[Survival benefit with intraarterial techniques in hepatocellular carcinoma]. / Beneficio sobre la supervivencia con las técnicas intraarteriales en el carcinoma hepatocelular.

The two intraarterial techniques used in the treatment of hepatocellular carcinoma (HCC) are the transarterial chemoembolization (TACE) and radioembolization (RE). TACE includes various procedures whose objective is to expose tumor cells to a chemotherapy agent and induce acute ischemia in the tumor. The survival benefit obtained by adding a chemotherapy agent or lipiodol to simple particle embolization has not been demonstrated in 2 meta-analyses, which suggests that the antitumor effect is primarily ischemic. RE is a form of brachytherapy that consists of an intraarterial injection of microspheres loaded with yttrium 90 as the source of radiation, a pure beta emitter with a mean tissue penetration of 2mm. TACE is performed in several sessions every 4-8 weeks, while RE is generally a single procedure. The guidelines adopted by the main research societies support the use of TACE for the palliative treatment of patients with intermediate stage HCC. This is a level 1 recommendation based on the positive results of 2 randomized clinical trials and 3 meta-analyses and on several uncontrolled studies with thousands of patients with unresectable HCC. Survival in clinical practice studies is heterogeneous due to the heterogeneity of the treated population. The survival rate varies from 8% to 26% at 5 years, and the median is 16-40 months in the early stage and 15-27 months in the intermediate stage. TACE with drug-eluting beads (DEB-TACE) has not shown superiority versus conventional TACE in terms of improved survival or tumor response, but it decreases the severe chemotherapy-related adverse events. One of its advantages is the standardization of the procedure, while its primary disadvantage is the onset of biliary complications when used nonselectively. There is level 2 evidence to support the use of RE in HCC, evidence that comes from patient cohorts with consistent results and case-control studies. The treated population includes mainly patients with unresectable tumors, who are considered suboptimal candidates for TACE or are progressing toward this condition, and those for whom TACE was directly contraindicated by the presence of portal vein thrombosis. Consequently, these patients tend to have large or extensively bilobar tumors and other factors for a poor prognosis. The overall survival reported for patients in the intermediate and advanced stages is 16-18 months and 7-17 months, respectively. A number of retrospective studies have reported comparable survival for patients treated with TACE and RE in the same institution; however, these results should be interpreted as a generator of ideas and not as an equivalent efficacy test. Although the combination of systemic agents such as sorafenib with intraarterial techniques is attractive, the results to date are not encouraging. In the only available randomized trial that compared the combination of a continuous regimen of sorafenib started before the first session of DEB-TACE versus DEB-TACE alone, neither the time to progression nor the overall survival were significantly different between the 2 groups. TACE and RE are contraindicated in cases of decompensated cirrhosis. TACE is also contraindicated for patients with considerable tumor burden in whom the procedure cannot be performed selectively and in patients with portal vein invasion.

Evaluation of results after 112 radioembolizations with 90Y-microspheres.

AIM: To determine the results of radioembolization transarterial (TARE), in the treatment of liver tumors, a retrospective evaluation was performed after 112 TARE with 90Y-microspheres administered in 82 patients in a single hospital, analyzing efficacy and safety, after a follow-up greater than or equal to 1 year post-TARE in all patients, and evaluating the possible relationship between treatment response and patient survival. MATERIAL AND METHODS: We have administered 57 single TARE and 55 multiple TARE in patients with hepatocellular carcinoma (53), liver metastases (25) and cholangiocarcinoma (4), with prior multidisciplinary evaluation, clinical, angiographic and gammagraphic (planar/SPECT/SPECT-CT with 99mTc-MAA), multicompartment model (MIRD equations), post-TARE screening (planar/SPECT/SPECT-CT), clinical and radiological follow-up, tumor response evaluation (mRECIST criteria) and Kaplan-Meier analysis to determine progression-free survival (PFS) and overall survival (OS). RESULTS: Therapeutic intention was palliative (82%) and as bridge to liver transplantation/surgical resection (17%). We obtained response (R), complete or partial, in 65.9% of cases. One year after TARE 34.7% of patients with R and 19.2% of non-R were progression-free (P: .003), with OS of 80% for R and 37.5% for non-R (P: .001). Survival analysis showed median OS of 18 months (95% CI 15.7-20.3) for R and 9 months (95% CI 6.1-11.8) for non-R (P: .03). We found mild (27.6%) and severe (5.3%) side effects, all of them resolved, without higher incidence after multiple TARE. CONCLUSION: TARE with 90Y-microspheres, in appropriately selected patients with liver tumors, provides therapeutic efficacy and low rate of toxicity, with higher PFS and OS in patients with TARE response compared to those who did not respond.

Efficacy and safety of Yttrium-90 radioembolization in the treatment of neuroendocrine liver metastases. Long-term monitoring and impact on survival. / Eficacia y seguridad de la radioembolización con 90Y en el tratamiento de metástasis hepáticas de tumores neuroendocrinos. Seguimiento a largo plazo y repercusión en la supervivencia.

INTRODUCTION AND OBJECTIVE: Neuroendocrine tumors (NETs) debut in 75% of cases with liver metastases (LMNETs), whose therapeutic approach includes surgical resection and liver transplantation, while liver radioembolization with 90 Y-microspheres (TARE) is reserved for non-operable patients usually due to high tumor burden. We present the accumulated experience of 10 years in TARE treatment of LMNETs in order to describe the safety and the effectiveness of the oncological response in terms of survival, as well as to detect the prognostic factors involved. MATERIAL AND METHODS: Of 136 TARE procedures, performed between January 2006 and December 2016, 30 LMNETs (11.1%) were retrospectively analyzed. The study variables were: Tumor response, time to liver progression, survival at 3 and 5 years, overall mortality and mortality associated with TARE. The radiological response assessment was assessed using RECIST 1.1 and mRECIST criteria. RESULTS: An average activity of 2.4 ± 1.3 GBq of 90 Y was administered. No patient presented postembolization syndrome or carcinoid syndrome. There were also no vascular complications associated with the procedure. According to RECIST 1.1 criteria at 6 months, 78.6% presented partial response and 21.4% stable disease, there was no progression or complete response (1 by mRECIST). Survival at 3 and 5 years was 73% in both cases. CONCLUSION: TARE treatment with 90 Y-microspheres in LMNETs, applied within a multidisciplinary approach, is a safe procedure, with low morbidity, capable of achieving a high rate of radiological response and achieving lasting tumor responses.

Radiation exposure of the operators in the preparation and administration of yttrium-90 microspheres in the treatment of malignant hepatic lesions: What is the risk?

Liver radioembolization is an emerging treatment against liver primary and secondary tumours. The whole procedure of radioembolization involves different health care specialists with different expertise. During the fractionation and infusion phases, the personnel manipulates high activities of 90Y. In our centre, the number of radioembolization treatments per year is increasing; the aim of this study is to monitor the dose to the operators and to estimate the radiological risk for the operators involved in the RE. At present, two medical devices are approved: Sir-Sphere® and Therasphere™, both loaded with 90Y. The dosimeters used were TLDs placed over the fingertips, for a total of 4 dosimeters for each phase; the selected dose descriptor was Hp0.07. The study concerned 17 patients affected by malignant hepatic lesions, treated from September 2017 to March 2018. We performed 27 procedures: 10 fractionations (with Sir-Sphere®) and 17 infusions to the patients (10 with Sir-Spheres®, 7 with Theraspheres™). For fractionation phase, the average activity of each preparation was 3.34 GBq, the average value of Hp0.07 was 0.50mSv. For infusion phase, the average activity was 1.51 GBq for Sir-Sphere® and 2.10 GBq for Theraspheres™, the average value of Hp0.07 was 0.10mSv. No significant differences were found between senior (Hp0.07 = 0.08mSv) and young operators (Hp0.07 = 0.09mSv), respectively. Similarly, no significant differences were found between the right and left hand, with the same average value of Hp0.07 (0.01mSv). In conclusion, the results are encouraging, since fingertips reported doses very low. The handling of 90Y microspheres and the radioembolization procedure can be carried out under safe conditions.

Podocyte infolding glomerulopathy; report of the first case in Latin America and review of the literature. / Glomerulopatía por invaginación podocítica; reporte del primer caso en Latinoamérica y revisión de la literatura.

BACKGROUND: Podocyte infolding glomerulopathy (PIG) is a condition of uncertain origin, frequently associated with autoimmune diseases. Its specific treatment and clinical course are unknown. It is characterised by thickening of the capillary walls due to the presence of non-argyrophilic intramembranous bubbles similar to those found in membranous glomerulopathy, but without electron-dense deposits of immune complexes in the ultrastructure, where translucent microspheres generated by invagination of the podocyte cytoplasm into the basement membranes are observed. OBJECTIVES: Generally reported in young females patients. To date, few cases in Asian patients have been reported. Our case is the first to be reported in a Latin American Caucasian patient. METHODS: A 38-year-old woman with SLE. In 2014 she presented with nephrotic syndrome empirically treated with corticosteroids (CO) and intravenous cyclophosphamide with good response. She had a relapse in April 2015 with normal renal function and no extrarenal lupus activity, so she was referred to our hospital to be biopsied. RESULTS: The biopsy reported focal segmental glomerular sclerosis without deposits of immune complexes in the immunofluorescence. However, methenamine silver staining revealed clear spaces in the capillary walls accompanied by marked podocyte alterations. On electron microscope study, numerous aggregates of microvesicular and cylindrical ultrastructures bound to the membranes were observed, without evidence of dense deposits, and diffuse effacement of pedicel foot processes, confirming the suspected diagnosis. CONCLUSIONS: This is the first reported case of what can be considered a new pathological glomerular entity in a Latin American Caucasian patient, whose clinical course and therapy are still unknown.

Retrospective analysis of the efficacy and survival associated with cTACE and DEB-TACE in the palliative treatment of hepatocellular carcinoma: experience of a tertiary care hospital in southern Brazil / Análise retrospectiva da eficácia e sobrevida associadas a cTACE e DEB-TACE no tratamento paliativo do carcinoma hepatocelular: experiência de um hospital de cuidado terciário no sul do Brasil

Abstract Objective: To compare conventional transarterial chemoembolization (cTACE) and drug-eluting bead TACE (DEB-TACE) in terms of efficacy, survival, and adverse effects in patients with hepatocellular carcinoma who are not candidates for curative therapy. Materials and Methods: This was a retrospective study of patients with hepatocellular carcinoma who underwent cTACE or DEB-TACE for palliative treatment between January 2009 and December 2021. The Kaplan-Meier method was used for survival analysis. Values of p < 0.05 were considered statistically significant. Results: We evaluated 268 patients, of whom 70 underwent DEB-TACE and 198 underwent cTACE. There was no significant difference between the groups regarding sex, age, or etiology of cirrhosis. The proportion of patients achieving a complete response on imaging examinations was higher in the cTACE group (31.8% vs. 16.1%), whereas that of patients achieving a partial response was higher in the DEB-TACE group (33.9% vs.19.7%), and the differences were significant (p = 0.014). The mortality rate was similar between the groups. The survival rate in the DEB-TACE and cTACE groups, respectively, was 87.0% and 87.9% at one year, 35.1% and 32.9% at three years, and 20.5% and 18.1% at five years (p = 0.661). There was no significant difference between the DEB-TACE and cTACE groups in terms of the frequency of adverse events (7.1% vs. 17.8%; p = 0.052). The most common complication in both groups was post-embolization syndrome. Conclusion: Although a complete response was more common among the patients who underwent cTACE, there was no difference in survival between the groups and the frequency of adverse events was similar.

Resumo Objetivo: Comparar a eficácia, sobrevida e efeitos adversos entre cTACE e DEB-TACE em pacientes com carcinoma hepatocelular não candidatos a terapia curativa. Materiais e Métodos: Estudo retrospectivo de pacientes com carcinoma hepatocelular submetidos a cTACE ou DEB-TACE para tratamento paliativo entre janeiro de 2009 e dezembro de 2021. Foi utilizado o método Kaplan-Meier para análise de sobrevida. Valor de p < 0,05 foi considerado estatisticamente significante. Resultados: Foram avaliados 268 pacientes, dos quais 70 foram submetidos a DEB-TACE e 198 foram submetidos a cTACE. Não houve diferença em relação ao sexo, idade e etiologia da cirrose. O grupo cTACE apresentou maior porcentual de resposta completa em exames de imagem (31,8% vs. 16,1%) e o grupo DEB-TACE apresentou maior porcentual de resposta parcial (33,9% vs.19,7%), com valor de p = 0,014. A mortalidade foi semelhante. As taxas de sobrevivência para os grupos DEB-TACE e cTACE foram 87,0% e 87,9% em um ano, 35,1% e 32,9% em três anos e 20,5% e 18,1% em cinco anos, respectivamente (p = 0,661). Em relação à frequência de eventos adversos, não houve diferença significativa entre os grupos (7,1% na DEB-TACE vs. 17,8% na cTACE; p = 0,052). A complicação mais comum, em ambos os grupos, foi a síndrome pós-embolização. Conclusão: Embora tenha sido observada maior frequência de resposta completa em pacientes submetidos a cTACE, não houve diferença na sobrevida dos pacientes entre os grupos. A taxa de eventos adversos também foi semelhante.

Uterine artery embolization with highly compressible calibrated microspheres for the treatment of uterine fibroids / Embolização de miomas uterinos com microesferas calibradas de alta compressibilidade

Abstract Objective: To evaluate the safety and efficacy of using highly compressible calibrated microspheres in uterine artery embolization (UAE) for the treatment of uterine fibroids. Materials and Methods: This was a prospective multicenter study. Thirty-two women with symptomatic uterine fibroids were selected for UAE between January 2019 and March 2020. The participants completed the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire, underwent contrast-enhanced pelvic magnetic resonance imaging (MRI), and were submitted to anti-Müllerian hormone measurement, subsequently undergoing UAE with Embosoft microspheres. After six months, the patients again completed the UFS-QOL questionnaire and underwent pelvic MRI. Results: The most common symptoms were abnormal uterine bleeding (in 81.3% of the cases), pelvic pain (in 81.3%), and compression (in 46.9%). Of the 32 patients evaluated, 12 (37.5%) had anemia due to abnormal uterine bleeding. Thirty patients completed the study. Among those patients, we observed median reductions of 21.4% in uterine volume and 15.9% in dominant fibroid volume. We identified no adverse events that could be attributed to the material itself, although there were events attributed to the UAE procedure in general. Conclusion: For the treatment of uterine fibroids, UAE using Embosoft microspheres shows satisfactory results, providing reductions in uterine and dominant fibroid volumes, with a low rate of adverse events, and improving patient quality of life, as well as demonstrating safety and efficacy.

Resumo Objetivo: Avaliar a eficácia e segurança da embolização da artéria uterina (EAU) com microesferas calibradas de alta compressibilidade no tratamento de miomas uterinos. Materiais e Métodos: Este foi um estudo prospectivo e multicêntrico. Foram selecionadas 32 mulheres com miomas uterinos sintomáticos para EAU de janeiro de 2019 a março de 2020. As participantes preencheram o questionário Uterine Fibroid Symptom and Quality of Life (UFS-QOL), realizaram ressonância magnética (RM) pélvica com contraste e teste para medição dos hormônios antimüllerianos, seguido de embolização de miomas com microesferas Embosoft. Após seis meses, as pacientes novamente preencheram o UFS-QOL e realizaram RM pélvica. Resultados: Os sintomas mais relatados foram sangramento uterino anormal (81,3%), dor pélvica (81,3%) e compressão (46,9%). Doze pacientes (37,5%) apresentaram anemia consequente a sangramento uterino anormal. Nas 30 pacientes que completaram o estudo, observou-se redução mediana de 21,4% no volume uterino e 15,9% no volume do mioma dominante. Não foram identificados eventos adversos possivelmente relacionados ao material utilizado, apenas em relação ao procedimento de EAU. Conclusão: EAU com microesferas Embrosoft mostrou resultados satisfatórios no tratamento de miomas uterinos, com redução dos volumes uterino e do mioma dominante, baixa taxa de eventos adversos e melhora na qualidade de vida, demonstrando segurança e eficácia.

Downstaging of bilobar hepatocellular carcinoma after radioembolization with 90Y microspheres as a bridge to liver transplantation. / Downstaging de carcinoma hepatocelular bilobar tras radioembolización con microesferas de 90Y como puente al trasplante hepático.

Hepatic radioembolization with 90Y is an increasingly widely used locoregional therapy in the treatment of hepatocellular carcinoma. Its potential benefit has recently been described as a downstaging treatment, achieving a decreased tumour burden and allowing patients to be rescued for more radical treatments, such as liver transplantation. The case is presented of a patient diagnosed with multifocal bilobar hepatocellular carcinoma, Barcelona Clinic Liver Cancer (BCLC) intermediate stage, in whom treatment with 90Y achieved a satisfactory radiological response with a very significant reduction of tumour burden, allowing rescue with liver transplantation.

Microcápsulas y microesferas: una visión a la caracterización integral y aplicación para la liberación de medicamentos biotecnológicos / Microcapsules and microspheres: A vision to integral characterization and applications for biotechnological drugs delivery

Resumen Los microacarreadores basados en microcápsulas y microesferas han sido ampliamente estudiados y ensayados para controlar la liberación de medicamentos biotecnológicos (MB), disminuyendo la dosificación o modificando la vía de administración. Los métodos para la obtención de microacarreadores, son complejos y variados, por lo que es necesario determinar los requisitos mínimos que debe cumplir el sistema. El objetivo de este trabajo fue establecer las principales características que deben ser evaluadas en los microacarreadores para garantizar que la actividad biológica de los medicamentos biotecnológicos permanezca intacta a través del proceso de microencapsulación y, por lo tanto, que la seguridad del MB (desarrollo de reacciones inmunes) se mantenga inalterada. Las características a evaluar de un microacarreador deben describir las propiedades del material, tamaño y forma del sistema, carga de la partícula, funcionalidad, eficiencia de la microencapsulación y la cinética de liberación. Mientras que la integridad de los MB puede ser evaluada a partir de parámetros críticos de calidad: estructura y función biológica del MB, pureza del producto, presencia de agregados de alto peso molecular, estructura de orden superior y ensayos de actividad biológica. La caracterización de los microacarreadores debe enfocarse en la seguridad del biopolímero y proteínas ensayadas.

Abstract Microcarriers based on microcapsules and microspheres have been widely studied and tested to control the release of biotechnological drugs (BD), diminishing the dosage or modifying the route of administration. The methods for obtaining microcarriers are complex and varied, so it is necessary to determine the minimum characteristics with which the system must comply. The aim of this work was to establish the main characteristics that should be evaluated in the microcarriers in order to guarantee that the biological activity of biotechnological drugs remains intact through the microencapsulation process, and therefore the safety of the BD (development of immune reactions) remains unaltered. The characteristics of a microcarrier to be evaluated must describe the properties of the material, the size and shape of the system, the particle load, functionalization, the microencapsulation efficiency, and the kinetics of liberation. Whereas the integrity of BD can be evaluated by critical quality parameter such as: structure and biological function of the BD, product purity, presence of high molecular weight aggregations, higher order structure and biological activity tests. The characterization of the microcarriers must focus on the safety of the biopolymer and proteins tested.

Regenerative potential of basic fibroblast growth factor contained in biodegradable gelatin hydrogel microspheres applied following vocal fold injury: Early effect on tissue repair in a rabbit model / Potencial regenerativo do fator básico de crescimento de fibroblastos contido em microesferas biodegradáveis de hidrogel de gelatina aplicadas após lesão de prega vocal: efeito inicial no reparo tecidual em modelo de coelho

Abstract Introduction Postoperative dysphonia is mostly caused by vocal fold scarring, and careful management of vocal fold surgery has been reported to reduce the risk of scar formation. However, depending on the vocal fold injury, treatment of postoperative dysphonia can be challenging. Objective The goal of the current study was to develop a novel prophylactic regenerative approach for the treatment of injured vocal folds after surgery, using biodegradable gelatin hydrogel microspheres as a drug delivery system for basic fibroblast growth factor. Methods Videoendoscopic laryngeal surgery was performed to create vocal fold injury in 14 rabbits. Immediately following this procedure, biodegradable gelatin hydrogel microspheres with basic fibroblast growth factor were injected in the vocal fold. Two weeks after injection, larynges were excised for evaluation of vocal fold histology and mucosal movement. Results The presence of poor vibratory function was confirmed in the injured vocal folds. Histology and digital image analysis demonstrated that the injured vocal folds injected with gelatin hydrogel microspheres with basic fibroblast growth factor showed less scar formation, compared to the injured vocal folds injected with gelatin hydrogel microspheres only, or those without any injection. Conclusion A prophylactic injection of basic fibroblast growth factor -containing biodegradable gelatin hydrogel microspheres demonstrates a regenerative potential for injured vocal folds in a rabbit model.

Resumo Introdução A disfonia pós-operatória é causada principalmente por cicatrizes nas pregas vocais. Tem sido relatado que o manejo cuidadoso da cirurgia das pregas vocais reduz o risco de formação de cicatriz. No entanto, a depender da lesão da prega vocal, o tratamento da disfonia pós-operatória pode ser desafiador. Objetivo Desenvolver uma nova abordagem regenerativa profilática para o tratamento de pregas vocais lesionadas após a cirurgia, com microesferas biodegradáveis de hidrogel de gelatina como sistema de administração de medicamentos para o Fator Básico de Crescimento de Fibroblastos (bFGF). Método A cirurgia laríngea videoendoscópica foi feita para criar lesão nas pregas vocais em 14 coelhos. Imediatamente após esse procedimento, microesferas biodegradáveis de hidrogel de gelatina com bFGF foram injetadas na prega vocal. Duas semanas após a injeção, as laringes foram excisadas para avaliação da histologia das pregas vocais e do movimento da mucosa. Resultados A presença de função vibratória deficiente foi confirmada nas pregas vocais lesionadas. A histologia e a análise de imagem digital demonstraram que as pregas vocais lesionadas injetadas com microesferas de hidrogel de gelatina com bFGF apresentaram menor formação de cicatriz, em comparação com as pregas vocais lesionadas injetadas apenas com microesferas de hidrogel de gelatina ou aquelas sem injeção. Conclusão Uma injeção profilática de microesferas biodegradáveis de hidrogel de gelatina com bFGF demonstra um potencial regenerativo para pregas vocais lesionadas em um modelo de coelho.

Extrahepatic visualization in the distribution of falciform artery in posttreatment Bremsstrahlung images after radioembolization with (90)Y microspheres.

We report the case of a 39-year-old female with metastatic colorectal cancer. Pretreatment SPECT/CT imaging revealed extrahepatic tracer accumulation along the falciform artery distribution. Prior to the administration of (90)Y microspheres, hepatic arterial anatomy was evaluated angiographically. It was not possible to identify the hepatic falciform artery so that no coil-embolization was performed. The patient tolerated the treatment well with only mild pain around the umbilicus during the procedure that spontaneously abated. As far as we know, this is the first report of Bremsstrahlung SPECT/CT images that has clearly shown that the microspheres accumulation in the anterior abdominal wall corresponds to hepatic falciform artery distribution on CT.

Recubrimiento de microesferas de quitosana-ibuprofeno con un complejo interpolimérico pH dependiente / Coating of chitosan-Ibuprofen microspheres with a pH-depending interpolymer complex

INTRODUCCIÓN: el efecto irritante sobre la mucosa gástrica que producen los antiinflamatorios no esteroideos es una de sus principales reacciones adversas. La encapsulación de estos en matrices poliméricas con propiedades entéricas constituye una alternativa tecnológica para solucionar dicho problema. OBJETIVO: obtener micropartículas de quitosana cargadas con ibuprofeno recubiertas con un complejo interpolimérico pH dependiente a base de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona) MÉTODOS: se prepararon micropartículas de quitosana cargadas con ibuprofeno mediante secado por aspersión y se determinó el rendimiento del proceso y la eficiencia de encapsulación. Las micropartículas se recubrieron con un complejo interpolimérico pH dependiente de poli(ácido acrílico)/poli(N-vinil-2-pirrolidona), empleando la técnica de emulsión/evaporación del disolvente. Mediante espectroscopia infrarroja de transformada de Fourier, se comprobó la formación del complejo, y la evaluación morfológica se realizó por microscopia electrónica de barrido. Los estudios de liberación se realizaron en fluido gástrico e intestinal simulados (FGS pH= 1,2; FIS pH= 6,8). RESULTADOS: en el proceso de obtención de las micropartículas de quitosana y quitosana-ibuprofeno hubo un rendimiento de 69 ± 1 por ciento y 54,4 ± 0,8 por ciento respectivamente. La eficiencia de encapsulación resultó de 46,8 ± 0,7 por ciento. Las micropartículas recubiertas presentaron una superficie rugosa. La formación del complejo se confirmó a través de los cambios observados en la posición de las bandas de absorción de los grupos funcionales involucrados en la formación del enlace por puente de hidrógeno. La liberación de ibuprofeno en FGS resultó del 40 por ciento para las micropartículas sin recubrimiento, mientras que fue despreciable en el caso de las micropartículas recubiertas durante el intervalo de tiempo estudiado. CONCLUSIONES: los resultados muestran las potencialidades del complejo interpolimérico poli(ácido acrílico)/poli(N-vinil-2-pirrolidona) como cubierta pH dependiente, con vistas a obtener un recubrimiento de tipo entérico que reduzca los efectos adversos sobre la mucosa gástrica de fármacos como los antiinflamatorios no esteroideos(AU)

INTRODUCTION: the irritating effect on the gastric mucosa caused by non-steroidal anti-inflammatory drugs is one of the main adverse reactions. Their encapsulation in polymer matrices with enteric properties is a technological alternative to solve the problem. OBJECTIVE: to obtain ibuprofen-loaded chitosan microparticles coated with a pH dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone). METHODS: Ibuprofen-loaded chitosan microparticles were prepared through the spray drying technique; the yield and the efficiency of encapsulation were evaluated. Microparticles were coated with a pH-dependent interpolymer complex based on poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) using the emulsion/solvent evaporation technique. The complex formation was verified by Fourier transform infrared spectroscopy and the morphological evaluation was made with the electronic scanning microscopy. Release studies used simulated gastric (SGF, pH= 1.2) and intestinal (SIF, pH= 6.8) fluids. RESULTS: in the process of obtaining the chitosan and chitosan-ibuprofen microparticles, the yield rates amounted to 69 ± 1 percent and 54.4 ± 0.8 percent respectively were obtained. The encapsulation efficiency was 46.8 ± 0.7 percent he coated microparticles presented rough surface. Complex formation was confirmed by changes in the position of the absorption bands of the functional groups involved in hydrogen bonding. The release of ibuprofen from uncoated microparticles in simulated gastrointestinal fluid reached 40 percent whereas it was neglectable in the coated microparticles during the study interval. CONCLUSIONS: the results show the potential of poly(acrylic acid)/poly(N-vinyl-2-pyrrolidone) interpolymer complex as pH dependent cover for use as enteric coating to reduce the side effects on the gastric mucosa of medications such as non-steroidal anti-inflammatory drugs(AU).

Estudo de formulação de microesferas de acetobutirato de celulose com diferentes concentrações de Poloxamer 188 / Formulation study of cellulose acetate butyrate microspheres withdifferent concentrations of Poloxamer 188

Microesferas de liberação prolongada de diclofenaco de sódio (DFS) foram preparadas empregando o acetobutirato de celulose (ABC) para obtenção da matriz polimérica. Buscando modular a velocidade de liberação do fármaco, a adição de Poloxamer 188 na formulação foi testada, com diferentes proporções de ABC: Pluronic F68 (1:0; 9:1; 3:1 e 1:1). Com exceção da formulação contendo ABC e Pluronic F68 na proporção de 1:1, as outras formulações testadas conduziram à formação de partículas esféricas de tamanho micrométrico. Quando a misturaA BC: Pluronic F68 (1:1) foi empregada, ocorreu à precipitação de uma massa polimérica, sendo este efeito relacionado à elevada concentração do polímero hidrofílico na preparação. Quando comparado com as microesferas preparadas unicamente com ABC, o teor e a eficiência de encapsulação aumentaram com o acréscimo de Poloxamer 188 às formulações. Efeito semelhante foi observado na avaliação da velocidade de liberação do fármaco em meio tampão fosfato pH 7,5. Enquanto as microesferas preparadas apenas com ABC conduziram à liberação de 25% do fármaco encapsulado após 12 horas de ensaio, as microesferas preparadas com relação ABC:Pluronic 9:1 e 3:1 conduziram à liberação de 30% e 70% do fármaco, respectivamente.

Extended-release microspheres containing sodium diclofenac were prepared using the cellulose acetate butyrate (CAB) to obtain the polymer matrix. Looking modulate the rate of drug release, the addition of Poloxamer 188 at different concentrations into formulations was tested in order to obtain CAB to Poloxamer ratio of 1:0, 9:1, 3:1 and 1:1. Excepting for the formulation containing CAB and Poloxamer 1:1, the other formulations resulted in formation of spherical particles of micrometer size range. When the mixture CAB:Poloxamer (1:1) was employed, the precipitation of a polymeric mass occorred, and this effect was related to the high concentration of the hydrophilic polymer in the preparation. When compared to the microspheres prepared only with CAB, the drug content and the encapsulation efficiency increased with the addition of Poloxamer 188 in the formulations. A similar effect was observed in the evaluation of the rate of drug release in pH 7.5 phosphate buffer. While the microspheres prepared with CAB led to release of 25% of the encapsulated drug after 12 hours of testing, the microspheres prepared with CAB: Poloxamer 9:1 and 3:1 resulted in release of 30% and 70% of the drug, respectively.

Tratamento endovascular de angiomiolipoma renal por embolização arterial seletiva / Endovascular treatment of renal angiomiolipoma by selective arterial embolization

Relata-se um caso de um paciente com queixa principal de dor lombar à esquerda, portador de angiomiolipomas renais (AMLRs) bilaterais, com a lesão mais volumosa de 6,2 cm em seu maior diâmetro, submetido a tratamento endovascular por embolização arterial superseletiva com microesferas. Os AMLRs são tumores benignos raros. A maioria é esporádica, enquanto uma minoria está associada à Esclerose Tuberosa Complexa (ETC). Os AMLRs maiores do que 4 cm devem ser tratados devido ao maior risco de complicações, principalmente hemorrágicas. A embolização arterial seletiva (EAS) é um tratamento efetivo e seguro para os AMLRs.

We report a case of a patient with a major complaint of left lumbar pain, diagnosed with bilateral renal angiomyolipomas (AMLRs), with the most voluminous lesion of 6.2 cm in its largest diameter, underwent endovascular superselective arterial embolization with microspheres. The AMLRs are rare benign tumors. Most are sporadic, while a minority is associated with Tuberous Sclerosis Complex (ETC). The AMLRs larger than 4 cm must be treated due to higher risk of complications, especially hemorrhagic. A selective arterial embolization (EAS) is an effective and safe treatment for AMLRs.

Comprimidos contendo microesferas de cetoprofeno como sistema de liberação bifásica / Tablets containing ketoprofen microspheres as abiphasic delivery system

Sistema de liberação bifásica é aquele que promove a liberação do fármaco em dois estágios: um de liberação imediata e o outro de liberação prolongada. No presente trabalho o cetoprofeno foi incorporado em microesferas de Kollidon® SR e acetobutirato de celulose e, posteriormente, as microesferas foram comprimidas com o intuito de obter comprimidos de liberação bifásica. As microesferas foram obtidas através do método de emulsão e evaporação do solvente óleo em água (O/A), originando partículas esféricas e eficiência de encapsulação de 81,9%, indicando que o processo de obtenção permitiu uma incorporação bastante eficiente do fármaco nas microesferas. Três formulações (F) de comprimidos foram obtidas por compressão direta utilizando-se uma prensa hidráulica: F1 - contendo as microesferas de cetoprofeno; F2 - contendo microesferas de cetoprofeno, crospovidona e celulose microcristalina; e F3 - contendo as microesferas de cetoprofeno, o cetoprofeno não encapsulado, além dos excipientes citados anteriormente (comprimidos bifásicos). Análises por microscopia eletrônica de varredura evidenciaram que o processo de compressão não afetou a morfologia das microesferas, as quais mantiveram sua integridade. A liberação do fármaco a partir dos comprimidos bifásicos inicialmente foi rápida, com 75% do fármaco dissolvido em uma hora, seguida de uma liberação prolongada, atingindo 88% de fármaco dissolvido em doze horas. Os resultados obtidos sugerem que o sistema proposto pode ser otimizado para a liberação do cetoprofeno em dois estágios, para administração por via oral.

A biphasic delivery system is one from which a drug is released in two stages, consisting of an immediate release and a prolonged release. In this study, ketoprofen was incorporated into Kollidon SR® and cellulose acetate butyrate microspheres, which were then compressed in order to obtain biphasic release tablets. The microspheres were produced by an oil-in-water (O/W) emulsion and solvent evaporation method, resulting in spherical particles and an encapsulation efficiency of 81.9%, indicating that the process allowed a very efficient incorporation of the drug into the microspheres. Three tablet formulations were compounded by direct compression in a hydraulic press: F1, containing only the ketoprofen microspheres; F2, containing ketoprofen microspheres, crospovidone and microcrystalline cellulose, and F3, containing the ketoprofen microspheres plus non-encapsulated ketoprofen, together with the aforementioned excipients (biphasic tablets). Examination by scanning electron microscopy showed that the compression process did not affect the morphology of the microspheres, which remained whole and undamaged. The drug release from the biphasic tablets was initially rapid, 75% of the drug being dissolved in one hour, followed by a sustained slow release, 88% of the drug being dissolved in twelve hours. These results suggest that the proposed delivery system can be optimized for two-stage ketoprofen release via oral administration.

Floating microspheres: a review

Gastric emptying is a complex process, one that is highly variable and that makes in vivo performance of drug delivery systems uncertain. A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. The main limitations are attributed to the inter- and intra-subject variability of gastro-intestinal (GI) transit time and to the non-uniformity of drug absorption throughout the alimentary canal. Floating or hydrodynamically controlled drug delivery systems are useful in such applications. Various gastroretentive dosage forms are available, including tablets, capsules, pills, laminated films, floating microspheres, granules and powders. Floating microspheres have been gaining attention due to the uniform distribution of these multiple-unit dosage forms in the stomach, which results in more reproducible drug absorption and reduced risk of local irritation. Such systems have more advantages over the single-unit dosage forms. The present review briefly addresses the physiology of the gastric emptying process with respect to floating drug delivery systems. The purpose of this review is to bring together the recent literature with respect to the method of preparation, and various parameters affecting the performance and characterization of floating microspheres.

O esvaziamento gástrico é um processo complexo, com elevada variabilidade e responsável pela incerteza do desempenho dos medicamentos in vivo. Dessa forma, os sistemas de liberação modificada de fármacos, com tempo de residência prolongado no estômago, em especial, considerando aqueles fármacos com janela de absorção na porção superior do intestino delgado, apresentam fundamental importância. As principais limitações relativas à absorção do fármaco são, no geral, atribuídas à variabilidade inter e intra-paciente do tempo de trânsito gastro-intestinal (GI) e da não-uniformidade da absorção do fármaco na extensão do canal alimentar. Assim, justifica-se a utilização dos sistemas flutuantes ou hidrodinâmicos de liberação de fármacos. Vários medicamentos gastrorretentivos estão disponibilizados no mercado e incluem comprimidos, cápsulas, pílulas, filmes laminados, microesferas flutuantes, grânulos e pós. As microesferas flutuantes apresentam maior destaque em função da distribuição granulométrica uniforme dessas formulações de dose múltipla. Como resultado, a absorção do fármaco apresenta maior reprodutibilidade e os riscos associados à irritação local são reduzidos. Tais sistemas apresentam maior vantagem quando comparado às formulações de dose única. A presente revisão tem como objetivo apresentar as publicações recentes referentes aos métodos de preparação, os vários parâmetros que afetam o desempenho e a caracterização das microesferas flutuantes. Além disso, o presente trabalho aborda a fisiologia do processo de esvaziamento gástrico no que se refere aos sistemas flutuantes de liberação de fármacos.

Microspheres prepared with biodegradable PHBV and PLA polymers as prolonged-release system for ibuprofen: in vitro drug release and in vivo evaluation

In this study, poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) and poly(l-lactide) (PLA) microspheres containing ibuprofen were prepared with the aim of prolonging the drug release. The oil-in-water (O/W) emulsion solvent evaporation technique was used, varying the polymer ratio. All formulations provided spherical particles with drug crystals on the surface and a porous and rough polymeric matrix when PHBV was used and smooth external surface when prepared with PLA. The in vitro dissolution profiles show that the formulation containing PHBV/PLA at the proportion of 30/70 presented the best results in terms of prolonging the ibuprofen release. The analysis of the concentration of ibuprofen in the blood of rats showed that maximum levels were achieved at between one and two hours after administration of the immediate-release form (pure drug), while the prolonged microspheres led to a small amount of the drug being released within the first two hours and reached the maximum level after six hours of administration. It was concluded that it is possible to prolong the release of ibuprofen through its incorporation into PHBV/PLA microspheres.

No presente estudo foram preparadas microesferas de poli(hidroxibutirato-co-hidroxivalerato) (PHBV) e poli(ácido láctico) (PLA) com o objetivo de prolongar a liberação do ibuprofeno, utilizado como fármaco modelo. Empregou-se o método de emulsificação e evaporação do solvente óleo em água (O/A), variando-se a proporção entre os polímeros. Todas as formulações originaram partículas esféricas com cristais de fármaco aderidos à superfície externa. As microesferas apresentaram superfície rugosa e porosa, quando o PHBV foi utilizado, e superfície externa lisa, quando preparadas com o PLA. Os perfis de dissolução in vitro evidenciaram que a formulação que continha PHBV/PLA na proporção de 30/70 apresentou melhores resultados para prolongar a liberação do ibuprofeno. Através da análise da concentração de ibuprofeno no plasma de ratos, após administração oral, verificou-se que os níveis máximos ocorreram entre 1 e 2 horas após a administração de ibuprofeno não encapsulado, enquanto o fármaco presente nas microesferas atingiu um pico máximo após 6 horas da administração. Conclui-se, portanto, que é possível prolongar a liberação do ibuprofeno após a sua incorporação às microesferas preparadas com os polímeros PHBV e PLA, especialmente na proporção de 30/70.

Treinamento físico de natação promove remodelamento cardíaco e melhora a perfusão sanguínea no músculo cardíaco de SHR via mecanismo dependente de adenosina / Swimming physical training promotes cardiac remodeling and improves

INTRODUÇÃO: Exercícios físicos são utilizados como terapia não farmacológica para o tratamento da hipertensão arterial, e o treinamento físico (TF) por natação é reconhecido por produzir remodelamento cardíaco em animais experimentais. Entretanto, a ação vasodilatadora da adenosina (ado) resultante do exercício físico como prevenção e tratamento da hipertensão é pouco explorada. OBJETIVO: Avaliar o remodelamento cardíaco e o papel da adenosina na distribuição do fluxo sanguíneo para o miocárdio após treinamento físico em SHR. Método: 28 SHR machos babies e adultos foram submetidos ao TF aeróbio de natação, durante 10 semanas (5x/sem -1h/dia). Foram utilizados protocolos de microesferas coloridas para avaliar fluxo sanguíneo, técnicas de morfologia para avaliar hipertrofia cardíaca e análises bioquímicas para verificar atividade de enzimas envolvidas na formação de adenosina. RESULTADOS: TF por natação atenuou a evolução da HA em SHR babies (S: 145 ± 2; T: 140 ± 2mmHg), promoveu bradicardia de repouso em SHR adultos (S: 340 ± 4; T: 321 ± 6bpm) e desenvolveu HC nos dois grupos (TB: 12 por cento; TA: 10 por cento). Na condição basal, o TF aumentou o FS coronário em SHR babies (S: 4.745 ± 2.145; T: 6.970 ± 2.374mi/coração) e maior resposta vasodilatadora à infusão de adenosina foi observada (S: 18.946 ± 6.685; T: 25.045 ± 7.031mi/coração). Neste grupo, o TF promoveu maior atividade da enzima 5'-nucleotidase, levando à maior formação de adenosina (S: 0,45 ± 0,09; T: 1,01 ± 0,05). CONCLUSÃO: O TF de natação, além de desenvolver HC e apresentar maior hidrólise de AMP, promoveu aumento no FS coronário, sendo mostrado que desempenha um importante papel na regulação da hipertensão.

Exercise training (ET) has been used as non-pharmacological therapy for hypertension treatment and swimming physical training is recognized for yielding cardiac remodeling in experiments. However, little is known on the effects of adenosine (Ado) resulting from ET as hypertension prevention and treatment. OBJECTIVE: To evaluate cardiac remodeling and the role of adenosine in cardiac blood flow distribution (BF) to the myocardium after aerobic ET on SHR. METHODS: 28 male SHR, babies and adults, were submitted to swimming training protocol during 10 weeks (5 times a week - 1 h a day). Colored micro spheres protocols were used to evaluate blood flow, morphological techniques were used to evaluate cardiac hypertrophy and biochemical analysis were performed to verify enzyme activity in the adenosine formation. RESULTS: ET attenuated the evolution of hypertension in the SHR babies group (S: 145 2; T: 140 2mmHg), HR was lower in adult SHR (S: 340 4; T: 321 6bpm) and CH increased in both groups (TB: 12 percent; TA: 10 percent). At basal condition, BF was increased in trained babies (S: 4.745 ± 2.145; T: 6.970 ± 2.374mi/heart) and higher vasodilatation response was observed due to adenosine infusion (S: 18.946 ± 6.685; T: 25.045 ± 7.031mi/heart). In this group, the ET promoted a higher 5'-nucleotidase enzyme activity leading to a higher adenosine formation (S: 0.45 ± 0.09; T: 1.01 ± 0.05). CONCLUSION: The swimming training developed CH as well as increased adenosine formation, leading to higher coronary blood flow, and its important role in hypertension regulation was demonstrated.

Efeito da massa molar do acetobutirato de celulose e da adição de poli(3-hidroxibutirato) sobre as características das microesferas e o prolongamento da liberação do cetoprofeno / Effects of cellulose acetate butyrate molar weight and addition of poly(3-hydroxybutyrate) on microsphere morphology and ketoprofen prolonged release

No presente trabalho, foram elaboradas microesferas de acetobutirato de celulose (ABC) contendo cetoprofeno com o objetivo de prolongar a liberação do fármaco. Utilizou-se a técnica de emulsão e evaporação do solvente, variando-se os seguintes parâmetros: massa molar do ABC e a adição ou não de poli(3-hidroxibutirato) (PHB), segundo um planejamento fatorial 22. Maiores eficiências de encapsulação do cetoprofeno foram obtidas quando utilizado ABC com maior massa molar e a adição do PHB levou a uma diminuição do percentual de fármaco encapsulado. Todas as formulações originaram partículas esféricas, com cristais de fármacos aderidos à superfície externa e matriz polimérica porosa quando adicionado o PHB. Os perfis de liberação in vitro indicaram que o aumento da massa molar do ABC levou a uma diminuição do percentual de fármaco inicialmente liberado e a um prolongamento de sua liberação. Por outro lado, a adição do PHB acelerou a liberação do cetoprofeno a partir das microesferas.

In the present study, cellulose acetate butyrate (CAB) microspheres containing ketoprofen were produced, with the objective of prolonging its release. The emulsion/solvent evaporation technique was used to make the spheres, varying the parameters (1) CAB molecular weight and (2) addition or not of poly(3-hydroxybutyrate) [PHB], to optimize drug encapsulation, following a 2² factorial design. Higher ketoprofen encapsulation efficiency was obtained when higher molecular weight CAB was used, while the addition of PHB caused a decrease in the percentage of encapsulated drug. All the preparations produced spherical particles, with drug crystals adhering to the external surface, and a porous polymer matrix when PHB was used. The in vitro release profiles indicated that lowering the CAB molecular weight led to a decrease in the drug initially released and a prolonged release. On the other hand, the addition of PHB accelerated the release of the ketoprofen from the microspheres.

Avaliação histopatológica do polimetilmetacrilato em ratos ao longo de um ano / Histopathological evaluation of polymethylmethacrylate in rats for one year

Avaliação histológica (do local aplicado e órgãos) após preenchimento com PMMA em ratos. Método: Utilizaram-se 60 ratos Wistar, todos receberam aplicação de 1ml de PMMA (Meta-Crill®) em plano profundo, próximo à região occipital. A eutanásia ocorreu em grupos de 15 ratos no 1º, 3º, 6º e 12º mês após aplicação. Resultados: Identificada presença de infiltrado inflamatório e fibrose no local injetado, além da diminuição da quantidade de PMMA em todas as amostras. Reação de corpo estranho (RCE) tipo granuloma ocorreu em 3,3% das amostras (2 ratos). A análise estatística mostrou-se significante pelo teste de Kruskal-Wallis. Conclusão: O PMMA utilizado apresentou maior RCE e evidente fibrose em amostras tardias, podendo ocorrer RCE tipo granuloma. Embora o PMMA pareça seguro, diversas complicações podem ocorrer. Sua utilização deve ser criteriosa, sabendo que granulomas ocorrem independente da técnica.

Histological evaluation (of the applied place and organs) after PMMA filling in rats. Methods: 60 Wistar rats were used; each received an application of 1 ml of PMMA (Meta-Crill®) in deep frame (near the occipital region). The euthanasia occurred in groups of 15 rats at 1, 3,6 and 12 months after application. Results: Presence of inflammatory infiltrate and fibrosis in the injected site, in addition to the reduced amount of PMMA in all samples. Foreign body reaction (FBR) granuloma type occurred in 3.3% of samples (2 mice). Statistical analysis was shown significant by Kruskal-Wallis. Conclusion: The PMMA used had a higher FBR and evident fibrosis in late samples, occurring FBR granuloma type. Although the PMMA seems safe, several complications can occur. Its use should be judicious, knowing that granulomas occur regard less of the technique.