Synthesis of New Indanyl Nucleoside Analogues and their Biological Evaluation on Hepatitis C Virus (HCV) Replicon.

Here, we report a convenient synthetic procedure for the preparation of four novel indanyl carbanucleoside derivatives in the racemic form. The action of these compounds against hepatitis C virus was evaluated in vitro using the replicon cell line, Huh7.5 SG. Contrary to our expectations, all these compounds did not inhibit, but rather promoted HCV genotype 1b (HCVg1b) replication. Similar effects have been reported for morphine in the replicon cell lines, Huh7 and Huh8. Several biological experiments and computational studies were performed to elucidate the effect of these compounds on HCVg1b replication. Based on all the experiments performed, we propose that the increase in HCVg1b replication could be mediated, at least in part, by a similar mechanism to that of morphine on the enhancement of this replication. The presence of opioid receptors in Huh7.5 SG cells was indirectly determined for the first time in this work.

Photochemical behavior of biosupramolecular assemblies of photosensitizers, cucurbit[n]urils and albumins.

Biosupramolecular assemblies combining cucurbit[n]urils (CB[n]s) and proteins for the targeted delivery of drugs have the potential to improve the photoactivity of photosensitizers used in the photodynamic therapy of cancer. Understanding the complexity of these systems and how it affects the properties of photosensitizers is the focus of this work. We used acridine orange (AO+) as a model photosensitizer and compared it with methylene blue (MB+) and a cationic porphyrin (TMPyP4+). Encapsulation of the photosensitizers into CB[n]s (n = 7, 8) modified their photoactivity. In particular, for AO+, the photo-oxidation of HSA was enhanced in the presence of CB[7]; meanwhile it was decreased when included into CB[8]. Accordingly, peroxide generation and protein fragmentation were also increased when AO+ was encapsulated into CB[7]. The triplet excited state lifetimes of all the photosensitizers were lengthened by their encapsulation into CB[n]s, while the singlet oxygen quantum yield was enhanced only for AO+ and TMPyP4+, but it decreased for MB+. The results obtained in this work prompt the necessity of further investigating these kinds of hybrid assemblies as drug delivery systems because of their possible applications in biomedicine.

Age-distribution and genotype-phenotype correlation for N-acetyltransferase in Argentine children under isoniazid treatment.

INTRODUCTION: Metabolic clearance of isoniazid (INH) may be up to 10 times faster in individuals who are rapid acetylators compared with slow acetylators. In addition, the acetylation phenotype has been suggested to change with age. A better knowledge of the age distribution of the acetylation genotype and phenotype in children requiring INH for tuberculosis treatment or prevention could be important to optimize safety and efficacy of INH use. OBJECTIVES: The aim of the present study was to evaluate the genotype and phenotype of NAT2 in an Argentinean pediatric population rom Buenos Aires. In addition, we wanted to describe genotype-phenotype correlation, as well as its distribution at different ages. METHODOLOGY: NAT2 genotyping was performed by RFLP technique, searching for common polymorphisms. Acetylisoniazid and isoniazid concentrations were measured by HPLC and NAT2 phenotype was defined from the ratio of both concentrations (Metabolic Ratio, MR). RESULTS: Almost half of the patients (46.02%) possessed wild-type haplotype, with 17.05% of individuals having two fully functional alleles, 57.95% one fully functional allele and 25% with no fully functional allele. According to phenotype, most children (96.59%) were classified as fast acetylators, whereas 1.14% of the cases were intermediate and 2.27% slow acetylators. There was a positive association between age and MR (R = 0.52985, p < 0.000001) with a significant MR difference between age categories (p < 0.001). CONCLUSIONS: We found a high proportion of rapid acetylators compared with other populations. Acetylator phenotype showed a positive correlation with age, with a significant change around the 4th year of life.

Thermophilic biogas production from microalgae-bacteria aggregates: biogas yield, community variation and energy balance.

Biogas production through anaerobic mesophilic digestion is the most straightforward biofuel production route integrated into microalgae-bacteria wastewater treatment plants. Improvement of this biofuel route without adding pretreatment units is possible through the temperature increase. This paper presents a comprehensive evaluation of the transitory effect of different temperatures (35 °C and 55 °C) and hydraulic retention times (HRT) of 15 and 30 d on the long-term methane production using non-pretreated microalgae-bacteria aggregates as a feedstock. The thermophilic transition from mesophilic inoculum adapted to microalgae-bacteria aggregate increased 1.7-fold the methane production (0.41 m3CH4 kgVS-1) at HRT of 30 d. A substantial decrease in the microbial community's diversity present in the anaerobic reactor was observed when thermophilic conditions were applied, explaining the long adaptation period needed. The increase of the operative temperature condition promotes changes in the dominance pathway of methanogenesis from hydrogenotrophic to acetolactic. The energy balance assessment showed a positive net energy ratio when the digester was operated at an HRT of 30 d. A maximum net energy ratio of 1.5 was achieved at mesophilic temperature. This study demonstrated, based on experimental data, that microalgal digestion with an HRT of 30 d favors energy self-sustainability in microalgal wastewater treatment plants.

Wrinkling on Stimuli-Responsive Functional Polymer Surfaces as a Promising Strategy for the Preparation of Effective Antibacterial/Antibiofouling Surfaces.

Biocompatible smart interfaces play a crucial role in biomedical or tissue engineering applications, where their ability to actively change their conformation or physico-chemical properties permits finely tuning their surface attributes. Polyelectrolytes, such as acrylic acid, are a particular type of smart polymers that present pH responsiveness. This work aims to fabricate stable hydrogel films with reversible pH responsiveness that could spontaneously form wrinkled surface patterns. For this purpose, the photosensitive reaction mixtures were deposited via spin-coating over functionalized glasses. Following vacuum, UV, or either plasma treatments, it is possible to spontaneously form wrinkles, which could increase cell adherence. The pH responsiveness of the material was evaluated, observing an abrupt variation in the film thickness as a function of the environmental pH. Moreover, the presence of the carboxylic acid functional groups at the interface was evidenced by analyzing the adsorption/desorption capacity using methylene blue as a cationic dye model. The results demonstrated that increasing the acrylic acid in the microwrinkled hydrogel effectively improved the adsorption and release capacity and the ability of the carboxylic groups to establish ionic interactions with methylene blue. Finally, the role of the acrylic acid groups and the surface topography (smooth or wrinkled) on the final antibacterial properties were investigated, demonstrating their efficacy against both gram-positive and gram-negative bacteria model strains (E. coli and S. Aureus). According to our findings, microwrinkled hydrogels presented excellent antibacterial properties improving the results obtained for planar (smooth) hydrogels.

Does 3D volumetric analysis predict the reach of endoscopically harvested buccal fat pad flap.

OBJECTIVES: To determine if the volume of buccal fat, ascertained by computed tomography (CT) scanning, would correspond to surface area and reach (length and width) of the flap intraoperatively to aid in the reconstruction of selected skull base defects. METHODS: Cadaveric study of five specimens, 10 sides. Methods CT imaging and evaluation using the Osirix 9 software (Pixmeo; Bernex, Switzerland). of cadaveric heads to calculate the volume of the buccal fat bilaterally. The flap was then harvested endoscopically. Measurements were taken. Two heads were also dissected via a transfacial approach. RESULTS: The volume of the buccal fat pad (BFP) as well as the maximum length and width of the endoscopically harvested flap were documented. There was a positive correlation shown between the calculated volume of the BFP based on CT imaging and the dissected length and width of the flap (Pearson correlation, r = 0.83 and r = 0.80, respectively). The transfacial dissection demonstrated the lobes of the BFP well, showing that most of the endoscopic mobilization of the BFP was limited to the posterior lobe, in particular to the temporalis and pterygoid components, with minimal displacement of the superficial components. This minimized the risk of visibly hollowing the buccal fullness. CONCLUSION: Preoperative calculation of the CT-based volume of the BFP correlates positively with the intraoperative maximum reach of the flap for both length and width. Whereas the volume may be lower in some instances, the BFP would still have adequate reach to provide coverage for the lower and mid-clival region in most patients. LEVEL OF EVIDENCE: NA. Laryngoscope, 130:1670-1673, 2020.

Extended Endoscopic Endonasal Clipping of Intracranial Aneurysms: An Anatomic Feasibility Study.

BACKGROUND: Intracranial aneurysms (IAs) located in the midline region represent formidable challenge owing to their deep location. The objective of this study was to assess feasibility and identify the limitations of endoscopic endonasal clipping of IAs. We further aimed to describe the locations and characteristics of aneurysms that may be amenable for endoscopic endonasal clipping; thus outlining the indications of these approaches. METHODS: Fifteen latex-injected cadaveric heads were used for endoscopic endonasal exposure of anterior and posterior cerebral circulations. An aneurysm simulator model with 2 different sizes was used at the common sites for IAs to emulate a real surgery. Key measured parameters included "exposure of vessels and their respective perforators," "ability to gain proximal/distal control," and "possibility of clip placement" according to the size, direction, and location of the aneurysm model. Maneuverability of instruments and the need for pituitary gland transposition were assessed and recorded as well. RESULTS: Exposure of the anterior communicating artery complex and the common sites of posterior circulation aneurysms were feasible. The size, location, and direction of the aneurysm model had an impact on obtaining proximal and/or distal control, and the ability of clip placement. CONCLUSIONS: Clipping of midline aneurysms of the posterior circulation is feasible via endoscopic endonasal approach. Small-sized ventrally and medially directed aneurysm models carried a better probability of getting proximal and/or distal control, as well as better overall ability to place a clip. The endonasal route seems to provide a limited condition for proper management of anterior circulation aneurysms.

Continuous enzymatic synthesis of lactulose in packed-bed reactor with immobilized Aspergillus oryzae ß-galactosidase.

Lactulose synthesis from fructose and lactose in continuous packed-bed reactor operation with glyoxyl-agarose immobilized Aspergillus oryzae ß-galactosidase is reported for the first time. Alternative strategies to conventional batch synthesis have been scarcely explored for lactulose synthesis. The effect of flow rate, substrates ratio and biocatalyst-inert packing material mass ratio (MB/MIM) were studied on reactor performance. Increase in any of these variables produced an increase in lactulose yield (YLu) being higher than obtained in batch synthesis at comparable conditions. Maximum YLu of 0.6 g·g-1 was obtained at 50 °C, pH 4.5, 50% w/w total sugars, 15 mL·min-1, fructose/lactose molar ratio of 12 and MB/MIM of 1/8 g·g-1; at such conditions yield of transgalactosylated oligosaccharides (YTOS) was 0.16 g·g-1, selectivity (lactulose/TOS molar ratio) was 5.4 and lactose conversion (XLactose) was 28%. Reactor operation with recycle had no significant effect on yield, producing only some decrease in productivity.

Aneurisma de arteria esplénica: tratamiento endovascular. A propósito de un caso / Splenic artery aneurysm: endovascular treatment. Case report

Objetivo: El objetivo de este trabajo es presentar un Caso Clínico de aneurisma de Arteria Esplénica (AAE) complicado y describir el enfoque terapéutico empleado. Caso Clínico: Paciente masculino de 52 años que presentó dolor abdominal de 15 días de evolución y fue diagnosticado con aneurisma de arteria esplénica complicado. Se realizó un abordaje endovascular mediante 2 Stent Graft, lo que permitió cubrir la totalidad del cuello del aneurisma, excluyendo la circulación de la arteria esplénica y logrando un flujo arterial no turbulento. Métodos: Se realizó una evaluación clínica completa y se solicitaron estudios complementarios para el diagnóstico de aneurisma de arteria esplénica complicado. Se llevó a cabo un ateneo multidisciplinario para definir el abordaje terapéutico más adecuado. Discusión: En la evaluación de tratamientos del AAE complicado se logró definir que el enfoque terapéutico endovascular fue la alternativa segura y efectiva para el manejo de este caso de aneurisma. Conclusión: El enfoque terapéutico endovascular debería ser considerado en un contexto multidisciplinario para definir un abordaje adecuado en cada caso.

Todo sobre una entidad poco conocida: el síndrome linfoproliferativo postrasplante / All about a little known entity: post transplant lymphoproliferative syndrome

Resumen El síndrome linfoproliferativo postrasplante (SLPT o PTLD por sus siglas en inglés, posttransplantation lymphoproliferative disorder) consiste en un grupo heterogéneo de enfermedades linfoproliferativas que ocurren en el marco de la inmunosupresión postrasplante, que pueden abarcar desde una simple hiperplasia linfoidea hasta un linfoma maligno de alto grado, con eventual evolución fatal. Se estima su desarrollo entre el 1 y el 20% de los pacientes trasplantados. Los principales factores asociados con el desarrollo de SLPT son el grado de inmunosupresión y el virus de Epstein Barr (VEB). La mayoría suceden dentro del primer año postrasplante, pero el riesgo de desarrollarlo continúa hasta los 10 años. Su presentación es variable, puede ser asintomático o con manifestaciones inespecíficas (fiebre, linfadenopatías), lo que dificulta su diagnóstico desde el punto de vista clínico. Por este motivo, los métodos de imagen cumplen un rol fundamental en su diagnóstico, siendo la tomografía computada (TC) el más utilizado. Se deberá sospechar desde las imágenes en todo paciente trasplantado con afección nodal, principalmente en retroperitoneo y mesenterio; y/o extranodal, como el tracto gastrointestinal, órganos y el sistema nervioso central. El objetivo del presente trabajo consiste en realizar una revisión sobre el SLPT mediante las imágenes y conocer la importancia de su sospecha y diagnóstico.

Abstract Post-transplantation lymphoproliferative disease (PTLD) is a heterogeneous group of lymphoproliferative diseases in behave of posttransplant immunosuppression, which ranges from relatively benign lymphoid hyperplasia to poorly differentiated lymphoma, affecting different organs with fatal evolution, eventually. PTLD constitutes a disease with an increasing incidence and detection, estimating its development between 1 and 20% of transplant patients. Although it is based on a multifactorial etiology, the main factors associated with the development of PTLD are the degree of immunosuppression and the Epstein Barr virus (EBV). Most cases of this disorder occur during the first year posttransplant, however, the risk of developing is included in the next 5 to 10 years. The clinical presentation is variable, and the patient may be asymptomatic, or with nonspecific manifestations such as fever, lymphadenopathy, or digestive symptoms, making it difficult to diagnose this entity from clinical suspicion. Imaging plays a fundamental role in diagnosis of PTLD, with the computed tomography (CT) being the most widely used. Findings can mimic those lymphoproliferative processes in patients with no transplant and should be suspect in every transplant patient with nodal affection, such as retroperitoneum and mesenteric¸ or extranodal compromise, like gastrointestinal tract, solid organs, and central nervous system. The aim of this paper is to revise all about the PTLD trough different imaging methods and to know the importance of its suspicion and diagnosis.

Calendario de vacunas en niños en un centro de atención primaria. Corrientes 2021 / Vaccine schedule in children in a primary care center.Corrientes 2021

Describir e identificar las razones por las cuales los padres o tutores no completaron el calendario de vacunación infantil en un Centro de Atención Primaria de Salud de la Ciudad de Corrientes en el año 2021. Metodología: Estudio descriptivo, transversal. Población: padres o tutores de niños con esquemas incompletos. Recolección de datos mediante encuesta validada en prueba piloto. Los datos plasmados en una matriz fueron sometidos a análisis descriptivos. Se contó con aval del Comité de Ética. Resultados: La muestra se integró con 53 unidades de análisis. Edad media 28 años; 79% eran las madres; 62% ya tenían dos o más hijos; 74% eran soltero/as; 47% no había concluido el secundario o la primaria; la mayoría eran desempleados o percibían planes sociales. El 66% pensaba que las vacunas curaban enfermedades;89% que las prevenían y 89% pensaban que eran seguras. Fuentes de información: el equipo médico y enfermería, 17% de familiares o amigos, 30% en internet o medios de comunicación. En motivosde incumplimiento, lo más frecuente falta de vacunas (31%), horarios de trabajo de padres o tutor (15%), enfermedades del infante (10%). Conclusión: La información sobre vacunas era brindada por equipo de salud, familias y medios de comunicación. Aunque afirmaban que prevenían enfermedades y eran seguras muchos sostenían que curaban enfermedades. Se señalaron como motivos del incumplimiento falta de vacunas, horarios laborales de los entrevistados y enfermedades del menor, restricciones horariasdel vacunatorio y por la pandemia[AU]

Describe and identify the reasons why parents or guardians did not complete the childhood vaccination schedule in a Primary Health Care Center of the City of Corrientes in the year 2021. Methodology: Descriptive, cross-sectional study. Population: parents or guardians of children with incomplete schemes. Data collection through a survey validated in a pilot test. The data captured in a matrix were subjected to descriptive analysis. It was endorsed by the Ethics Committee. Results: The sample was integrated with 53 units of analysis. Mean age 28 years; 79% were mothers; 62% already had two or more children; 74% were single; 47% had not completed secondary or primary school; most were unemployed or received social plans. 66% thought that vaccines cured diseases; 89% prevented them and 89% thought they were safe. Sources of information: the medical and nursing team, 17% from family or friends, 30% on the internet or the media. In non-compliance reasons, the most frequent lack of vaccines (31%), parent or guardian work schedules (15%), infant diseases (10%). Conclusion: The information on vaccines was provided by the health team, families and the media. Although they claimed that they prevented diseases and were safe, many maintained that they cured diseases. Reasons for non-compliance were noted as lack of vaccines, work schedules of the interviewees and illnesses of the minor, time restrictions of the vaccination and those given by the pandemic[AU]

Descrever e identificar os motivos pelos quais os pais ou responsáveis não completaram o calendário de vacinação infantil em um Centro de Atenção Primária à Saúde da Cidade de Corrientes no ano de 2021. Metodologia: Estudo descritivo, transversal. População: pais ou responsáveis de crianças com esquemas incompletos. Coleta de dados por meio de questionário validado em teste piloto. Os dados capturados em uma matriz foram submetidos à análise descritiva. Foi aprovado pelo Comitê de Ética. Resultados: A amostra foi integrada com 53 unidades de análise. Idade média 28 anos; 79% eram mães; 62% já tinham dois ou mais filhos; 74% eram solteiros; 47% não concluíram o ensino médio ou fundamental; a maioria estava desempregada ou recebia planos sociais. 66% achavam que as vacinas curavam doenças; 89% os preveniram e 89% acharam que eram seguros. Fontes de informação: equipe médica e de enfermagem, 17% de familiares ou amigos, 30% na internet ou na mídia. Nos motivos de não conformidade, a falta de vacinas mais frequente (31%), horários de trabalho dos pais ou responsáveis (15%), doenças infantis (10%). Conclusão: As informações sobre vacinas foram fornecidas pela equipe de saúde, famílias e mídia. Embora afirmassem que preveniam doenças e eram seguros, muitos sustentavam que curavam doenças. Os motivos da não adesão foram apontados como falta de vacinas, horários de trabalho dos entrevistados e doenças do menor, restrições de horário da vacinação e as dadas pela pandemia[AU]

INVESTIGACIÓN DE LA CALIDAD DE SANITIZANTES PARA MANOS SECUESTRADOS POR LA JUSTICIA EN EL MARCO DE LA PANDEMIA DE COVID-19 / Research on the quality of hand sanitizers seized by the Department of Justice in the context of COVID-19 pandemic

En el marco de la pandemia de COVID-19, las agencias reguladoras del mundo, junto a la Organización Mundial de la Salud, recomendaron el uso de sanitizantes de manos para disminuir la transmisión viral. El repentino incremento del uso de estos productos por parte de la población derivó, entre otras cosas, en la aparición de vías de comercialización no autorizadas. Como consecuencia, y por intervención de la justicia, el Laboratorio Nacional de Control del Instituto Nacional de Medicamentos recibió numerosas muestras a fin de conocer la composición cuali-cuantitativa dado que, por la apariencia de los envases y rótulos, denotaban ilegitimidad. Para ello, se llevaron a cabo diversos análisis físico-químicos por picnometría, cromatografía gaseosa y espectrofotometría de infrarrojo medio. Los resultados indicaron que, si bien las muestras analizadas contenían etanol y/o isopropanol, en la mayoría de los casos su concentración no se hallaba en los valores recomendados y casi todos los envases no cumplían con la normativa vigente de rotulado

In the context of COVID-19 pandemic, the use of hand sanitizers was recommended to reduce viral transmission by the global regulatory agencies together with the World Health Organization. The sudden increase in the use of these products by the population led, among other things, to the emergence of unauthorized marketing channels. As a result, and due to judicial intervention, numerous samples were received by the National Control Laboratory of the National Institute of Medicines in order to determine the qualitative-quantitative composition, since the appearance of the containers and labels denoted illegitimacy. To that end, various physicochemical analyses were carried out by pycnometry, gas chromatography and mid-infrared spectrophotometry. Although the analyzed samples contained ethanol and/or isopropanol, the results showed that in most cases the concentration was not within the recommended values and almost all the containers did not comply with the current labeling regulations.

Estudio in vitro de la relación entre resistencia de unión a esmalte dental y microfiltración en resinas compuestas fotopolimerizables / In vitro study of the relationship between bond strength to dental enamel and microleakage in photopolymerizable composite resins

Objetivos. Evaluar y comparar la relación entre la resistencia de unión inmediata a esmalte y microfiltración de dos sistemas restauradores a base de resina compuesta. Métodos. 40 terceros molares se dividieron aleatoriamente en dos grupos: 20 molares restaurados utilizando el sistema Adper Single bond 2 + Filtek Z250 XT (3M ESPE; ST PAUL, MN, USA); y 20 molares restaurados con el sistema Tetric N Bond + Tetric N Ceram (Ivoclar Vivadent; Schaan, Liechtenstein). La mitad de los dientes de cada grupo se utilizaron para un ensayo de microtracción, mientras que la otra mitad fueron utilizados para un ensayo de microfiltración (n = 10). Resultados. Las medias y el desvío padrón de la resistencia de unión a microtracción fueron de 27.93 (±9.55) para Adper Single bond 2 + Filtek Z250 XT MPa y 33.12 (±8.18) MPa para Tetric N Bond + Tetric N Ceram (p = 0,049). En cuanto a los valores de microfiltración, no hubo diferencias estadísticamente significativas entre los grupos (p = 0,478). No fue observada una correlación significativa entre la resistencia de unión a la microtracción y la microfiltración (R2 = 0.0909; p = 0.196). Conclusiones. No se encontró una relación entre los valores de resistencia de unión y el grado de microfiltración.

Objectives. To evaluate and compare the relationship between enamel bond strength and microleakage of two composite based restorative systems. Methods. 40 third molars were randomly divided into two groups: 20 molars restored with the Adper Single bond 2 + Filtek Z250 XT (3M ESPE; ST PAUL, MN, USA) system and 20 with the Tetric N Bond + Tetric N Ceram (Ivoclar Vivadent; Schaan, Liechtenstein) system. "Half of the teeth" in each group were subjected to a bond strength test, while the others were subjected to the microleakage test. Results. The means and standard deviation of the bond strength resistance were 27.93 (± 9.55) MPa for Adper Single bond 2 + Filtek Z250 XT system and 33.12 (± 8.18) MPa for Tetric N Bond + Tetric N Ceram system (p = 0.049). Regarding microleakage values, there were no statistically significant differences between the groups (p = 0.478). No significant correlation was observed between microtensile bond strength and microleakage (R2 = 0.0909, p = 0.196). Conclusions. No relationship was found between adhesive bond values and degree of microleakage.

Objetivos. Avaliar e comparar a relação entre a resistência de união imediata ao esmalte e a microfiltração de dois sistemas restauradores baseados em resina composta. Métodos. 40 terceiros molares foram divididos aleatoriamente em dois grupos: 20 molares restaurados usando o sistema Adper Single bond 2 + Filtek Z250 XT (3M ESPE; ST PAUL, MN, EUA); e 20 molares restaurados com o sistema Tetric N Bond + Tetric N Ceram (Ivoclar Vivadent; Schaan, Liechtenstein). Metade dos dentes de cada grupo foi utilizada para um teste de resistência de união à microtração, enquanto a outra metade foi utilizada para um teste de microfiltração (n = 10). Resultados. As mídias e o padrão de resistência de união à microtração foram 27,93 (± 9,55) para Adper Single bond 2 + Filtek Z250 XT MPa e 33,12 (± 8,18) MPa para Tetric N Bond + Tetric N Ceram (p = 0,049). Em relação aos valores de microfiltração, não houve diferença estatisticamente significativas entre os grupos (p = 0,478). Não houve correlação significativa observada entre a resistência de união à microtração e a microfiltração (R2 = 0,0909; p = 0,196). Conclusões. Não foi encontrada relação entre os valores de resistência de união e o grau de microfiltração.

Sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial.

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) is an effective therapy in non-muscle-invasive bladder cancer (NMIBC), but it has limitations in terms of recurrence and toxicity. OBJECTIVE: To determine whether the sequential combination of mitomycin C (MMC) and BCG is superior to BCG alone in increasing a disease-free interval (DFI). DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective randomized trial including 407 patients with intermediate- to high-risk NMIBC and allocated 211 to the MMC and BCG arm and 196 to the BCG-alone arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The trial was designed to provide concurrently a power of 80% for the detection of a relative risk reduction of 35% (hazard ratio [HR]: 0.65) of disease relapse with a type I error of 0.05. Times to events were estimated using cumulative incidence functions and compared using the Cox regression model. We used the Kaplan-Meier technique to estimate survival curves. RESULTS AND LIMITATIONS: In the intention-to-treat analysis at 5 yr, DFI was significantly improved by the sequential scheme (HR: 0.57; 95% confidence interval [CI], 0.39-0.83; p=0.003), reducing the disease relapse rate from 33.9% to 20.6%. Higher toxicity was observed with the combination, even reducing the MMC dose, especially in G3 local toxicity compared with BCG with a difference of 17.4% (95% CI, 7.6-27.2; p<0.001). In recurrent T1 tumors, the potential benefit of the sequential scheme was more evident than in the remaining subgroup (18.8% vs 12.8%), with a number needed to treat of five versus eight to avoid an event and with similar toxicity. CONCLUSIONS: Although the sequential scheme is more effective than BCG alone in reducing disease relapse, due to higher toxicity it could be offered only to patients with a high likelihood of recurrence, such as those with recurrent T1 tumors. PATIENT SUMMARY: We analyzed the outcomes of a randomized trial demonstrating that in intermediate- to high-risk non-muscle-invasive bladder cancer, mitomycin C and bacillus Calmette-Guérin (BCG) reduced disease relapse compared with BCG alone but was more toxic. Consequently, it could be offered only to patients with recurrent T1 tumors. TRIAL REGISTRATION: CUETO 93009.

Péptidos Sintéticos: Actualización. Próximos desafíos desde el enfoque regulatorio. / Synthetic peptides: update. Next challenges from the regulatory approach

Los péptidos son cadenas de menos de 50 aminoácidos unidos covalentemente, con un peso molecular menor a 5000 Da. Algunos poseen actividad biológica con lo cual son de particular interés en la industria farmacéutica. Se han desarrollado diferentes rutas y métodos de síntesis con el fin de optimizar su producción, considerando el diverso tamaño y complejidad, así como también sus propiedades farmacocinéticas y farmacodinámicas. Esto los distingue de los productos biológicos ya que, al ser de origen sintético, sus estructuras y procesos de fabricación son altamente conocidos. En consecuencia, algunas autoridades regulatorias (entre ellas la ANMAT), proponen que el registro de medicamentos a base de péptidos se realice bajo la modalidad de sintéticos, la cual posee la ventaja de poder presentar productos como genéricos y similares. A partir de la evaluación de la codificación de monografías en las farmacopeas internacionalmente reconocidas y la existencia de estándares primarios de los péptidos sintéticos, se observa que no todos se encuentran disponibles. Para abordar más en profundidad estos temas, se realizó una reseña de las áreas emergentes y tendencias en el mercado en el campo de péptidos sintéticos.

Peptides are chains of less than 50 amino acids that are covalently bonded, with a molecular weight of less than 5000 Da. Some of them have biological activity which is of interest in the pharmaceutical industry. Different routes and synthesis methods have been developed to optimize their production, considering their diverse size and complexity as well as their pharmacokinetic and pharmacodynamic properties. This distinguishes them from biological products, since them being of synthetic origin, their structure and manufacturing process are well known. Consequently, some regulatory authorities (including ANMAT), proposed that the registration of peptide-based medicines was carried out under the synthetic modality, which has the advantage of being able to present products as generic and similar. Based on the evaluation of the codification of monographs in internationally recognized pharmacopoeias and the existence of primary standards for synthetic peptides, it is observed that not all of them are available. A review of the emerging areas and trends in the field of synthetic peptides was made to analyze these topics more in depth.

Ciclofosfamida inyectable: primera investigación del programa de vigilancia farmacéutica activa / Injectable cyclophosphamide: first investigation of the active pharmaceutical surveillance program

El Programa de Vigilancia Farmacéutica Activa tiene como función evaluar la calidad de las especialidades medicinales que contienen ingredientes farmacéuticos activos con alta frecuencia de notificación en el Sistema Nacional de Farmacovigilancia y/o que tengan un impacto en la salud de la población. La ciclofosfamida es un citostático e inmunosupresor ampliamente utilizado en terapéutica. Se ha observado que el producto inyectable, al ser sometido a una temperatura de conservación mayor a la autorizada, puede tornarse amarillento, degradarse y en estas condiciones no debe ser administrado. Debido a esta problemática, este producto fue seleccionado como primer caso del estudio del Programa de Vigilancia Farmacéutica Activa. Se realizó un estudio integral de la ciclofosfamida en su presentación de polvo liofilizado inyectable 1000 mg, el cual incluyó la evaluación de documentación, datos relevados en las inspecciones, e identificación de puntos críticos donde se puede actuar para asegurar la calidad y reducir el riesgo en la salud de los pacientes. Los resultados obtenidos indicarían que el ajuste en la humidificación durante la elaboración, podría permitir obtener un producto terminado más estable y menos sensible a las variaciones de temperatura durante el transporte y almacenamiento.

The Active Pharmaceutical Surveillance Program function is to evaluate the quality of medicines that contain active pharmaceutical ingredients which are frequently notified in the National Pharmacovigilance System and/or that have a high impact on population health. Cyclophosphamide is a cytostatic and immunosuppressant widely used in therapy. When the injectable product is stored at a higher temperature than the one authorized, it was observed that it becomes yellowish, suffers degradation and then, under these conditions, it must not be given to anyone. Due to this issue, this medicine was selected as the first case of study in the Active Pharmaceutical Surveillance Program. A comprehensive study of cyclophophamide in its 1000 mg of injectable lyophilized powder presentation was carried out, which included manufacturer records evaluation, regulatory inspections data analysis, and identification of critical points where actions can be taken to ensure quality and reduce risk on patients health. The results would suggest that adjustment in the humidification process during the elaboration would allow to obtain a product with better stability and less sensitive to temperature variations during transport and storage.

Desarrollo y validación de un método de valoración de ketoconazol en comprimidos utilizando infrarrojo medio en modo transmitancia / Development and validation of Ketoconazole assay in tablets by infrared spectrophotometry in transmittance mode

El ketoconazol es un antimicótico utilizado para micosis superficiales y sistémicas cuyas formulaciones en el mercado varían desde cremas tópicas a shampús y comprimidos. En relación a este último, los métodos actuales de valoración del ingrediente farmacéutico activo implican el uso de técnicas de cromatografía líquida de alta performance en las que se requiere el procesamiento previo de las muestras. En conocimiento de esto, y en vistas de implementar mejoras en el sistema de control, se propuso como objetivo del trabajo desarrollar y validar un método de valoración de ketoconazol en comprimidos utilizando espectrofotometría de infrarrojo medio en modo transmitancia. Un procedimiento en el que la ventaja viene dada por la disminución del tiempo de análisis y del costo de la técnica debido a que no requiere separación previa del principio activo de la matriz de excipientes. El sistema analítico consistió en un equipo de infrarrojo medio Perkin Elmer, modelo Spectrum Two, provisto de una celda sellada para líquidos, con ventanas de cloruro de sodio, de 1 mm de paso óptico. La concentración de trabajo fue 1,5 mg por ml, el diclorometano fue el solvente de elección y el rango de número de onda para cuantificar fue 1521 cm-1 - 1498 cm-1. Los ensayos de validación demostraron que la técnica resultó ser lineal, exacta, precisa y específica en el rango de 1,2 mg/ ml a 1,8 mg/ ml.

Ketoconazole is an antifungal medication used for superficial and systemic mycoses whose formulations on the market vary from topical creams to shampoos and tablets. Regarding this matter, the current methodologies for quantify the active pharmaceutical ingredient involve the use of high performance liquid chromatography techniques in which pre-processing of the samples is required. In light of this, and also the need of implementing improvements in the control system, the objective proposed was to develop and validate a ketoconazole quantification method in tablets using medium infrared spectrophotometry in transmittance mode. Some advantages of this procedure are the reduction of analysis time and the cost of the technique due to the fact that it does not require to extract previously the active principle of matrix excipients. The analytical system consisted in a Perkin Elmer medium infrared device, Spectrum Two, equipped with a sealed liquid cell, with sodium chloride windows, 1 mm optical path. The working concentration was 1.5 mg per ml, dichloromethane was the solvent of choice and the wavenumber range to quantify was 1521 cm-1 - 1498 cm-1. The validation tests showed that the technique was linear, accurate, precise and specific in the range of 1.2 mg / ml to 1.8 mg / ml.

Desarrollo de una metodología por cromatografía gaseosa acoplada a espectrometría de masas (GC-MS) para el análisis de benzodiacepinas en productos farmacéuticos

Las benzodiacepinas son psicofármacos sintéticos que poseen las siguientes propiedades farmacológicas: son ansiolíticos, sedativos, hipnóticos. Suelen ser utilizadas como drogas de abuso, por lo que es necesario un exhaustivo control de la venta y uso porque generan gran tolerancia y dependencia. Con la finalidad de generar una base de datos propia, se incorporaron espectros de masas de diversas sustancias de interés farmacológico y toxicológico a la biblioteca del cromatógrafo gaseoso que tiene acoplado un detector espectrométrico de masas. Se desarrolló una metodología para la detección e identificación de benzodiacepinas, ya que se pueden aislar los analitos de interés mediante una extracción líquido-líquido y luego analizar por cromatografía gaseosa. Puede ser aplicable en primera instancia para la búsqueda de analitos conocidos o no declarados en muestras de diverso origen que ingresan al Laboratorio Nacional de Control, para posteriormente continuar el análisis utlizando técnicas farmacopeicas u otros métodos para la cuantificación de benzodiacepinas. Es por ello que puede ser considerada como una técnica confirmatoria y/o complementaria. Mediante esta metodología de screening general por GC-MS se determina simultáneamente gran parte de las benzodiacepinas, siendo aplicable para el análisis de distintos tipos muestras lo cual permite dar una rápida respuesta acerca de la identidad química de los analitos.

Tetralogía de Fallot con síndrome de válvula pulmonar ausente: Presentación de un caso y revisión de la literatura / Tetralogia de Fallot com síndrome da valva pulmonar ausente: Relato de caso e revisão da literatura / Tetralogy of Fallot with absent pulmonary valve syndrome: Case report and literature review

La tetralogía de Fallot es la cardiopatía congénita cianótica más frecuente del adulto. El síndrome de válvula pulmonar ausente constituye una variante poco frecuente, que representa del 3% al 6% de los pacientes con tetralogía de Fallot. Presentamos el caso de un paciente masculino de 29 años de edad, con tetralogía de Fallot y síndrome de válvula pulmonar ausente, los hallazgos del examen físico y los principales exámenes complementarios; como así también su evolución y una revisión de la literatura.

The tetralogy of Fallot is the most frequent cyanotic congenital heart disease in adult. Absent pulmonary valve syndrome is a rare variant, representing 3% to 6% of patients with tetralogy of Fallot. We present the case of a 29-year-old male patient with tetralogy of Fallot and absent pulmonary valve syndrome, physical examination findings and major complementary examinations; as well as its evolution and a review of the literature.

A tetralogia de Fallot é a doença congênita cianótica mais comum cardíacas em adultos. A síndrome valva pulmonar ausente é uma variante rara, que representa de 3% a 6% dos pacientes com tetralogia de Fallot. Apresentamos o caso de um paciente masculino de 29 anos de idade, com tetralogia de Fallot e síndrome da valva pulmonar ausente, exame físico e os principais estudos complementares; bem como a sua evolução e uma revisão da literatura.