Pharmaceutical suspensions of ursodeoxycholic acid for pediatric patients: in vitro and in vivo studies.

Ursodeoxycholic acid (UDCA) is used in the oral therapy of hepatobiliary cholestatic diseases. Due to UDCA low aqueous solubility, two pediatric oral suspensions (25 mg/mL) were formulated with a few excipients, suspension A (SA) and suspension B (SB) with a vehicle, including two suspending agents. Physical, chemical and microbiological stability and a rheological study were performed at three different conditions (5 °C ± 3 °C, 25 °C ± 2 °C/60% RH ± 5% RH and 40 °C ± 2 °C/75% RH ± 5% RH) for 120 days. Moreover, dissolution study, content uniformity, related substances, and a study of relative oral bioavailability were also carried out. Both suspensions were physically, chemically and microbiologically stable throughout the study. SA and SB can be stored at 25 °C and 5 °C for at least 120 days whereas SA can be kept at 40 °C for at least 90 days and SB for 120 days. They both met USP specifications for dissolution, content uniformity, and related substances. SA and SB showed an improved relative oral bioavailability compared to the solid dosage form and they both displayed similar relative oral bioavailability with no significant differences between them. The developed suspensions proved to be safe and adequate and they are ideal for pediatric use for their acceptability, accurate dose administration and treatment adherence.

Role of mitochondria in the differential action of sodium deoxycholate and ursodeoxycholic acid on rat duodenum.

Sodium deoxycholate (NaDOC) inhibits the intestinal Ca2+ absorption and ursodeoxycholic acid (UDCA) stimulates it. The aim of this study was to determine whether NaDOC and UDCA produce differential effects on the redox state of duodenal mitochondria altering the Krebs cycle and the electron transport chain (ETC) functioning, which could lead to perturbations in the mitochondrial dynamics and biogenesis. Rat intestinal mitochondria were isolated from untreated and treated animals with either NaDOC, UDCA, or both. Krebs cycle enzymes, ETC components, ATP synthase, and mitochondrial dynamics and biogenesis markers were determined. NaDOC decreased isocitrate dehydrogenase (ICDH) and malate dehydrogenase activities affecting the ETC and ATP synthesis. NaDOC also induced oxidative stress and increased the superoxide dismutase activity and impaired the mitochondrial biogenesis and functionality. UDCA increased the activities of ICDH and complex II of ETC. The combination of both bile acids conserved the functional activities of Krebs cycle enzymes, ETC components, oxidative phosphorylation, and mitochondrial biogenesis. In conclusion, the inhibitory effect of NaDOC on intestinal Ca2+ absorption is mediated by mitochondrial dysfunction, which is avoided by UDCA. The stimulatory effect of UDCA alone is associated with amelioration of mitochondrial functioning. This knowledge could improve treatment of diseases that affect the intestinal Ca2+ absorption.

Esclerodermia y Cirrosis Biliar Primaria (Síndrome de Reynolds): Descripción de un Caso / Scleroderma and Primary Biliary Cirrhosis (Reynolds syndrome): Case Description

El síndrome de Reynolds, se define como cirrosis biliar primaria en pacientes con esclerodermia; este síndrome debe ser sospechado en aquellos pacientes que desarrollen un patrón colestásico. Se reporta una paciente con antecedente de esclerodermia que se presenta con ictericia, a quien se le confirma con estudios inmunológicos y biopsia hepática, el diagnóstico de cirrosis biliar prima­ ria (ahora se denomina colangitis biliar primaria). Se ordena ácido ursodesoxicólico 15mg/día.

Reynolds syndrome is defined as primary biliary cirrhosis in patients with scleroderma; this syndro­me should be suspected in those patients who develop a cholesteric pattern. We report a patient with scleroderma who presented with jaundice. After immunological and liver biopsy, a diagnosis of Primary Biliary Cholangiopathy (new name) was confirmed. Ursodeoxycholic acid 15mg / day was prescribed

Mecanismos de acción y aplicaciones terapéuticas del ácido ursodeoxicólico en las enfermedades hepáticas colestásicas / Potential mechanisms of action and therapeutic applications of the ursodeoxycholic acid in cholestasis

El ácido ursodeoxicólico es un ácido biliar hidrofílico, que representa una pequeña fracción del pool de ácidos biliares. En las dos últimas décadas, numerosas enfermedades hepáticas colestásicas crónicas (cirrosis biliar primaria, colangitis esclerosante primaria, colestasia intrahepática del embarazo) han sido tratadas con AUDC. Sin embargo, hasta hoy su eficacia sólo ha sido demostrada en la cirrosis biliar primaria, siendo necesario realizar estudios que permitan definir claramente sus indicaciones. Su efecto es mediado por una disminución del daño de los ácidos biliares tóxicos retenidos sobre la membrana celular de los hepatocitos, a través de una estimulación de la secreción biliar, mejoría del flujo biliar y disminución del daño hepático mediado por el sistema inmune

Morphologic changes in livers of hamsters treated with high doses of ursodeoxycholic acid: correlation with bile acids in bile.

The effects of high doses of ursodeoxycholic acid on bile acid composition and the liver morphology was examined in 60 male Syrian golden hamsters. The animals were allocated to five groups: I, control; II and IV received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 30 days and III and V received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 60 days. Bile acids were determined by high performance liquid chromatography. In all treated groups there was a significant increase in chenodeoxycholic and lithocholic acid in the bile. The mean glyco/tauro ratio was significantly higher than in the control group, reaching values > 1 for individual bile acids, except for lithocholic acid values which remained < 1. Under light microscopy, the livers of the hamsters showed damage which was dose/time related, namely portal inflammatory infiltrate, bile duct proliferation, cholestasis, fat infiltration and necrosis. Electron microscopy revealed pronounced changes starting with microvilli edema and extending to canalicular membrane destruction and necrosis. The changes observed in the relation glyco/tauro lithocholic acids, may be due to defence mechanisms to avoid hepatotoxicity. The hepatotoxicity resulting from ursodeoxycholic acid administration is presumed to be due primarily to lithocholic acid or some lithocholic acid metabolite.