Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model.

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Tailored green synthesized silymarin-selenium nanoparticles: Topical nanocarrier of promising antileishmanial activity.

Poor drug penetration, emerging drug resistance, and systemic toxicity are among the major obstacles challenging the current treatment of cutaneous leishmaniasis. Hence, developing advanced strategies for effective and targeted delivery of antileishmanial agents is crucial. Several drug delivery carriers have been developed till current date for dermal/transdermal delivery, especially those which are fabricated using eco-friendly synthesis approaches, since they protect the environment from the harmful effects of chemical waste disposal. This work describes the preparation of selenium nanoparticles loaded with silymarin via one-pot green reduction technique, for treatment of cutaneous leishmaniasis. The selected silymarin loaded selenium nanoparticles (SSNs4-0.1) displayed good loading efficiency of 58.22 ± 0.56 %, zeta potential of -30.63 ± 0.40 mV, hydrodynamic diameter of 245.77 ± 11.12 nm, and polydispersity index of 0.19 ± 0.01. It exhibited good physical stability, as well as high ex vivo deposition % in the epidermis (46.98 ± 1.51 %) and dermis (35.23 ± 1.72 %), which was further proven using confocal laser microscopy. It also exhibited significant cytocompatibility and noticeable cellular internalization of 90.02 ± 3.81 % in human fibroblasts, as well as high trypanothione reductase inhibitory effect (97.10 ± 0.30 %). Results of this study confirmed the successful green synthesis of silymarin-loaded selenium nanoparticles; delineating them as one of the promising antileishmanial topical delivery systems.

Erythrocyte membrane-camouflaged mesoporous silica composite nanoparticles for loading and controlled release of the hepatoprotective agent silibinin: A-synthesis and physicochemical characterization.

OBJECTIVES: Milk thistle has long been used in the treatment of liver and biliary disorders. In the present study, to make a long-acting delivery system for silibinin (SBN, a major active constituent of milk thistle seeds with antioxidant and hepatoprotective function), mesoporous silica composite nanoparticles (NC) were synthesized and coated with RBC membrane. METHODS: A modified Stöber method was used for NC synthesis, which was then characterized using FE-SEM, DLS, TEM, FTIR, and EDAX techniques. A suitable lysis buffer was used to prepare RBC-ghost, and sonication was used to coat SBN-loaded NC (SBN-NC). The RBC-ghost coated SBN-NC (SBN-NC-RBCG) was evaluated by SDS-PAGE, Bradford, TEM, EDAX, and DLS methods. SBN release was then compared for the SBN-NC and SBN-NC-RBCG samples. KEY FINDINGS: the RBC membrane proteins were recovered from the coating of SBN-NC-RBCG, and SBN release was sustained over 24 h when compared with the SBN-NC. CONCLUSIONS: Overall, through prolonging circulation in the bloodstream and evading the immune system, the developed system can improve SBN bioavailability in liver inflammation and fibrosis conditions that need further research.

Chemoprevention of polyp recurrence with curcumin followed by silibinin in a case of multiple colorectal adenomas

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Ascorbic acid is superior to silymarin in the recovery of ethanol-induced inflammatory reactions in hepatocytes of guinea pigs

Both oxidative stress and inflammatory reactions play a major role in alcoholic liver fibrosis. We evaluated the efficacy of ascorbic acid (AA) and silymarin in the regression of alcohol-induced inflammation in hepatocytes of guinea pigs (Cavia porcellus). Animals were administered with ethanol at a daily dose of 4 g/kg body weight (b.wt) for 90 days. On the ninety-first day, ethanol administration was stopped and animals were divided into alcohol abstention group and silymarin- (25 mg/100 g b.wt) and AA- (25 mg/100 g b.wt) supplemented groups and maintained for 30 days. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and Gamma-glutamyl transpeptidase in the serum of the ethanol group. The intracellular reactive oxygen species (ROS) and expressions of cytochrome P4502E1 and nuclear factor KappaB1, tumor necrosis factor-Alpha, and transforming growth factor-Beta(1) in hepatocytes were significantly increased in ethanol group. The fibrotic markers Alpha -smooth muscle actin and Alpha(1)(I) collagen and activity of cytotoxicity marker caspase-3 were significantly increased and AA content was significantly reduced in hepatocytes of alcohol-treated guinea pigs. But the AA and silymarin supplementation significantly reduced these changes in comparison with alcohol abstention group. AA could induce greater reduction of inflammatory and fibrotic markers in hepatocytes than silymarin. This indicates that AA is superior to silymarin in inhibiting intracellular ROS generation and thereby reducing the ethanol-induced inflammation in hepatocytes

Interés terapéutico del fruto cardo mariano / Therapeutic interest of milk thistle fruit

La actividad antipatotóxica del fruto de cardo mariano y de la silimarina es conocida desde hace muchos años. Su efecto positivo sobre el hígado está basado en las acciones antioxidante, estabilizadora de membrana, favorecedora de la síntesis proteica, antivirásica, antiinflamatoria, inmunomoduladora y anticolestásica de la silimarina y su principal componente, la silibinina. Su eficacia clínica ha sido demostrada en distintos tipos de alteraciones hepáticas, principalmente en las producidas por alcohol y las causadas po virus. Diversos estudios han establecido el papel quimiopreventivo de la silimarina y de la silibinina en distintas áreas celulares cancerosas, así como su efecto estimulante sobre la secreción láctea, además de su actuación en otros ámbitos (protección ósea, neuroprotección, aterogénesis, etc.). a este conjunto de datos, que apuntan hacia posibles nuevas aplicaciones de los productos obtenidos a partir del cardo mariano, se une su amplio margen terapéutico y su baja toxicidad (AU)

Antihepatotoxic activity of milk thistle fruit and silymarin has been known for many years. The positive effect on the liver is based on the antioxidant, membrane stabilizing, protein synthesis increase, antiviral, anti-inflammatory, immunomodulatory and anticolestatic actions of sylimarin and its major constituten, silybinin. Its clinical efficacy has been shown in several types for liver disorders, namely those produced by alcohol and those caused by virus. Several studies have established the chemopreventive role of sylimarin and silybinin in different cancer cell lines and its stimulating effect on lactation, as well as their beneficial effects in other areas (bone protection, neuroprotection, atherogenesis,e tc.). All these data point to possible new applications of the products derived from milk thistle that, in addition, show a wide therapeutic range and low toxicity (AU)

Estabilización clínica en enfermedades neurodegenerativas: estudio clínico en fase II / Clinical stabilisation in neurodegenerative diseases: clinical study in phase II

Introducción. Los trastornos neurodegenerativos, como enfermedad de Parkinson (EP), enfermedad de Alzheimer (EA) y esclerosis múltiple (EM), son patologías progresivas cuyos tratamientos actuales no han demostrado eficacia para detener su progresión (estabilización clínica). Aunque tienen características clínicas muy distintas, comparten mecanismos fisiopatológicos de progresión. Desarrollamos un compuesto diseñado para obtener estabilización clínica, al controlar el daño celular por apoptosis aberrante, oxidación, depósito de metales y proteínas anormales y de vías enzimáticas fisiopatológicas, como la de las caspasas y el sistema MAPK. Pacientes y métodos. Incluimos 42 pacientes con EA, EP y EM. Les administramos el compuesto cada 12 horas y los citamos trimestralmente para evaluación clínica y revisión de exámenes de laboratorio generales. Resultados. Se realizó seguimiento de 3 a 24 meses (media: 8,85 ± 5,99 meses). No se registraron efectos clínicos adversos y sólo aisladas y leves alteraciones en los resultados de laboratorio, sin importancia clínica. Obtuvimos estabilización clínica en todos los pacientes (100%) con EM y mejoría en las puntuaciones de la Expanded Disability Status Scale en 4 pacientes (40%); estabilización clínica en 17 pacientes (100%) con EP y mejoría en puntuación de la Unified Parkinson’s Disease Rating Scale en 15 (88,2%); y estabilización clínica en los 12 pacientes (100%) con EA y aumento de la calificación del test minimental en 9 (75%). Conclusión. El compuesto es seguro y una opción terapéutica prometedora, al observarse una evidente tendencia hacia la estabilización clínica por medio de su utilización. Debe realizarse un estudio experimental para establecer el alcance terapéutico del compuesto, su posible efecto preventivo y valorar otras indicaciones (AU)

Introduction. Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and multiple sclerosis (MS), are progressive pathological conditions in which current treatments have not proved to be effective at curbing their progress (clinical stabilisation). Although they have very different clinical characteristics, they share the same pathophysiological mechanisms of progression. We developed a compound designed to obtain clinical stabilisation which acts by controlling cell damage due to aberrant apoptosis, oxidation, abnormal deposits of metals and proteins, and pathophysiological enzymatic pathways, such as that of caspases and the MAPK system. Patients and methods. Forty-two patients with AD, PD and MS were included in the study. The compound was administered to them every 12 hours and they were given appointments every three months for a clinical evaluation and a review of general lab analyses. Results. Subjects were submitted to a follow-up of between 3 and 24 months (mean: 8.85 ± 5.99 months). No clinical side effects were recorded and there were only some slight alterations in the lab test results, although they were not clinically relevant. Clinical stabilisation was achieved in all the patients (100%) with MS and the scores on the Expanded Disability Status Scale improved in four patients (40%); clinical stabilisation in 17 patients (100%) with PD and improvements in the score on the Unified Parkinson’s Disease Rating Scale in 15 of them (88.2%); and clinical stabilisation in 12 patients (100%) with AD, and an increase in the score obtained on the minimental test in nine cases (75%). Conclusions. The compound is safe and a promising therapeutic option, since there is a clear tendency towards clinical stabilisation when it is being used. An experimental study needs to be conducted in order to determine the therapeutic scope of the compound and its possible preventive effects, as well as to evaluate other indications (AU)

Análisis fitofarmacológico de los frutos de Luffa acutangula para determinar su actividad antihepatotóxica / Phytopharmacological screening of Luffa acutangula fruits for its antihepatotoxic activity

Se examinó el extracto acuoso y etanólico (100 mg/kg) de Luffa acutangula Linn (frutos) para determinar la actividadantihepatotóxica en ratas druckrey mediante la hepatotoxicidad inducida por tetracloruro de carbono (CCl4)y paracetamol (PCM). Se demostró que el extracto posee un efecto hepatoprotector signifi cativo, ya que reduce losniveles séricos de transaminasas (SGPT y SGOT), fosfatasa alcalina (ALP) y bilirrubina. La signifi cativa actividadhepatoprotectora de Luffa acutangula es comparable a la de la silimarina, agente hepatoprotector estándar, lo quejustifi ca su uso en afecciones del hígado

The ethanolic and aqueous extract (100mg/kg) of Luffa acutangula Linn(fruits) was examined for antihepatotoxic activityin druckrey rats by inducing hepatotoxicity with Carbon tetrachloride(CCl4) and Paracetamol(PCM). The extracthas shown to posses signifi cant hepatoprotective effect by lowering the serum level of transaminases (SGPT & SGOT),Alkaline phosphatase (ALP) and bilirubin. The signifi cant hepatoprotective activity of Luffa acutangula is comparableto that standard hepatoprotective agent silymarin, which justify its use in liver affection

Sillybum marianum / Sillybum marianum

El cardo mariano ha sido utilizado en Europa desde el siglo IV aCpara el tratamiento de trastornos hepáticos, picaduras de animalese intoxicaciones. Actualmente, se sabe que la molécula activa es unflavonoide llamado silimarina, que se utiliza, además de para estas“indicaciones” clásicas, por su efecto citoprotector ante el envejecimientoy los mecanismos moleculares que provocan daño celularmediados por agentes relacionados con la respuesta inflamatoria.Existen estudios in vitro e in vivo con animales que apuntan a unacierta actividad citoprotectora ante moléculas oxidantes derivadasdel metabolismo. Además, también se ha demostrado que la silimarinaes capaz de modificar ciertos pasos previos a la formaciónde moléculas relacionadas con la respuesta inflamatoria.No existe evidencia que demuestre un efecto beneficioso sobre lostrastornos hepáticos (hepatitis, cirrosis, etc.).El consumo de cardo mariano provoca en algunos casos leves alteracionesgastrointestinales. No existen tampoco interaccionesmedicamentosas descritas

A plant called sillybum marianum has been used in Europe sincethe IV century BC for the treatment of hepatic disorders, animalbites and intoxications. At present, we know that the active moleculeis a flavonoid called silimarine used, besides this classical indications,for its cytoprotector effect on the ageing process and themolecular mechanisms that cause cell damaged mediated by inflammatoryresponse-related agentsThere is no evidence showing a beneficial effect on liver disorders(hepatitis, cirrhosis, etc.).The consumption of sillybum marianum causes in some cases mildgastrointestinal alterations. No drug interactions have been described

Estudios sobre el mecanismo bioquímico de acción del flavonoide silyvina: relación con sus propiedades terapéuticas / Studies on the biochemical mechanism of action of the flavonoid silyvin: relationship with its therapeutic properties

Este estudio presenta en forma sucinta los aspectos más relevantes de nuestro trabajo de investigación con el flavonoide silyvina. Su mecanismo de acción como citoprotector se relacionaría con una acción a tres niveles: como antioxidante, evitando la lipoperoxidación celular inducida por xenobióticos; aumentando la concentración intracelular de glutatión, permitiendo mejorar la función protectora y de desintoxicación de este tripéptido, y regulando la permeabilidad de las membranas celulares en forma relativamente específica a la entrada o salida de metabolitos. Se discuten las proyecciones terapéuticas del flavonoide, así como su efecto protector específico en la toxicidad hepática de la fenilhidrazina, el etanol y el acetaminofeno