Estudo da permeabilidade de fármacos por meio do modelo de saco intestinal de ratos / Study of drug permeability through the rat gut sac model

Os parâmetros de permeabilidade e solubilidade são fundamentais à absorção oral de fármacos e a partir dessas características, foi criado o Sistema de Classificação Biofarmacêutica, através do qual os fármacos são divididos em quatro classes. Atualmente, para a determinação da solubilidade de um fármaco, existem diversos métodos padronizados por agências regulatórias, no entanto, para a determinação da permeabilidade, os ensaios são passíveis de diversas variações em sua execução, diminuindo a confiabilidade dos resultados obtidos e impossibilitando a comparação dos mesmos quando realizados com técnicas diferentes umas das outras. O objetivo do presente trabalho é avaliar as variáveis experimentais do modelo do saco intestinal que podem influenciar nos resultados de permeabilidade aparente de fármacos e na viabilidade do tecido. O presente estudo foi aprovado pelo Comitê de Ética no Uso de Animais da FCF-USP (109.2018-P574). Foram utilizados 33 Rattus norvegicus da linhagem Wistar, machos, jovens adultos, com peso entre 200 g e 300 g. Para realização do procedimento, cada animal permaneceu em jejum por cerca de quatro horas e após adequada anestesia a porção do jejuno do intestino delgado foi retirada e dividida em seis segmentos de aproximadamente 8,5cm cada. Foram realizados experimentos com e sem inversão do saco intestinal, submetidos a diferentes tempos de banho de gelo após sua ressecção, na presença ou ausência de inibidor da glicoproteína-P (verapamil). Os fármacos naproxeno e famotidina foram empregados como marcadores de alta e baixa permeabilidade, respectivamente. A losartana foi utilizada como substrato da glicoproteína P. Cada um dos sacos intestinais foi colocado em um tubo de ensaio contendo tampão Krebs, a 37°C, saturado com gás carbogênio. Para avaliação da integridade e viabilidade dos segmentos intestinais, observou-se a presença de movimentos peristálticos e coletaram-se amostras do meio de incubação nos tempos 0, 30, 45, 60, 90 e 120 minutos para quantificação dos fármacos e de glicose, uma vez que esta é ativamente transportada para a serosa do intestino delgado. Determinou-se a permeabilidade aparente de cada fármaco e as concentrações de glicose nas diferentes condições experimentais, realizou-se planejamento fatorial multinível e os resultados foram analisados por análise variância (ANOVA), seguida de pós-teste de Tukey. Observou-se que as variáveis experimentais interferiram de forma significativa na viabilidade tecidual e na permeabilidade aparente dos fármacos. Não foram observadas diferenças significativas da permeabilidade de fármacos nos diferentes segmentos do jejuno. A glicose mostrou-se um bom marcador de viabilidade tecidual e foi constatado que a presença ou ausência de movimentos peristálticos não está relacionada diretamente com a viabilidade do tecido. Uma vez que foram constatadas tantas interferências nos resultados, é imprescindível que os procedimentos experimentais sejam padronizados, para que os resultados apresentem menor variabilidade e possam ser comparados entre si

The permeability and solubility parameters are fundamental to the oral absorption of drugs and from these characteristics, the Biopharmaceutical Classification System was created, through which drugs are divided into four classes. Currently, for the determination of the solubility of a drug, there are several methods standardized by regulatory agencies, however, for the determination of permeability, the tests are subject to several variations in their execution, reducing the reliability of the results obtained and making it impossible to compare the results obtained. same when performed with different techniques. The aim of this study is to evaluate if different experimental conditions can influence the results of apparent drug permeability and tissue viability on gut sac model. The present study was approved by the Ethics Committee for the Use of Animals of FCF-USP (109.2018-P574). Thirty-three male, young adult Rattus norvegicus were used, weighing between 200 g and 300 g. To perform the procedure, each animal fasted for about four hours and after adequate anesthesia, the portion of the jejunum of the small intestine was removed and divided into six segments of approximately 8.5 cm each. Experiments were performed with and without inversion of the gut sac, submitted to different times of ice bath after its resection, in the presence or absence of a P-glycoprotein inhibitor (verapamil). The drugs naproxen and famotidine were used as markers of high and low permeability, respectively. Losartan was used as a substrate for P-glycoprotein. Each of the gut sacs was placed in a test tube containing Krebs buffer, at 37°C, saturated with carbogen gas. To evaluate the integrity and viability of the intestinal segments, the presence of peristaltic movements was observed and samples of the incubation medium were collected at 0, 30, 45, 60, 90 and 120 minutes for quantification of drugs and glucose, as it is actively transported to the serosa of the small intestine. The apparent permeability of each drug and the glucose concentrations were determined under different experimental conditions, multilevel factorial design was performed and the results were analyzed by analysis of variance (ANOVA), followed by Tukey's post-test. It was observed that the experimental variables significantly interfered in the tissue viability and in the apparent permeability of the drugs. No significant differences in drug permeability were observed in the different segments of the jejunum. Glucose proved to be a good marker of tissue viability and it was found that the presence or absence of peristaltic movements is not directly related to tissue viability. Since so many interferences were found in the results, it is essential that the experimental procedures be standardized, so that the results show less variability and can be compared between different authors

Quiste mesentérico en el recién nacido / Mesenteric cyst present in newborn

El quiste mesentérico es una enfermedad rara en la etapa neonatal, y suele confundirse imagenológicamente con múltiples patologías de los órganos intraabdominales. Se presenta un caso clínico con diagnóstico prenatal por imagen anecoica del hemiabdomen superior. El paciente requirió múltiples intervenciones quirúrgicas por presentar un quiste mesentérico que coexistía con atresia intestinal ileal en forma de cáscara de manzana, y el tratamiento clínico y nutricional fue difícil.

Mesenteric cyst is a rare condition in neonatal stage and often is confounded with multiple pathologies of intra-abdominal organs. A clinical case diagnosed with prenatal diagnosis by anechoic image of superior hemi-abdomen. Patient required of many surgical interventions due to a mesenteric cyst coexisting with an apple shell ileal intestinal atresia. Clinical and nutritional treatment was difficult.

Association of biliary atresia with jejuno-ileal atresia

Jejuno-ileal atresia [JIA] is a congenital anomaly characterized clinically by bilious vomiting and abdominal distension. The incidence of JIA is between 1: 330 to 1: 3000 live births in different parts of the world. It has been associated with various congenital anomalies but the association of JIA with biliary atresia is extremely rare [0-3.2%]. We herein present a case of jejunal atresia with meconium peritonitis associated with biliary atresia. The patient was a boy who was born at 39 weeks of gestation with polyhydramnious detected on Prenatal Ultra Sonography done at 8th month of gestation. It is important to explore gallbladder in cases of JIA especially when associated with meconium peritonitis

Atresia of the jejunum and ileum: what is the difference?

BACKGROUND: Atresia of the jejunum and ileum is one of the major causes of neonatal intestinal obstruction. Most affected newborn infants present with bilious emesis and abdominal distention. Traditionally, jejunal and ileal atresia have been grouped together as jejunoileal atresia. OBJECTIVE: To elucidate the difference between jejunal and ileal atresia. MATERIAL AND METHOD: A retrospective analysis of patients diagnosed with jejunal or ileal atresia, who were treated at the Department of Surgery, Queen Sirikit National Institute of Child Health during January 1988 to December 2007, was carried out. RESULTS: There were 74 patients with jejunal atresia and 68 patients with ileal atresia. The mean birth weight and gestational age of patients with jejunal atresia were significantly lower than those with ileal atresia. Antenatal perforation occurred more frequently in ileal atresia. Postoperative course was more prolonged and mortality was higher injejunal atresia. Prolonged ileus and anastomotic dysfunction requiring long-term parenteral nutrition were the major causes of complications leading to death. CONCLUSION: There were many differences between patients with jejunal atresia and those with ileal atresia. The more compliant jejunal wall allows massive dilatation upon obstruction with subsequent loss of peristaltic activity, thus poorer outcome in comparison with ileal obstruction. We suggest that atresia of the jejunum and ileum be considered differently.

Comorbilidad y letalidad en el primer año de vida en niños con atresia yeyunoileal / Co-morbidity and mortality during the first year of life in children with jejunoileal atresia

Objective. To identify the co-morbidity and mortality during the first year of life in children with jejunoileal atresia. Design. Descriptive, comparative cohort. Site. Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social. Population. Seventy children with jejunoileal atresia. Measures. Following variables were registered: gestational age, birth weight, sex, type and site of atresia, other congenital defects, surgical management, number of surgeries, duration of fasting, re-hospitalizations, weight and height at 6 months and one year of life, co-morbidity and mortality. Results. Intestinal atresia types I and II were present in 27% of the patients respectively and type IIIa in 24%. Co-morbidity in the neonatal period was 64.2%, being the most common conditions sepsis (47.1%) and anastomotic stricture (18.5%). During the first year of life co-morbidity was 51.4%, presented as functional intestinal obstruction (21.4%). Mortality was 11.4% (n = 8), the main causes of death were sepsis (n = 6) and liver failure (n = 2). The mortality rate according to the type of atresia was 44.4% for type IV, 33.3% for type IIIb and 1.3% for type I. Conclusions. Co-morbidity during the first year of life in children with jejunoileal atresia is high, and related to infections and anastomosis inherent problems. Mortality is higher for intestinal atresia type IV.

Objetivo. Identificar la comorbilidad y la letalidad durante el primer año de vida en niños con atresia yeyunoileal. Diseño. Cohorte descriptiva, comparativa. Lugar. Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS. Pacientes. Se estudiaron 70 niños. Mediciones. Se registraron las siguientes variables: edad gestacional, peso al nacimiento, sexo, tipo de atresia, sitio de la atresia, malformaciones asociadas, tratamiento quirúrgico, reintervenciones quirúrgicas, tiempo de ayuno, rehospitalizaciones, peso y talla a los seis meses y al año de edad, comorbilidad y letalidad. Resultados. La atresia tipo I y II se presentaron en 27% cada una y la tipo IIIa en 24%. La comorbilidad en el periodo neonatal fue de 64.2%, las causas más frecuentes fueron sepsis (47.1%) y estenosis de la anastomosis (18.5%) y en el primer año de vida fue de 51.4%; la causa más frecuente fue oclusión intestinal funcional (21.4%). La letalidad fue de 11.4% (n = 8); las principales causas de muerte fueron sepsis (n = 6), e insuficiencia hepática (n = 2). La letalidad por tipo de atresia fue de 44.4% en la tipo IV, 33.3% en la IIIb y 10.5% en la tipo I. Conclusiones. La comorbilidad en el primer año de vida en niños con atresia intestinal fue elevada, las principales causas fueron infecciosas y problemas inherentes a la anastomosis. La atresia con mayor letalidad fue la tipo IV.

Waugh's Syndrome.

A case of Waugh's Syndrome, association of malrotation and intussusception, is being reported. It is suggested that this possibility must be kept in mind and looked for, when a case of intussusception is being treated either by surgery or by hydrostatic reduction. If not when the child develops intestinal problems like obstruction, secondary to malrotation, in the post operative period, it could be misdiagnosed as recurrent intussusception.

Perforation in a jejunal duplication lined by ectopic gastric mucosa.

We report a 3-year-old child with jejunal duplication with localized perforation and bleeding in the adjacent normal intestine. The entire duplicated jejunum was lined by gastric mucosa. This was successfully treated by mucosal excision of the duplicated intestine and resection of a short segment of normal jejunum.

Ectopic pancreas mimicking superior mesenteric artery syndrome.

Ectopic pancreas rarely produces symptoms and often goes undetected. We report a 28-year-old man with ectopic pancreas presenting with symptoms and radiological findings mimicking superior mesenteric artery syndrome. Excision of the lesion and duodeno-jejunostomy led to relief.

Symptomatic volvulus due to mid gut malrotation in an adult.

Anomalies of rotation and fixation of gut occur most commonly in the neonatal period and usually become symptomatic in infancy. We report an adult patient with symptomatic volvulus due to mid gut malrotation.

Gastrosquisis asociada a múltiples malformaciones intestinales congénitas / Multiple intestinal congenital malformations associated to gastroschisis. A case report

Introducción. La asociación de gastrosquisis y múltiples atresias de intestino, suboclusión duodenal por bandas de Ladd y malrotación intestinal es un evento extraordinariamente raro y de consecuencias casi siempre fatales. Caso clínico. Se reporta el caso de una recién nacida con gastrosquisis, 7 atresias intestinales localizadas en yeyuno-íleon, suboclusión duodenal extrínseca por bandas de Ladd y malrotación intestinal. En una primera intervención quirúrgica se efectuó enterolisis duodenal, duodenoplastia simple, yeyunostomía a nivel del primer segmento de atresia, introducción de asas intestinales y cierre de pared en 2 planos. En una segunda intervención quirúrgicas, 17 días después, se efectuó: desprendimiento de yeyunostomía, 5 anastomosis T-T en un plano, gastrostomía tipo Stamm, dejando una sonda en estómago para drenaje y otra sonda de silastic en yeyuno para alimentación. Se implementaron medidas generales de apoyo, ventilación asistida, alimentación parenteral periférica y dieta elemental, seguida de una fórmula con hidrolizado de proteínas, triglicéridos de cadena media y enriquecido con hierro. La ablactación se inició a los 5 meses de edad en forma progresiva y actualmente a los 5 años 10 meses de edad, tiene una dieta y un tránsito intestinal normales, así como un desarrollo pondestatural y psicomotriz de acuerdo a su edad cronológica. Conclusiones. En la revisión de la literatura no se encontró un caso similar, considerándose éste el primer reporte de sobrevida mayor de 1 año. Por lo tanto el manejo instituido en esta paciente pudiera ser sugerido como el adecuado en casos de esta compleja patología

Duplicación intestinal tóraco-abdominal / Thoraco-abdominal duplication

Introducción. Es bien conocido que la duplicación intestinal intraabdominal es una malformación congénita poco frecuente; la torácica es aún menos; y la tóraco-abdominal es excepcional. Presentamos el caso de un niño que sufrió este último defecto y estudiamos en detalle los hallazgos clínicos, radiológicos y quirúrgicos. Caso clínico. Lactante masculino de 11 meses de edad que fue hospitalizado por infección de vías respiratorias y palidez cutánea. el día de su ingreso se le efectuo estudio radiológico de tórax, que revelo la presencia de un nivel hidroaéro en el hemitórax izquierdo y hemivértebras. La tomografía axial computada mostró la presencia de tumoración en mediastino posterior. Fue intervenido quirúrgicamente encontrándose duplicación tóraco-abdominal. Esta fue extirpada y el extremo diafragmático fue suturado. Como externo, se le efectuó tránsito intestinal y gamagrafía abdominal, refiriéndose posible comunicación con el tubo digestivo proximal y mucosa gástrica ectópica. En la laparotomía exploradora se encontró conexión del yeyuno con el residuo de la duplicación Se efectuó resección intestinal y entero-enteroanastomosis. Conclusiones: este es un defecto raro que requiere de intervención quirúrgica