RESUMEN
Nanoparticles (NPs) exhibit remarkable potential in the diagnosis and treatment of various liver ailments, including primary liver cancer or hepatocellular carcinoma (HCC), liver cirrhosis, viral hepatitis, and alcoholic and non-alcoholic liver diseases. High surface area-to-volume ratio with distinct physicochemical and bio-pharmaceutical properties have contributed numerous benefits to NPs, such as high intracellular uptake and efficient drug delivery capabilities stemming from their ability to encapsulate a diverse range of drugs. Lipid-based nanosystems have demonstrated significant potential as reliable and efficient transport vehicles for a variety of actives, including small interfering RNA, targeting the liver, owing to their excellent in vivo compatibility, biodegradable nature, and non-toxic properties. Multiple aspects of various lipid-based materials, lipid nanosystems like solid lipid NPs, nanovesicles such as nanoemulsions, liposomes, and nanomicelles for liver-specific active targeting have been comprehensively reviewed. Ongoing and completed clinical trials of lipid nanosystems developed for HCC, hepatic fibrosis, and hepatitis are tabulated. Types of receptors and ligands typically used for active liver targeting in HCC are extensively discussed. The US FDA's recent approval for the use of Onpattro (Patisiran) injection to treat polyneuropathy in adult patients is indicative of the rapid development of lipid nanosystems employed for hepatic targeting. Nanoemulsions loaded with diagnostic imaging agents for multi-modal liver imaging were briefly discussed. Emerging technologies are being developed to integrate desirable properties of nanoparticles (NPs), including high stability, efficient drug loading, opsonization avoidance, active liver targeting, and facilitation of endosomal escape. Clinical translations of many lipid NPs for drug and gene therapy applications targeting different liver diseases are expected in the near future.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Cirrosis Hepática , LípidosRESUMEN
Toxicological studies are essential for developing novel medications in pharmaceutical industries including ayurvedic preparation. Hence, the present study is aimed to evaluate acute and 28-days repeated dose oral toxicity of anti-obesity polyherbal granules (PHG) in Sprague Dawley rats by OECD guidelines No 425 and 407, respectively. In an acute oral toxicity study, a single dose of 2 g/kg PHG was administered to rats and mortality, body weight, and clinical observations were noted for fourteen days. However, in the subacute oral toxicity study, the PHG was administered orally at doses of 0.3, 0.5 and 1 g/kg daily for 28 days to rats. Food intake and body weight were recorded weekly. On the 29th day, rats were sacrificed and subjected to haematological, biochemical, urine, necropsy, and histopathological analysis. In an acute oral toxicity study, no treatment-related, mortality, behavioral changes, and toxicity were found throughout fourteen days. Likewise, in the sub-acute toxicity study, no mortality and toxic effects were found in haematology, biochemical, urine, necropsy and histopathological analysis in rats for 28 days of treatment with PHG. Based on these results, the LD50 of PHG was found to be greater than 2 g/kg and the no-observed-adverse-effect level (NOAEL) of PHG for rats was found to be 0.5 g/kg/day. Thus, anti-obesity polyherbal granules showed a good safety profile in animal studies and can be considered an important agent for the clinical management of obesity.
Asunto(s)
Obesidad , Animales , Peso Corporal , Relación Dosis-Respuesta a Droga , Nivel sin Efectos Adversos Observados , Obesidad/inducido químicamente , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad Aguda/métodosRESUMEN
Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While ß-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other ß-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these ß-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple ß-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.
Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Antibacterianos/uso terapéutico , Depresores del Sistema Nervioso Central/efectos adversos , Etanol/efectos adversos , Transportador 2 de Aminoácidos Excitadores/metabolismo , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Ampicilina/líquido cefalorraquídeo , Ampicilina/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Cefazolina/líquido cefalorraquídeo , Cefazolina/uso terapéutico , Cefoperazona/líquido cefalorraquídeo , Cefoperazona/uso terapéutico , Condicionamiento Operante/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Preferencias Alimentarias/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Proteínas Mitocondriales/metabolismo , Núcleo Accumbens/metabolismo , Proteína Oncogénica v-akt/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificación , Factores de TiempoRESUMEN
PURPOSE: The overall objective of this study was to investigate and characterize the expression of folate transport proteins in Staten's Seruminstitut rabbit corneal (SIRC) epithelial cell line. METHODS: [(3)H]Folic acid uptake was studied with respect to time, pH, temperature, sodium, and chloride ion dependency. Inhibition studies were conducted with structural analogs, vitamins, and metabolic inhibitors. [(3)H]Folic acid uptake was also determined with varying concentrations of cold folic acid. Uptake kinetics was studied in the presence of various modulators of intracellular regulatory pathways, protein kinases A and C (PKA and PKC), protein tyrosine kinase (PTK), and calcium-calmodulin modulators. Ex vivo corneal permeability studies were carried out with [(3)H]folic acid in the presence and absence of 1 mM cold folic acid. RESULTS: Linear increase in [(3)H]folic acid uptake was observed over 30 min. The process followed saturation kinetics with apparent K(m) of 14.2 ± 0.2 nM, V(max) of (1.5 ± 0.1)*10(-5) micro.moles/min/mg protein, and K(d) of (2.1 ± 0.2)*10(-6) min(-1). The uptake process was found to be dependent on pH, sodium ions, chloride ions, temperature, and energy. Uptake was inhibited in the presence of structural analogs (cold folic acid, methyltetrahydro folate, and methotrexate), but structurally unrelated vitamins did not show any effect. Membrane transport inhibitors SITS, DIDS, probenecid and endocytic inhibitor, colchicine significantly inhibited the [(3)H]folic acid uptake indicating the involvement of receptor/transporter mediated process. PKA, PTK, and Ca(2+)/calmodulin pathways significantly regulate the process. RT-PCR and Western blot analysis confirmed the presence of folate receptor-α (FR-alpha) and proton-coupled folate transporter (PCFT). Permeability of [(3)H]folic acid across the rabbit cornea was (1.48 ± 0.13)*10(-05) cm/sec, and in the presence of cold folic acid it was (1.08 ± 0.10)*10(-05) cm/sec. CONCLUSIONS: This work demonstrated the functional and molecular presence of FR-alpha and PCFT in SIRC epithelial cell line.
Asunto(s)
Epitelio Corneal/metabolismo , Receptor 1 de Folato/metabolismo , Transportador de Folato Acoplado a Protón/metabolismo , Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-disulfónico/farmacología , Animales , Western Blotting , Línea Celular , Inhibidores Enzimáticos/farmacología , Epitelio Corneal/efectos de los fármacos , Receptor 1 de Folato/genética , Ácido Fólico/metabolismo , Expresión Génica , Concentración de Iones de Hidrógeno , Moduladores del Transporte de Membrana/farmacología , Transportador de Folato Acoplado a Protón/genética , ARN Mensajero/metabolismo , Conejos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad por Sustrato , Temperatura , Factores de TiempoRESUMEN
Lopinavir (LVR) is extensively metabolized by CYP3A4 and is prevented from entering the cells by membrane efflux pumps such as P-gp and MRP2. In an approach to evade the first-pass metabolism and efflux of LVR, peptide prodrugs of LVR [valine-valine-lopinavir (VVL) and glycine-valine-lopinavir (GVL)] were synthesized. Prodrugs were identified with 1H and 13C NMR spectra and LC/MS/MS was employed to evaluate their mass and purity. Solubility studies indicated that the prodrugs have enhanced aqueous solubilities relative to parent LVR. Accumulation and transport data of VVL and GVL across MDCKII-MDR1 and MDCKII-MRP2 cells indicated evasion of prodrugs' efflux by P-gp and MRP2 significantly. Permeability studies across Caco-2 cells indicated that the prodrugs are transported by peptide transporters and have increased permeability as compared with LVR. VVL and GVL exhibited significantly better degradation rate constants as compared with LVR in rat liver microsomes. Enzymatic stability studies in Caco-2 cell homogenate indicated that the peptide prodrugs are first converted to the ester intermediate (amino acid prodrug VL) and then finally to the parent drug. Overall, the advantages of utilizing peptide prodrugs include chemical modification of the compound to achieve targeted delivery via peptide transporters present across the intestinal epithelium, significant evasion of efflux and CYP3A4 mediated metabolism and significantly better solubility profiles. Therefore, in vitro studies demonstrated that peptide prodrug derivatization of LVR may be an effective strategy for evading its efflux and enhancing its systemic concentrations.