Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
J Hepatol ; 74(6): 1416-1428, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33340584

RESUMEN

BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation. METHODS: We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (hABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c.Abcb4-/- mice. RESULTS: We show that treatment with liver-targeted hABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the hABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4-/- mice, with rapid and dramatic normalisation of all clinically relevant parameters such as inflammation, ductular reaction, and liver fibrosis. Synthetic mRNA therapy also promoted favourable hepatocyte-driven liver regeneration to restore normal homeostasis, including liver weight, body weight, liver enzymes, and portal vein blood pressure. CONCLUSIONS: Our data provide strong preclinical proof-of-concept for hABCB4 mRNA therapy as a potential treatment option for patients with PFIC3. LAY SUMMARY: This report describes the development of an innovative mRNA therapy as a potential treatment for PFIC3, a devastating rare paediatric liver disease with no treatment options except liver transplantation. We show that administration of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/genética , Eliminación de Gen , Liposomas/química , Sistema de Administración de Fármacos con Nanopartículas/química , Nanopartículas/química , Fenotipo , ARN Mensajero/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Colestasis Intrahepática/metabolismo , Modelos Animales de Enfermedad , Células HEK293 , Homocigoto , Humanos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , ARN Mensajero/genética , Transfección , Resultado del Tratamiento , Miembro 4 de la Subfamilia B de Casete de Unión a ATP
2.
Int J Pharm ; 511(1): 436-445, 2016 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-27444552

RESUMEN

Multidrug resistance (MDR) among breast cancer cells is the paramount obstacle for the successful chemotherapy. In this study, anti-EGFR antibody h-R3 was designed to self-assembled h-R3-siRNA-PAMAM-complexes (HSPCs) via electrostatic interactions for siRNA delivery. The physicochemical characterization, cell uptake, MDR1 silencing efficiency, cell migration, cell growth and cell apoptosis were investigated. The HSPCs presented lower cytotoxicity, higher cellular uptake and enhanced endosomal escape ability. Also, HSPCs encapsulating siMDR1 knockdowned 99.4% MDR1 gene with up to ∼6 times of enhancement compared to naked siMDR1, increased the doxorubicin accumulation, down-regulated P-glycoprotein (P-gp) expression and suppressed cellular migration in breast cancer MCF-7/ADR cells. Moreover, the combination of anticancer drug paclitaxel (PTX) and siMDR1 loaded HSPCs showed synergistic effect on overcoming MDR, which inhibited cell growth and induced cell apoptosis. This h-R3-mediated siMDR1 delivery system could be a promising vector for effective siRNA therapy of drug resistant breast cancer.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Dendrímeros/administración & dosificación , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Dendrímeros/química , Resistencia a Múltiples Medicamentos/fisiología , Femenino , Humanos , Células MCF-7
3.
Pharmacogenomics ; 15(2): 179-88, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24444408

RESUMEN

BACKGROUND: Tacrolimus (TAC), acting as a calcineurin inhibitor, is an immunosuppressant widely used after kidney transplantation. TAC requires blood concentration monitoring due to large interindividual variability in its pharmacokinetics and a narrow therapeutic index. Since genetic factors are considered responsible for a part of the observed pharmacokinetic variability, hereby SNPs within the CYP3A4, CYP3A5 and ABCB1 genes in kidney transplant patients of Polish Caucasian origin were investigated. PATIENTS & METHODS: A total of 241 patients treated with TAC through the first year after kidney transplantation were genotyped for the presence of common SNPs: rs776746:A>G (CYP3A5*3), rs35599367:C>T (CYP3A4*22), rs2740574:A>G (CYP3A4*1B) and rs1045642:C>T (ABCB1 3435C>T) using TaqMan(®) assays. RESULTS: CYP3A5 expressers received significantly higher weight-adjusted TAC doses, and were characterized by markedly lower C0 and dose adjusted C0 values in the course of treatment. CYP3A4*1B was significantly associated with TAC pharmacokinetics in univariate analysis. Impact of the CYP3A4*22 allele was significant only at particular time points, that is, 3 months after transplantation, with marginal significance 6 months after transplantation. The ABCB1 genotype did not influence TAC pharmacokinetics. Multivariate analysis of all the studied loci demonstrated that only the CYP3A5*1 (starting from month 1) and CYP3A4*22 alleles (at 3 and 6 months) were independent predictors of TAC dose-adjusted C0. CONCLUSION: Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.


Asunto(s)
Citocromo P-450 CYP3A/administración & dosificación , Tacrolimus/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/administración & dosificación , Humanos , Terapia de Inmunosupresión/métodos , Trasplante de Riñón/efectos adversos , Polimorfismo de Nucleótido Simple
4.
Drug Metab Dispos ; 32(4): 405-12, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15039293

RESUMEN

Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with high-performance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg(-1) significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.


Asunto(s)
Berberina/sangre , Bilis/metabolismo , Hígado/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/administración & dosificación , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/farmacocinética , Animales , Área Bajo la Curva , Berberina/administración & dosificación , Berberina/farmacocinética , Bilis/química , Bilis/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Ciclosporina/administración & dosificación , Ciclosporina/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/administración & dosificación , Sistema Enzimático del Citocromo P-450/farmacocinética , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Interacciones Farmacológicas , Glucurónidos/antagonistas & inhibidores , Glucurónidos/biosíntesis , Semivida , Inyecciones Intravenosas , Hígado/efectos de los fármacos , Masculino , Metilación/efectos de los fármacos , Microdiálisis/métodos , Proteínas de Transporte de Catión Orgánico/administración & dosificación , Proteínas de Transporte de Catión Orgánico/farmacocinética , Proadifeno/administración & dosificación , Proadifeno/farmacocinética , Probenecid/administración & dosificación , Probenecid/farmacocinética , Quinidina/administración & dosificación , Quinidina/farmacocinética , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray/métodos , Factores de Tiempo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...