RESUMEN
Recurrence of hepatitis C (HCV) postliver transplant is universal, with a subgroup developing rapid hepatic fibrosis. Toll-like receptors (TLRs) are critical to innate antiviral responses and HCV alters TLR function to evade immune clearance. Whether TLRs play a role in rapid HCV recurrence posttransplant is unknown. We stimulated peripheral blood mononuclear cells (PBMCs) from 70 patients with HCV postliver transplant with TLR subclass-specific ligands and measured cytokine production, TLR expression and NK cell function. Rate of fibrosis progression was calculated using posttransplant liver biopsies graded by Metavir scoring (F0-4; R=fibrosis stage/year posttransplant; rapid fibrosis defined as >0.4 units/year). Thirty of 70 (43%) patients had rapid fibrosis progression. PBMCs from HCV rapid-fibrosers produced less IFNα with TLR7/8 stimulation (p=0.039), less IL-6 at baseline (p=0.027) and with TLR3 stimulation (p=0.008) and had lower TLR3-mediated monocyte IL-6 production (p=0.028) compared with HCV slow fibrosers. TLR7/8-mediated NKCD56 dim cell secretion of IFNγ was impaired in HCV rapid fibrosis (p=0.006) independently of IFNα secretion and TLR7/8 expression, while cytotoxicity remained preserved. Impaired TLR3 and TLR7/8-mediated cytokine responses may contribute to aggressive HCV recurrence postliver transplantation through impaired immune control of HCV and subsequent activation of fibrogenesis.
Asunto(s)
Hepatitis C/fisiopatología , Trasplante de Hígado , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismo , Adulto , Estudios Transversales , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Hepacivirus , Hepatitis C/metabolismo , Humanos , Interferón-alfa/metabolismo , Interferón gamma/metabolismo , Interleucina-6/metabolismo , Células Asesinas Naturales/citología , Leucocitos Mononucleares/citología , Ligandos , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/virología , Fallo Hepático/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , RecurrenciaRESUMEN
Obesity is the major cause of type 2 diabetes with hyperlipidemia as one of its complications and antioxidants were found to be beneficial in such disease conditions. The present investigation is geared towards reduction of the dose required/improve the bioavailability of the combination of antioxidants, ellagic acid and coenzyme Q10 by co-encapsulating them into nanoparticles and study the possible synergism in ameliorating hyperlipidemia in high fat diet fed rats. The co-encapsulated particles at 10% (w/w of polymer) loading of ellagic acid and coenzyme Q10 have particle size of 260 nm. Male Sprague-Dawley (SD) rats on feeding high fat diet for over 4 weeks developed hyperlipidemia. The hyperlipidemic rats on 2 weeks post treatment with antioxidant combination administered as oral suspension or nanoparticles found to ameliorate the hyperlipidemic conditions and nanoparticles were found to be equally/more effective at 3 times lower dose in sustaining cholesterol lowering effect for extended periods, lowering glucose and triglycerides and in improving endothelial functioning, indicating the ability of the nanoparticles in improving efficacy of the duo. The results promise the potential of nanoparticles in improving the efficacy of ellagic acid and coenzyme Q10 in treating high fat diet induced hyperlipidemia in rats.
Asunto(s)
Antioxidantes/administración & dosificación , Grasas de la Dieta/efectos adversos , Portadores de Fármacos/química , Ácido Elágico/administración & dosificación , Hiperlipidemias/prevención & control , Nanopartículas/uso terapéutico , Ubiquinona/análogos & derivados , Administración Oral , Animales , Composición de Medicamentos/métodos , Ácido Elágico/química , Hiperlipidemias/diagnóstico , Masculino , Nanopartículas/química , Nanopartículas/ultraestructura , Ratas , Ratas Sprague-Dawley , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Ubiquinona/químicaRESUMEN
Atorvastatin calcium (AC) is a second-generation 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor approved for clinical use as a lipid lowering agent. AC, the world's best selling drug is associated with poor oral bioavailability and serious adverse effects like rhabdomyolysis on chronic administration. A biodegradable nanoparticulate approach was introduced here with a view to improving the efficacy and safety of AC. Poly lactide-co-glycolic acid (PLGA) nanoparticles containing atorvastatin calcium were prepared using two stabilizers i.e. didodecyl dimethyl ammonium bromide (DMAB) and Vitamin E tocopheryl polyethylene glycol 1000 succinate (Vit E-TPGS) using a co-solvent approach by emulsion-diffusion-evaporation method. AC loaded PLGA nanoparticles prepared using DMAB and Vit E-TPGS were found to be 120.0 +/- 4.2 nm and 140.0 +/- 1.5 nm (z-average) in size respectively. In vitro release studies at pH 7.4 revealed a zero order release profile for nanoparticles. Efficacy and safety parameters of the prepared nanoparticles against marketed formulation were evaluated in high fat diet fed (hyperlipidemic) rats. It was found that atorvastatin calcium nanoparticles were equally effective in comparison to Lipicure, at a 66%-reduced dose in treating the hyperlipidemia characterized by alterations in PTC, LDL-C, VLDL-C, HDL-C, PTG and PGL in the high fat diet fed rats. On the other hand, when evaluated for safety, nanoparticulate formulation showed no/negligible myotoxicity characterized by lower PC, BUN, CK, LDH and AST levels in comparison to the marketed formulation.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Ácidos Heptanoicos/administración & dosificación , Hiperlipidemias/tratamiento farmacológico , Nanopartículas/administración & dosificación , Pirroles/administración & dosificación , Administración Oral , Animales , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/toxicidad , Atorvastatina , Glucemia/análisis , Colesterol/sangre , Modelos Animales de Enfermedad , Ácidos Heptanoicos/farmacocinética , Ácidos Heptanoicos/uso terapéutico , Ácidos Heptanoicos/toxicidad , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/toxicidad , Hiperlipidemias/inducido químicamente , Hiperlipidemias/enzimología , Ácido Láctico , Lípidos/sangre , Masculino , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Pirroles/farmacocinética , Pirroles/uso terapéutico , Pirroles/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Antioxidants are emerging as prophylactic and therapeutic agents. These are the agents, which scavenge free radicals otherwise reactive oxygen species and prevent the damage caused by them. Free radicals have been associated with pathogenesis of various disorders like cancer, diabetes, cardiovascular diseases, autoimmune diseases, neurodegenerative disorders and are implicated in aging. Several antioxidants like SOD, CAT, epigallocatechin-3-O-gallate, lycopene, ellagic acid, coenzyme Q10, indole-3-carbinol, genistein, quercetin, vitamin C and vitamin E have been found to be pharmacologically active as prophylactic and therapeutic agents for above mentioned diseases. Antioxidants are part of diet but their bioavailability through dietary supplementation depends on several factors. This major drawback of dietary agents may be due to one or many of the several factors like poor solubility, inefficient permeability, instability due to storage of food, first pass effect and GI degradation. Conventional dosage forms may not result in efficient formulation owing to their poor biopharmaceutical properties. Principles of novel drug delivery systems need to be applied to significantly improve the performance of antioxidants. Novel drug delivery systems (NDDS) would also help in delivery of these antioxidants by oral route, as this route is of prime importance when antioxidants are intended for prophylactic purpose. Implication of NDDS for the delivery of antioxidants is largely governed by physicochemical characteristics, biopharmaceutical properties and pharmacokinetic parameters of the antioxidant to be formulated. Recently, chemical modifications, coupling agents, liposomes, microparticles, nanoparticles and gel-based systems have been explored for the delivery of these difficult to deliver molecules. Results from several studies conducted across the globe are positive and provided us with new anticipation for the improvement of human healthcare.
Asunto(s)
Antioxidantes/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Depuradores de Radicales Libres/administración & dosificación , Administración Oral , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Disponibilidad Biológica , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Química Farmacéutica , Sistemas de Liberación de Medicamentos/métodos , Estabilidad de Medicamentos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacocinética , Depuradores de Radicales Libres/uso terapéutico , Radicales Libres/metabolismo , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Nanotecnología , Estrés Oxidativo , Permeabilidad , SolubilidadRESUMEN
Antioxidants are gaining tremendous interest as chemopreventive as well as chemotherapeutic agents. Ellagic acid (EA) is a plant derived compound with very poor solubility in water and very low octanol/water partition coefficient and coenzyme Q(10) (CoQ(10)) is a highly lipophilic compound, which is synthesized in the body and can be derived from food supplements as well. The new insights in the combination therapy are promising a better future in many challenging diseases. Synergism is among the key advantages of combination therapy apart from decreased intensity of unwanted effects of a compound, increased patient compliance and reduction in cost of therapy. EA and CoQ(10) supplementation in combination will be beneficial in strengthening the weakened antioxidant defense system in many diseases related to oxidative stress. Here we report first derivative UV spectroscopic and HPLC methods for the simultaneous analysis of these two agents in pharmaceutical preparations. Results obtained indicate that the derivative spectroscopy is as efficient as HPLC method in quantitative analysis. Retention of ellagic acid can be increased using PEG bonded column which is poorly retained on C(18) column. PEG column can be used for rapid simultaneous analysis of EA and CoQ(10), which are having diverse physicochemical properties.
RESUMEN
Mixed cultures of the protozoan Tetrahymena pyriformis and the bacterium Escherichia coli were propagated in chemostats fed with glucose and minimal mineral salts medium. The interior surfaces of some chemostats were treated with a silicone compound but those of other chemostats were not. Data obtained showed that bacteria but not protozoans were attached strongly to the walls of the chemostats, that silicone treatment reduced the density of the attached bacteria by two orders of magnitude or more, and that the presence of the attached bacteria had significant effects on the dynamics of the microbial predator-prey system. Attempts were made to simulate the data by various mathematical models. It was found that a model based on combination of the Topiwala-Hamer model for wall attachment and a multiple saturation model for growth of the protozoans on the bacteria gave a reasonable fit of all the data.
RESUMEN
A female patient suffering from donovanosis of the oral cavity without associated lesions elsewhere is reported. The importance of remembering donovanosis in the differential diagnosis of chronic granulomatous ulceration of the mouth is emphasized.