (HPV) E6 and E7 oncogenes. We confirmed expression of a keratinocyte marker protein, keratin 14 and two viral oncoproteins in these immortalized HFKs. We also observed their robust responsiveness to various exogenous stimuli, which was evidenced by increased mRNA expression of epithelial differentiation markers and pro-inflammatory genes in response to three reactive chemicals. In addition, their applicability to cytotoxicity assessment turned out to be comparable to that of HaCaT cells. Finally, we confirmed their differentiation capacity by construction of well-stratified three dimensional skin cultures. These newly established immortalized HFKs will be valuable tools not only for generation of in vitro skin disease models but also for prediction of potential toxicities of various cosmetic chemicals.
Assuntos
Humanos , Antígenos de Diferenciação , Biologia , Prepúcio do Pênis , Técnicas In Vitro , Queratina-14 , Queratinócitos , Proteínas Oncogênicas , Oncogenes , RNA Mensageiro , Dermatopatias , Pele , ZidovudinaRESUMO
ABSTRACT Zidovudine (AZT) mucoadhesive solid dispersions (SD) were prepared using a sodium starch glycolate (SSG) and hypromellose phthalate (HPMCP) mixtures as carrier to enhance the intestinal permeability and bioavailability of zidovudine. SDs were prepared using the co-precipitation method followed by solvent evaporation and characterized according to their physicochemical properties such as particle size, crystallinity, thermal behavior, and liquid uptake ability. In vitro drug dissolution, mucoadhesiveness and AZT intestinal permeability were also determined. Thermal behavior and X-ray diffraction patterns demonstrated the amorphous state of AZT in SD systems. The HPMCP polymer restricted the liquid uptake ability in the acid medium; however, this property significantly increased with higher pH values. SDs allowed drug dissolution to occur in a controlled manner. HPMCP decreased the dissolution rates in the acid medium. The mucoadhesiveness of SDs was demonstrated and the permeability of AZT carried in solid dispersions was significantly improved. The effect of the SD carrier polymers on blocking efflux pump can be an important approach to improve the bioavailability of AZT.