Reações de hipersensibilidade a vacinas / Hypersensitivity reactions to vaccines

O desenvolvimento e a ampliação do uso das vacinas durante décadas contribuíram para o controle e erradicação de doenças infecciosas, causando um grande impacto na saúde pública no mundo. A análise de segurança das vacinas percorre criteriosos processos e fases dos estudos clínicos, um dos pilares essenciais para aprovação regulatória e utilização do produto na população. O evento supostamente atribuído à vacinação e imunização (ESAVI), terminologia atual, é definido como qualquer ocorrência médica indesejada após a vacinação que possui, ou não, uma relação causal com o uso de uma vacina ou outro imunobiológico. Cabe ressaltar que eventos adversos mais raros ou inesperados, incluindo os eventos de hipersensibilidade, poderão ocorrer na fase pós-comercialização, quando as vacinas são aplicadas em milhões de pessoas. Neste artigo, serão discutidos os principais aspectos relacionados aos eventos adversos de hipersensibilidade pós-vacinais de interesse do especialista, e os desafios frente ao reconhecimento do agente causal e conduta a ser adotada. Além disso, serão revisados os potenciais alérgenos presentes nas vacinas de uso rotineiro para auxiliar o profissional de saúde na identificação de pacientes com potencial de risco de ESAVI por tais componentes. A atualização do conhecimento acerca da segurança e dos benefícios das vacinas pelos profissionais de saúde, sobretudo em populações especiais, contribui para condutas em imunização mais apropriadas, reduzindo o risco de exposição a um possível alérgeno em pessoas comprovadamente alérgicas às vacinas ou a alguns dos seus componentes, além de evitar contraindicações desnecessárias em eventos coincidentes ou não graves.

The expansion of vaccine use and development in recent decades has contributed to the control and eradication of infectious diseases, causing a major impact on public health worldwide. Vaccine safety analysis, which involves careful processes and clinical study, is one of the essential pillars of regulatory approval and use in the population. In current terminology, events supposedly attributable to vaccination and immunization (ESAVI) are defined as any unwanted medical occurrence after vaccination that may or may not have a causal relationship with vaccines or other immunobiologicals. It is noteworthy that rare or unexpected adverse events, including hypersensitivity, can occur during the post-marketing phase, when vaccines are administered to millions of people. In this article, we will discuss the main aspects of post-vaccine hypersensitivity events of interest to specialists and challenges to recognizing the causal agent and appropriate clinical practice. Potential allergens in routine vaccines will also be reviewed to help health professionals identify patients with a potential risk of ESAVI due to such components. Updating health professionals' knowledge about the safety and benefits of vaccines, particularly in special populations, can contribute to more appropriate clinical practice regarding immunization, reducing the risk of exposure to possible allergens in people with allergies to vaccines or their components, avoiding unnecessary contraindications in coincidental or non-serious events.

PVP solid dispersions containing Poloxamer 407 or TPGS for the improvement of ursolic acid release

Abstract Solid dispersions (SDs) of ursolic acid (UA) were developed using polyvinylpyrrolidone K30 (PVP K30) in combination with non-ionic surfactants, such as D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or poloxamer 407 (P407) with the aim of enhancing solubility and in vitro release of the UA. SDs were investigated using a 24 full factorial design, subsequently the selected formulations were characterized for water solubility, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), particle diameter, scanning electron microscopy, drug content, physical-chemical stability and in vitro release profile. SDs showed higher UA water-solubility than physical mixtures (PMs), which was attributed by transition of the drug from crystalline to amorphous or molecular state in the SDs, as indicated by XRD and DSC analyses. SD1 (with P407) and SD2 (with TPGS) were chosen for further investigation because they had higher drug load. SD1 proved to be more stable than SD2, revealing that P407 contributed to ensure the stability of the UA. Furthermore, SD1 and SD2 increased UA release by diffusion and swelling-controlled transport, following the Weibull model. Thus, solid dispersions obtained with PVP k-30 and P407 proved to be advantageous to enhance aqueous solubility and stability of UA.

Synthesis and In Vivo Hypolipidemic Effect of Some N-(Benzoylphenyl)-Carboxamide Derivatives in Triton WR-1339-Induced Hyperlipidemic Rats

A series of N-(benzoylphenyl)-carboxamide derivatives (2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a and 6b) was prepared with good yields by reacting the corresponding carbonyl chlorides with aminobenzophenones at room temperature. This was followed by evaluating the hypotriglyceridemic and hypocholesterolemic effects of 3b, 5a and 5b. Triton WR-1339 (300 mg/kg) was intraperitoneally administered to overnight-fasted rats to induce hyperlipidemia. Rats were divided into six groups: control, hyperlipidemic, hyperlipidemic plus compounds 3b, 5a and 5b and hyperlipidemic plus bezafibrate. Results showed that after 18 h of treatment at a dose of 15 mg/kg body weight of each of the test compounds, the elevated plasma levels of triglycerides (TG) and total cholesterol (TC) were significantly lowered by compounds 5b and 3b (p < 0.001) and by 5a (p < 0.0001), compared to the hyperlipidemic control group. Compounds 3b and 5a significantly increased levels of high-density lipoprotein cholesterol (HDL-C) by 58 and 71%, respectively. In addition, compounds 3b and 5a caused significant reduction (p < 0.0001) of low-density lipoprotein cholesterol (LDL-C) levels compared to the control group. These results suggest a promising potential for compounds 3b, 5a and 5b as lipid-lowering agents, which may contribute to reducing the risk of atherosclerosis and cardiovascular disease

Effect of carrier materials on the properties of the andrographolide solid dispersion

Abstract In the work the andrographolide (AG)-solid dispersions (SDs) were prepared by the spray-drying method, using polyethylene glycol 8000 (PEG8000), Poloxamer188, polyvinylpyrrolidone K30 (PVPK30), Soluplus® as carrier materials. The effect of different polymers as carrier materials on the properties of the AG-SDs were studied. The results showed obvious differences in intermolecular interaction, thermal stability, drug state, powder properties, dissolution behavior, and so on of AG-SDs prepared using different polymers as carrier materials. AG-PEG8000-SD was a partial-crystalline and partial-amorphous powder with smaller surface area and pore volume, but it was easy to wetting and did not swell in contact with dissolved medium. AG-Soluplus®-SD was completely amorphous powder with larger specific surface area and pore volume, but it swelled in contact with water. Therefore, the dissolution profile of AG in AG-PEG8000-SD was similar to that in AG-Soluplus®-SD. Soluplus® and PEG8000 were suitable polymers to design AG-SDs, considering both physicochemical properties and dissolution behaviors. The results of this reseach showed that when selecting carrier materials for SD, we should not only consider the state of drugs in SD and the powder properties of SD, but also consider whether there is swelling when the carrier materials are in contact with the dissolution medium.

Reactive aqueous two-phase systems for the production and purification of PEGylated proteins

BACKGROUND PEGylation, defined as the covalent attachment of polyethylene glycol, allows the synthesis of PEGylated therapeutic proteins with enhanced physicochemical properties. Traditional alkylating Nterminal PEGylation reactions on amine groups involve the use of modified linear mono-methoxy polyethylene glycol (mPEG) molecules looking for the synthesis of mono-PEGylated products. However, this approach requires different purification steps since inevitably undesired cross-linked products are synthesized. Herein, we propose the use of reactive aqueous two-phase systems (ATPS) to produce and purify PEGylated therapeutic conjugates using Ribonuclease A (RNase A) as a model protein. RESULTS: Selected linear 5 kDa and 20 kDa mPEG ­ potassium phosphate systems were produced according to equilibrium data obtained from constructed binodal curves. All reactive systems were able to generate biphasic systems and to PEGylate RNase A. Two 5 kDa and two 20 kDa systems were selected based on the reaction yield percentage and the feasibility of purifying the mono-PEGylated RNase A from the diPEGylated and native RNase A by contrasting the differences in their partition behaviors. The remnant biological activity was of 94% and of 100% for the mono-PEGylated RNase A purified from the 5 kDa and 20 kDa mPEG systems when compared to the mono-PEGylated conjugate obtained by standard procurement methods.

Efectividad y tolerabilidad de tres tipos de productos de preparación para colonoscopia / Effectiveness and tolerability of three types of colonoscopy preparation products

Resumen Objetivo: establecer las diferencias entre tres tipos de productos de preparación para colonoscopia, en cuanto a efectividad y tolerabilidad. Materiales y métodos: estudio de corte transversal, analítico, prospectivo, ciego para el evaluador de la escala de Boston. Se incluyeron pacientes adultos, mayores de 18 años con requerimiento de colonoscopia y diligenciamiento de la encuesta sobre el tipo de preparación realizada para la limpieza del colon. Resultados: se evaluaron 3 grupos de productos (polietilenglicol, picosulfatos, sales de sulfato) en 907 pacientes, se aplicó la escala de Boston total y por segmentos, sin encontrar diferencias estadísticamente significativas entre ellos (Odds ratio [OR]: 1,10; intervalo de confianza [IC] 95 %: 0,6-1,8; p = 0,728). El 60 % de la población fueron mujeres y la edad promedio 52 años. Se observó el cumplimiento de la dieta en el 99 % de los participantes. La preparación dividida tuvo mejores resultados en la escala de Boston (OR: 5,06; IC 95 %: 3,2-8,01; p = 0,001). Los picosulfatos tuvieron mayor aceptabilidad (OR: 15,8; IC 95 %: 8,83-28,3; p = 0,001) y menores efectos secundarios como distensión abdominal (OR: 0,59; IC 95 %: 0,3-0,9; p = 0,033) y vómito (OR: 0,25; IC 95 %: 0,07-0,82; p = 0,015). Se observó mejor resultado cuando se realizó el examen antes de 6 horas de finalizada la preparación (OR: 6,38; IC 95 %: 3,84-10,6; p = 0,001). Conclusiones: los productos evaluados no presentaron diferencias entre sí con respecto a su efectividad. Los picosulfatos tuvieron menores efectos secundarios y mejor aceptabilidad. Se obtuvo una mejor preparación del colon con preparación dividida y si el examen es hasta 6 horas de finalizada la preparación.

Abstract Objective: To establish the differences between three types of colonoscopy preparation products in terms of effectiveness and tolerability. Materials and methods: An analytical, prospective, blind, cross-sectional study of the Boston Bowel Preparation Scale was carried out. Adult patients over 18 years of age with a requirement for colonoscopy and completion of the survey on the type of preparation carried out for colon cleansing were included. Results: Three groups of products (polyethylene glycol, picosulfates, and sulfate salts) were evaluated in 907 patients. Total and segment Boston Bowel Preparation Scale was applied, without finding statistically significant differences between them (OR 1.10; 95%CI: 0.6-1.8; p = 0.728). 60% of the population were women and the average age was 52 years. Compliance with the diet was observed in 99% of the participants. Split-dose bowel preparation performed best on the Boston scale (OR 5.06; 95%CI; 3.2-8.01; p= 0.001). Picosulfates had greater acceptability (OR 15.8; 95%CI: 8.83-28.3; p= 0.001) and fewer side effects such as abdominal distension (OR 0.59; 95%CI: 0.3-0.9; p= 0.033) and vomiting (OR 0.25; 95%CI: 0.07-0.82; p= 0.015). The best result was observed when the test was performed within 6 hours of completion of preparation (OR 6.38; 95%CI: 3.84-10.6; p = 0.001). Conclusions: The products evaluated did not show differences between them regarding their effectiveness. Picosulfates had fewer side effects and better acceptability. Split-dose and testing up to 6 hours after preparation resulted in better bowel preparation.

Morphometric study of rat sciatic nerve recovery after three nerve repair techniques: epineural suture, polyethylene glycol hydrogel and fibrin sealant / Estudio morfométrico de la recuperación del nervio ciático de rata después de tres técnicas de reparación nerviosa: sutura epineural, hidrogel de polietilenglicol y sellante de fibrina

SUMMARY: The effectiveness of microsurgical technique has a direct impact on the recovery of the injured peripheral nerve. The aim of our study was to investigate the result of sciatic nerve regeneration in rats after complete neurotomy and after nerve repair techniques including: 1) epineural suture; 2) polyethylene glycol hydrogel (PEG) (DuraSeal); 3) fibrin sealant (Tisseel). The cross-section of distal sciatic nerve was studied at 14th, 30th and 60th days after nerve repair. Morphometry of myelinated nerve fibers in the distal stump of the sciatic nerve was performed. A significant increase in the number of myelinated nerve fibers was found, especially between 14 and 30 days. The density of myelinated nerve fibers in the distal stump at day 60 was significantly higher after using nerve repair technique including PEG and fibrin versus epineural suture (29.2 % and 32.1 % versus 21.5 %, P <0.05), and a higher level of remyelination of nerve fibers observed in the group with PEG. On day 60, complete elimination of PEG and fibrin sealant was not observed, encapsulation was found around the clusters of hydrogel. Thereby, three peripheral nerve repair techniques were equally effective, only with the use of PEG remyelination of nerve fibers was increasing.

RESUMEN: La efectividad de la técnica microquirúrgica tiene un impacto directo en la recuperación del nervio periférico lesionado. El objetivo de nuestro estudio fue investigar el resultado de la regeneración del nervio ciático en ratas después de una neurotomía completa y después de técnicas de reparación nerviosa que incluyeron: 1) sutura epineural; 2) hidrogel de polietilenglicol (PEG) (DuraSeal); 3) sellante de fibrina (Tisseel). La sección transversal del nervio ciático distal se estudió a los 14, 30 y 60 días después de la reparación del nervio. Se realizó la morfometría de fibras nerviosas mielinizadas en el muñón distal del nervio ciático. Se observó un aumento significativo en el número de fibras nerviosas mielinizadas, especialmente entre los 14 y 30 días. La densidad de las fibras nerviosas mielinizadas en el muñón distal en el día 60 fue significativamente mayor después de usar una técnica de reparación nerviosa que incluye PEG y fibrina en comparación con la sutura epineural (29,2 % y 32,1 % versus 21,5 %, P <0,05), y un mayor nivel de remielinización del nervio en fibras observadas en el grupo con PEG. El día 60, no se observó la eliminación completa de PEG y sellador de fibrina, se encontró encapsulación alrededor de los grupos de hidrogel. Por lo tanto, tres técnicas de reparación de nervios periféricos fueron igualmente efectivas, solo que aumentaba la remielinización de fibras nerviosas con PEG.

PEG-asparaginase and native Escherichia coli L-asparaginase in acute lymphoblastic leukemia in children and adolescents: a systematic review

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the cancer with the highest incidence in childhood and adolescence, and pharmacotherapy is the primary form of treatment. Objective and methods A systematic review of the efficacy and safety of polyethylene glycol (PEG)-asparaginase in acute lymphoblastic leukemia therapy in children and adolescents was conducted to compare it with native Escherichia coli L-asparaginase. PubMed, Web of Science, Science Direct, Cochrane Library, Scopus, LILACS (Latin American and Caribbean Health Sciences Literature) and EMBASE databases were selected. The following outcomes were analyzed: complete remission of the disease, event-free survival, overall survival, anti-asparaginase antibody level, hypersensitivity reactions, asparaginase and asparagine serum levels, number of postdiagnosis events, and overall mortality. Five randomized controlled trials were included. Analysis of the quality of evidence and risk of bias was performed using the Cochrane recommendation tool and the GRADE system. Results The assessment results suggest that the level of certainty on the technology addressed is relatively weak from a methodological point of view. Evidence is insufficient to assess the effects on health outcomes because of the limited number and power of studies and important flaws in their design or conduct in classifying PEG-asparaginase as a superior drug or not, in the pharmacotherapy of ALL in children and adolescents. PEG-asparaginase can be used as a substitute for native E. coli L-asparaginase, demonstrating similar efficacy and safety. Conclusion The study may help decision-makers in the public health system to offer a more in-depth judgment on the therapeutic alternatives used to treat this neoplasm in children and adolescents.

Assessment of tolerance and acceptability between mannitol solution and polyethylene glycol as bowel preparation for colonoscopy: a three-center study / Evaluación de tolerancia y aceptabilidad entre la solución de manitol y el polietilenglicol como preparación intestinal para la colonoscopía: un estudio de tres centros

ABSTRACT Introduction: Adequate bowel preparation is one of the most important factors related to the yield of colonoscopy. Low quality bowel preparation has been associated with lower adenoma detection rates and increased healthcare expenses. Bowel preparation is a major impediment to undergo colonoscopy since it is perceived as an unpleasant experience by patients. Objective: This study was aimed to assess tolerance and acceptability of the bowel preparation using either polyethylene glycol (PEG) or mannitol solution. Materials and methods: We enrolled 140 patients with indications of screening for colorectal cancer or with suspected large bowel diseases. They received either mannitol solution or PEG as bowel preparation. Patients were asked to fill a questionnaire about the bowel preparation experience. Results: Patients perceived more burdensome the preparation with PEG than mannitol for the variables nausea overall experience, post-procedure discomfort, disagreeable flavor, volume ingested and cost (p<0.05). A similar tolerance was reported for abdominal pain, bloating and anal irritation (p>0.05). The acceptability was 82.9% and 71.4% in the Mannitol group and in the PEG group, respectively (p=0.10). Conclusion: Acceptance of the bowel preparation between mannitol solution and PEG was comparable. However, mannitol was better tolerated by the patients in regard to most of the evaluated items.

RESUMEN Introducción: La preparación intestinal adecuada es uno de los factores más importantes relacionados con el rendimiento de la colonoscopía. La preparación intestinal de baja calidad se ha asociado con tasas de detección de adenoma más bajas y mayores gastos de atención sanitaria. La preparación intestinal es un impedimento importante para someterse a una colonoscopía, ya que los pacientes la perciben como una experiencia desagradable. Objetivo: Este estudio tuvo como objetivo evaluar la tolerancia y la aceptabilidad de la preparación intestinal utilizando polietilenglicol (PEG) o solución de manitol. Materiales y métodos: Fueron incluidos 140 pacientes con indicación de pesquisa de cáncer colorrectal o con sospecha de enfermedades del intestino grueso. Los pacientes recibieron solución de manitol o PEG como preparación intestinal. Se pidió a los pacientes que completaran un cuestionario sobre la experiencia de preparación intestinal. Resultados: Los pacientes percibieron más agobiante la preparación con PEG que el manitol para las variables náuseas, experiencia general, molestias posteriores al procedimiento, sabor desagradable, volumen ingerido y costo (p<0,05). Se informó una tolerancia similar para el dolor abdominal, distensión abdominal e irritación anal (p>0,05). La aceptabilidad fue de 82,9% y 71,4% en el grupo de manitol y en el grupo de PEG, respectivamente (p=0,10). Conclusión: La aceptación de la preparación intestinal entre la solución de manitol y el PEG fue comparable. Sin embargo, el manitol fue mejor tolerado por los pacientes con respecto a la mayoría de las variables evaluadas.

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

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

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

Cost-effectiveness analysis is a mandatory strategy for health systems: evidence from a study involving therapies for hepatitis C / Análise de custo-efetividade é uma estratégia essencial para os sistemas de saúde: as evidências de um estudo sobre terapias para hepatite C / El análisis de coste-efectividad es una estrategia esencial para los sistemas de salud: evidencias de un estudio sobre terapias para hepatitis C

Abstract: Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.

Resumo: A análise de custo-efetividade tem sido essencial para a tomada de decisões em saúde. Diversos países utilizam esse tipo de análise como síntese das evidências para incorporar as tecnologias em saúde. Os inibidores de protease (IPs) boceprevir (BOC) e telaprevir (TVR) são indicados para o tratamento da hepatite C crônica e foram incorporados nas diretrizes internacionais. Os ensaios clínicos pré-marketing demonstraram taxas mais altas de resposta virológica sustentada em relação às terapias anteriores, mas a incorporação dos IPs gerou um impacto financeiro significativo. O estudo teve como objetivo discutir a relevância da análise de custo-efetividade, através de um estudo que envolveu a inclusão de IPs em um protocolo clínico. A análise fez parte de um estudo de vida real que incluiu pacientes com infecção pelo vírus da hepatite C, genótipo 1, tratados em um hospital universitário terciário no Brasil. As terapias triplas (TTs) com ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) e BOC ou TVR foram comparadas às terapias duplas com RBV e Peg-INF α-2a. A análise de sensibilidade da custo-efetividade indicou odds de 88,2% de TTs apresentarem custo mais elevado por paciente curado. Em todos os cenários propostos, as razões de custo-efetividade incremental (ICERs) superaram em três vezes o produto interno bruto (PIB) per capita brasileiro. A sensibilidade da ICER mostrou probabilidade de 88,4% das TTs não serem custo-efetivas. O impacto da incorporação dos IPs foi negativo, e a conduta teria sido diferente se tivesse sido realizada uma análise prévia de custo-efetividade.

Resumen: El análisis de coste-efectividad ha sido esencial para la toma de decisiones en salud. Diversos países utilizan este tipo de análisis como síntesis de evidencias para incorporar tecnologías en salud. Los inhibidores de proteasa (IPs) boceprevir (BOC) y telaprevir (TVR) se indican para el tratamiento de la hepatitis C crónica y fueron incorporados en directrices internacionales. Los ensayos clínicos pre-marketing demostraron tasas más altas de respuesta virológica sostenida, respecto a las terapias anteriores, pero la incorporación de los IPs generó un impacto financiero significativo. El objetivo del estudio fue discutir la relevancia del análisis de coste-efectividad, a través de un estudio que implicó la inclusión de IPs en un protocolo clínico. El análisis formó parte de un estudio de vida real que incluyó a pacientes con infección por el virus de la hepatitis C, genotipo 1, tratados en un hospital universitario terciario en Brasil. Las terapias triples (TTs) con ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) y BOC o TVR se compararon con las terapias dobles con RBV y Peg-INF α-2a. El análisis de sensibilidad del coste-efectividad indicó odds de 88,2% de que las TTs presentaran un coste más elevado por paciente curado. En todos los escenarios propuestos, las razones de coste-efectividad incremental (ICERs) superaron tres veces el producto interno bruto (PIB) per cápita brasileño. La sensibilidad de la ICER mostró una probabilidad de que un 88,4% de las TTs no eran costo-efectivas. El impacto de la incorporación de los IPs fue negativo, y el resultado habría sido diferente si se hubiese realizado un análisis previo de coste-efectividad.

Resin-dentin bond stability of etch-and-rinse adhesive systems with different concentrations of MMP inhibitor GM1489

Abstract Enzymatic degradation of the hybrid layer can be accelerated by the activation of dentin metalloproteinases (MMP) during the bonding procedure. MMP inhibitors may be used to contain this process. Objective To evaluate the degree of conversion (DC%), dentin bond strength (µTBS) (immediate and after 1 year of storage in water), and nanoleakage of an experimental (EXP) and a commercial (SB) adhesive system, containing different concentrations of the MMP inhibitor GM1489: 0, 1 µM, 5 µM and 10 µM. Methodology DC% was evaluated by FT-IR spectroscopy. Dentin bond strength was evaluated by µTBS test. Half of beams were submitted to the µTBS test after 24 h and the other half, after storage for 1 year. From each tooth and storage time, 2 beams were reserved for nanoleakage testing. Data were analyzed using ANOVA and Tukey's test to compare means (α=0.05). Results All adhesive systems maintained the µTBS after 1 year of storage. Groups with higher concentrations of inhibitor (5 µM and 10 µM) showed higher µTBS values than groups without inhibitor or with 1 µM. The nanoleakage values of all groups showed no increase after 1 year of storage and values were similar for SB and EXP groups, in both storage periods. The inhibitor did not affect the DC% of the EXP groups, but the SB5 and SB10 groups showed higher DC% values than those of SB0 and SB1. Conclusions The incorporation of GM1489 in the adhesive systems had no detrimental effect on DC%. The concentrations of 5 µM GM1489 for SB and 5 µM or 10 µM for EXP provided higher μTBS than groups without GM1489, in the evaluation after 1 year of storage; whereas the concentration of inhibitor did not affect adhesive systems nanoleakage.

A nanoemulsion-based delivery system for imatinib and in vitro anticancer efficacy

A self-nanoemulsifying drug delivery system (SNEDDS) composed of ethyl oleate, Tween 80 and polyethylene glycol 600 was prepared as a new route to improve the efficacy of imatinib. The drug-loaded SNEDDS formed nanodroplets of ethyl oleate stabilized by Tween 80 and polyethylene glycol 600 with a diameter of 81.0±9.5 nm. The nanoemulsion-based delivery system was stable for at least two months, with entrapment efficiency and loading capacity of 16.4±0.1 and 48.3±0.2%, respectively. Imatinib-loaded SNEDDS was evaluated for the drug release profiles, and its effectiveness against MCF-7 cell line was investigated. IC50 values for the imatinib-loaded SNEDDS and an imatinib aqueous solution were 3.1 and 6.5 µg mL-1, respectively.

Can composition and preheating improve infiltrant characteristics and penetrability in demineralized enamel?

Abstract The composition of infiltrants can influence their physical properties, viscosity and depth of penetration (DP). Strategies are used to increase the DP, such as the addition of diluents or the use of heat. This study aimed to evaluate the effect of preheating and composition on physical properties and DP of infiltrants in demineralized enamel. The groups were assigned, and the following experimental formulations were made: 25%BisEMA +75%TEGDMA; 25%BisEMA +65%TEGDMA +10%ethanol; 25%BisEMA +65%TEGDMA +10%HEMA; 100%TEGDMA; 90%TEGDMA +10%ethanol; 90%TEGDMA +10%HEMA. The samples were photoactivated at two temperatures (25°C and 55°C). Degree of conversion (DC) was performed using an infrared spectrophotometer. Elastic modulus (E), flexural strength (FS) and contact angle (CA) tests were also performed. The DP of an infiltrant in demineralized enamel was determined by confocal laser scanning microscopy (CLSM) using an indirect labeling technique. The data were analyzed by two-way ANOVA and Tukey's test. DC increased after preheating in all the groups; however, 90%TEGDMA+10%ethanol showed the lowest DC for both temperatures, and the lowest E. Preheating did not influence E or FS. The CA increased at 55°C for most groups, but decreased for groups containing HEMA. Temperature did not seem to influence DP, and Icon showed the lowest DP values. The 100%TEGDMA composition showed more homogeneous penetration, whereas Icon showed heterogeneous and superficial penetration. The preheating technique does not improve all properties in all the material compositions. The composition of a material can influence and improve its properties.

Germination and osmotic adjustment in Salvia hispanica L. (Lamiaceae) seedlings under water and thermal stress / Germinação e ajustamento osmótico em plântulas de Salvia hispanica L. (lamiaceae) sob estresse hídrico e térmico

Salvia hispanica seedlings have stood out for their potentialities in nutrients for agri-food industries. Nevertheless, studies related to this species are still scarce, especially with respect to agronomic factors that enable its propagation and development. Hence, this study aimed to evaluate germination, vigor and osmotic adjustment of S. hispanica seeds and seedlings subjected to water and thermal stress. The experimental design was completely randomized, with treatments arranged in factorial scheme, corresponding to five levels of polyethylene glycol (PEG 6000) (0.0; -0.1; -0.2; -0.3 and -0.4 MPa) and five temperatures (20, 25, 30 and 20-30 °C), with four replicates of 50 seeds in each treatment. Germination test was set on blotter paper, moistened with PEG 6000 solutions at the previously mentioned potentials, under 8-h photoperiod. The following variables were analyzed: germination, germination speed index, seedling shoot length, seedling root length, seedling dry matter and contents of chlorophyll, carotenoids, amino acids, proline and sugars. Polyethylene glycol levels of -0.4 MPa at all temperatures and -0.3 MPa at 30 °C and 20-30 °C enable germination and vigor of S. hispanica seedlings. S. hispanica seedlings are able to perform osmotic adjustment under water stress conditions up to the level of -0.3 MPa, when grown from seeds germinated at temperatures of up to 25 ºC.

As sementes de S. hispanica têm se destacado pela sua potencialidade em nutrientes para as indústrias agroalimentares. No entanto, ainda são escassas as pesquisas relacionadas a esta espécie, principalmente no tocante aos fatores agronômicos que viabilizem a sua propagação e desenvolvimento. Com isso, objetivou-se verificar a germinação, vigor e ajustamento osmótico de sementes e plântulas de S. hispanicasubmetidas aos estresses hídrico e térmico. O delineamento experimental foi o inteiramente casualizado, com tratamentos distribuídos em esquema fatorial, correspondente a cinco níveis de polietileno glicol (PEG 6000) (0,0; -0,1; -0,2; -0,3 e -0,4 MPa) e quatro temperaturas (20, 25, 30 e 20-30 °C), com quatro repetições de 50 sementes para cada tratamento. Para isso, instalou-se o teste de germinação em substrato mata-borrão, umedecidos com soluções de PEG 6000 nos potenciais mencionados, sob fotoperíodo de 8 horas de luz. As variáveis analisadas foram germinação, índice de velocidade de germinação, comprimento de parte aérea e das raízes das plântulas, massa seca de plântulas, teores de clorofila e carotenoides, aminoácidos, prolina e açúcares. O nível de polietilenoglicol de -0,4 MPa para todas as temperaturas estudadas, e -0,3 MPa nas temperaturas de 30 °C e 20-30 °C inviabilizam a germinação e o vigor das plântulas de S. hispanica. As plântulas de S. hispanica são capazes de realizar ajuste osmótico sob condições de estresse hídrico até os níveis de -0,3 MPa, quando provenientes de sementes germinadas em temperaturas de até 25 ºC.

Effect of polyethylene glycol versus lactulose on abdominal pain in children occult constipation: a randomized controlled study: un estudio controlado aleatorio / Efecto del polietilenglicol versus lactulosa sobre el dolor abdominal en el estreñimiento oculto en niños

Introduction and aim: Functional abdominal pain (FAP) is one of the major gastrointestinal complaints in childhood. Studies have reported occult constipation (OC) as one of the leading causes of abdominal pain. Recent researches have proposed laxatives as potent therapeutic targets for abdominal pain in patients with OC. However, no study has compared effect of poly ethylene glycol (PEG) and lactulose on occult constipation. Materials and methods: 51 patients aged 4 to 18 years with abdominal pain who had OC (defined as fecal impaction in abdominal X ray) were studied. Demographic and clinical data including age, sex, body weight, height, abdominal pain duration, abdominal pain rate and fecal odor were registered. They were randomly assigned to receive PEG (1gr/kg) or Lactulose (1cc/kg) for at least two weeks. All patients were reevaluated by pain measurement scale after at least two weeks of treatment. Results: It is indicated that the efficacy of PEG for reducing abdominal pain in OC was 48% while it was 37% for Lactulose. This study indicated that this efficacy is not affected significantly by sex and fecal odor, however this efficacy is influenced by age, body weight, abdominal pain duration and abdominal pain rate for both PEG and Lactulose. Conclusion: It could be concluded that PEG is a more efficient drug for treating abdominal pain in occult constipation than Lactulose and its optimum effect can be achieved in elder patients with more severe abdominal pain.

Introducción y objetivo: El dolor abdominal funcional (FAP) es una de las principales molestias gastrointestinales en la infancia. Los estudios han informado que el estreñimiento oculto (OC) es una de las principales causas de dolor abdominal. Investigaciones recientes han propuesto laxantes como objetivos terapéuticos potentes para el dolor abdominal en pacientes con OC. Sin embargo, ningún estudio ha comparado el efecto del polietilenglicol (PEG) y la lactulosa sobre el estreñimiento oculto. Materiales y métodos: Se estudiaron 51 pacientes de 4 a 18 años con dolor abdominal que tenían OC (definida como impactación fecal en rayos X abdominales). Se registraron datos demográficos y clínicos que incluyen edad, sexo, peso corporal, altura, duración del dolor abdominal, tasa de dolor abdominal y olor fecal. Fueron asignados aleatoriamente para recibir PEG (1 gr/kg) o lactulosa (1 cc/kg) durante al menos dos semanas. Todos los pacientes fueron reevaluados por la escala de medición del dolor después de al menos dos semanas de tratamiento. Resultados: Se indica que la eficacia de PEG para reducir el dolor abdominal en OC fue del 48% mientras que fue del 37% para la lactulosa. Este estudio indicó que esta eficacia no se ve afectada significativamente por el sexo y el olor fecal, sin embargo, esta eficacia está influenciada por la edad, el peso corporal, la duración del dolor abdominal y la tasa de dolor abdominal tanto para PEG como para lactulosa. Conclusión: Se podría concluir que el PEG es un fármaco más eficaz para tratar el dolor abdominal en el estreñimiento oculto que la lactulosa y que su efecto óptimo se puede lograr en pacientes mayores con dolor abdominal más severo.Palabras clave: dolor abdominal, estreñimiento oculto, polietilenglicol, lactulosa.

Synthesis, characterization, and in vitro evaluation of gamma radiationinduced PEGylated isoniazid

Background: The search for innovative anti-tubercular agents has received increasing attention in tuberculosis chemotherapy because Mycobacterium tuberculosis infection has steadily increased over the years. This underlines the necessity for new methods of preparation for polymer-drug adducts to treat this important infectious disease. The use of poly(ethylene glycol)(PEG) is an alternative producing anti-tubercular derivatives. However, it is not yet known whether PEGylated isonicotinylhydrazide conjugates obtained by direct links with PEG are useful for therapeutic applications. Results: Here, we synthesized a PEGylated isoniazid (PEG-g-INH or PEG­INH) by gamma radiation-induced polymerization, for the first time. The new prodrugs were characterized using Raman and UV/Vis spectrometry. The mechanism of PEGylated INH synthesis was proposed. The in vitro evaluation of a PEGylated isonicotinylhydrazide macromolecular prodrug was also carried out. The results indicated that PEG­INH inhibited the bacterial growth above 95% as compared with INH, which showed a lower value (80%) at a concentration of 0.25 µM. Similar trends are observed for 0.1, 1, and 5 µM. Conclusions: In summary, the research suggests that it is possible to covalently attach the PEG onto INH by the proposed method and to obtain a slow-acting isoniazid derivative with little toxicity in vitro and higher antimycobacterial potency than the neat drug.