Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 101
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
World J Gastroenterol ; 25(32): 4580-4597, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528088

RESUMO

Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Hepatite B Crônica/tratamento farmacológico , Hepatite D Crônica/tratamento farmacológico , Superinfecção/tratamento farmacológico , Terapias em Estudo/métodos , Antivirais/farmacologia , Coinfecção/epidemiologia , Coinfecção/virologia , Quimioterapia Combinada/métodos , Carga Global da Doença , Antígenos de Superfície da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/virologia , Hepatite D Crônica/epidemiologia , Hepatite D Crônica/virologia , Vírus Delta da Hepatite/imunologia , Vírus Delta da Hepatite/patogenicidade , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Literatura de Revisão como Assunto , Superinfecção/epidemiologia , Superinfecção/virologia , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Resultado do Tratamento , Montagem de Vírus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
2.
PLoS One ; 14(6): e0218459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31233523

RESUMO

Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased the total amount of bile acid in feces. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition. Non-alcoholic fatty liver disease activity score (NAS) was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1ß, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of NASH pathophysiology.


Assuntos
Benzotiepinas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Glicosídeos/farmacologia , Reguladores do Metabolismo de Lipídeos/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Tecido Adiposo Bege/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fatores de Risco
3.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
4.
Neurogastroenterol Motil ; 30(12): e13448, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30129138

RESUMO

BACKGROUND: Chronic constipation affects 14%-17% of the population. Elobixibat, a novel, ileal bile acid transporter (IBAT) inhibitor, has been approved as a new chronic constipation drug in Japan in January 2018. The present study aimed to examine the pharmacological effects of elobixibat on colonic motility in conscious dogs using a telemetry system. METHODS: Six male beagle dogs were surgically implanted with strain gauge force transducers for gastrointestinal (GI) motility recording. The motility index was calculated from GI motility at each recording site in conscious and nonrestraint dogs. The fasted dogs were orally administered elobixibat (3, 10, or 30 mg kg-1 ) or 30 mg kg-1 of sennoside as positive control or vehicle using a crossover design and washout period of more than 6 days. One hour after drug administration, the dogs were fed chow, and GI motility and defecation were observed for 10 hours; GI motility was quantified to calculate giant migrating contractions (GMCs). Fecal bile acids (BAs) were determined as well. KEY RESULTS: Elobixibat and sennoside significantly increased the number of defecations, fecal wet weight, and water content within 10 hours after administration. Elobixibat dose-dependently decreased the time to first bowel movement, increased the amount of total fecal BAs, and rapidly induced mild GMCs during defecation; however, higher strength of GMCs was observed with sennoside. CONCLUSIONS & INFERENCE: Elobixibat induces bowel movements faster than sennoside through a different mechanism. Elobixibat locally inhibits IBAT in the ileal lumen, leading to elevated fecal BAs in the colon and induced mild GMCs during defecation.


Assuntos
Defecação/efeitos dos fármacos , Dipeptídeos/farmacologia , Fármacos Gastrointestinais/farmacologia , Complexo Mioelétrico Migratório/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Estado de Consciência , Cães , Íleo/efeitos dos fármacos , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores
7.
Biochem Biophys Res Commun ; 501(3): 820-825, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29723527

RESUMO

Fasiglifam is a selective partial agonist of G-protein-coupled receptor 40 (GPR40), which was developed for the treatment of type 2 diabetes mellitus. However, the clinical development of fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects. Fasiglifam showed an inhibitory effect on sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV) infections. Therefore, in this study, we hypothesised that fasiglifam would be a good candidate for a novel HBV entry inhibitor, and its effects were evaluated by using NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and human hepatocytes (PXB cells) obtained from PXB mice. Pre-treatment with fasiglifam at a concentration of 30 µM prior to HBV infection significantly suppressed supernatant HBV DNA levels after HBV infection in NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and PXB cells. Fasiglifam did not suppress supernatant HBV DNA levels up to 50 µM in HepG2.2.15.7 cells, which are stably transfected with a complete HBV genome without HBV infection. These results indicated that fasiglifam only affect on HBV infection via NTCP inhibition. For HBV treatment of fasiglifam, further investigation including additional non clinical research in addition to the evaluation of safety and efficacy in humans would be needed in the future study.


Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonas/farmacologia , Simportadores/antagonistas & inibidores , Animais , Linhagem Celular , Células Hep G2 , Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Humanos , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Internalização do Vírus/efeitos dos fármacos
8.
Sci Rep ; 8(1): 6658, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29704003

RESUMO

Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients' pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7α-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients.


Assuntos
Colestase/complicações , Inibidores Enzimáticos/administração & dosagem , Cirrose Hepática Biliar/complicações , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Prurido/tratamento farmacológico , Simportadores/antagonistas & inibidores , Idoso , Ácidos e Sais Biliares/sangue , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
9.
Hepatology ; 68(3): 1057-1069, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29572910

RESUMO

Accumulation of bile salts (BSs) during cholestasis leads to hepatic and biliary injury, driving inflammatory and fibrotic processes. The Na+ -Taurocholate Cotransporting Polypeptide (NTCP) is the major hepatic uptake transporter of BSs, and can be specifically inhibited by myrcludex B. We hypothesized that inhibition of NTCP dampens cholestatic liver injury. Acute cholestasis was induced in mice by a 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet or by bile duct ligation (BDL). Chronic cholestasis was investigated in Atp8b1-G308V and Abcb4/Mdr2 deficient mice. Mice were injected daily with myrcludex B or vehicle. Myrcludex B reduced plasma alkaline phosphatase (ALP) levels in DDC-fed, Atp8b1-G308V and BDL mice by 39%, 27% and 48% respectively. Expression of genes involved in fibrosis, proliferation and inflammation was reduced by myrcludex B treatment in DDC-fed and Atp8b1-G308V mice. NTCP-inhibition increased plasma BS levels from 604±277 to 1746±719 µm in DDC-fed mice, 432±280 to 762±288 µm in Atp8b1-G308V mice and from 522±130 to 3625±378 µm in BDL mice. NTCP-inhibition strongly aggravated weight loss in BDL mice, but not in other cholestatic models studied. NTCP-inhibition reduced biliary BS output in DDC-fed and Atp8b1-G308V mice by ∼50% while phospholipid (PL) output was maintained, resulting in a higher PL/BS ratio. Conversely, liver injury in Abcb4 deficient mice, lacking biliary phospholipid output, was aggravated after myrcludex B treatment. Conclusion: NTCP-inhibition by myrcludex B has hepatoprotective effects, by reducing BS load in hepatocytes and increasing the biliary PL/BS ratio. High micromolar plasma BS levels after NTCP-inhibition were well tolerated. NTCP-inhibition may be beneficial in selected forms of cholestasis. (Hepatology 2018).


Assuntos
Colestase/tratamento farmacológico , Lipopeptídeos/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Animais , Ácidos e Sais Biliares/sangue , Colestase/sangue , Avaliação Pré-Clínica de Medicamentos , Lipopeptídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipídeos/metabolismo
10.
Curr Med Chem ; 25(23): 2709-2721, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29473495

RESUMO

Hepatitis B Virus (HBV) is a major global health burden. Interferon alpha and nucleos(t)ide analogues are currently the standard-of-care for chronic HBV infection. However, these antiviral agents have limited efficacy and do not result in a sustained virological response in the majority of infected patients. Virtual Screening (VS) strategies have now a strong impact on drug discovery, the strength of this research field has been corroborated by recent contributions in the development of novel drug candidates which are in clinical trials or which are already available in the clinics. In this context, different VS strategies have been applied to HBV in order to discover novel inhibitors. In this review, we summarize the VS efforts to identify and design novel HBV interventions. We believe that the combination of in silico and in vitro tools can lead to faster validation of novel drug targets which could accelerate the HBV drug discovery and development efforts.


Assuntos
Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Simulação de Acoplamento Molecular , Antivirais/química , Antivirais/farmacologia , Proteínas do Capsídeo/antagonistas & inibidores , Proteínas do Capsídeo/metabolismo , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/metabolismo , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Relação Quantitativa Estrutura-Atividade , DNA Polimerase Dirigida por RNA/química , DNA Polimerase Dirigida por RNA/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Transativadores/antagonistas & inibidores , Transativadores/metabolismo
11.
BMC Gastroenterol ; 18(1): 3, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29304731

RESUMO

BACKGROUND: Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS: Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS: Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 µmol/24 h) and ~8 times higher in T2DM (1786.0 µmol/24 h) than with placebo (HVs: 386.93 µmol/24 h; T2DM: 220.00 µmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS: Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).


Assuntos
Benzotiepinas/administração & dosagem , Benzotiepinas/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicosídeos/administração & dosagem , Glicosídeos/efeitos adversos , Glicoproteínas de Membrana/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Adolescente , Adulto , Idoso , Benzotiepinas/farmacocinética , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/metabolismo , Glicemia/metabolismo , Colestenonas/sangue , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Fezes/química , Feminino , Glicosídeos/farmacocinética , Homeostase , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Expert Rev Gastroenterol Hepatol ; 12(3): 277-285, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29310470

RESUMO

INTRODUCTION: In most cholestatic liver diseases the primary cholestasis-causing lesions are located in the biliary tree and may be of (auto)immune origin. Bile salts are responsible for the secondary toxic consequences. Bile salt and nuclear hormone directed therapies primarily aim at improving this secondary toxic injury. In primary biliary cholangitis, trials show statistically significant responses on biochemical endpoints. Preclinical studies suggest that FXR- and PPAR-agonists, inhibitors of the apical sodium-dependent bile salt transporter (ASBT-inhibitors) and the C23 UDCA derivative nor-UDCA are promising agents for the treatment of primary sclerosing cholangitis (PSC). Area covered: Pharmaceuticals that interfere with bile salt signaling in humans for the treatment of chronic cholestatic liver disease are reviewed. Expert commentary: Nuclear hormone receptors, bile salt transport proteins and receptors provide targets for novel therapies of cholestatic liver disease. These drugs show positive results on biochemical endpoints. For histological endpoints, survival and transplant-free survival, long-term trials are needed. For relief of symptoms, such as fatigue and pruritus, these drugs have yet to prove their value.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colangite/tratamento farmacológico , Colangite/metabolismo , Colagogos e Coleréticos/uso terapêutico , Colangite/complicações , Colestase/etiologia , Doença Crônica , Humanos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Ácido Ursodesoxicólico/uso terapêutico
13.
Clin Pharmacol Ther ; 103(2): 341-348, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28543042

RESUMO

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.


Assuntos
Antivirais/administração & dosagem , Ácidos e Sais Biliares/sangue , Lipopeptídeos/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Biomarcadores/sangue , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Feminino , Humanos , Injeções Subcutâneas , Lipopeptídeos/efeitos adversos , Lipopeptídeos/farmacocinética , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Estudos Prospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Regulação para Cima , Adulto Jovem
14.
Sci Rep ; 7(1): 15307, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127322

RESUMO

The sodium taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the main hepatic transporter of conjugated bile acids, and the entry receptor for hepatitis B virus (HBV) and hepatitis delta virus (HDV). Myrcludex B, a synthetic peptide mimicking the NTCP-binding domain of HBV, effectively blocks HBV and HDV infection. In addition, Myrcludex B inhibits NTCP-mediated bile acid uptake, suggesting that also other NTCP inhibitors could potentially be a novel treatment of HBV/HDV infection. This study aims to identify clinically-applied compounds intervening with NTCP-mediated bile acid transport and HBV/HDV infection. 1280 FDA/EMA-approved drugs were screened to identify compounds that reduce uptake of taurocholic acid and lower Myrcludex B-binding in U2OS cells stably expressing human NTCP. HBV/HDV viral entry inhibition was studied in HepaRG cells. The four most potent inhibitors of human NTCP were rosiglitazone (IC50 5.1 µM), zafirlukast (IC50 6.5 µM), TRIAC (IC50 6.9 µM), and sulfasalazine (IC50 9.6 µM). Chicago sky blue 6B (IC50 7.1 µM) inhibited both NTCP and ASBT, a distinct though related bile acid transporter. Rosiglitazone, zafirlukast, TRIAC, sulfasalazine, and chicago sky blue 6B reduced HBV/HDV infection in HepaRG cells in a dose-dependent manner. Five out of 1280 clinically approved drugs were identified that inhibit NTCP-mediated bile acid uptake and HBV/HDV infection in vitro.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/metabolismo , Hepatite B , Hepatite D , Vírus Delta da Hepatite/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos , Animais , Cães , Hepatite B/tratamento farmacológico , Hepatite B/metabolismo , Hepatite B/patologia , Hepatite D/tratamento farmacológico , Hepatite D/metabolismo , Hepatite D/patologia , Humanos , Lipopeptídeos/farmacologia , Células Madin Darby de Rim Canino , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Rosiglitazona/farmacologia , Sulfassalazina/farmacologia , Simportadores/genética , Simportadores/metabolismo , Compostos de Tosil/farmacologia , Tri-Iodotironina/análogos & derivados , Tri-Iodotironina/farmacologia , Azul Tripano/farmacologia
15.
Curr Opin Gastroenterol ; 33(3): 149-157, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28257308

RESUMO

PURPOSE OF REVIEW: The only currently approved treatment for primary sclerosing cholangitis (PSC) is liver transplantation, with a median time to transplant of 12-18 years after diagnosis. There are a number of emerging drugs that have the potential to meet this critically unmet need that will be summarized and discussed herein. RECENT FINDINGS: Although the cause of PSC is unknown, there are a number of novel therapeutics under development. These drugs target presumed pathogenic mechanisms largely extrapolated from ex-vivo and in-vivo preclinical models, as well as translational observations. SUMMARY: Future therapeutic strategies for PSC may include a multitude of complex pathogenic mechanisms encompassing pathways of immunomodulation, the microbiome and inflammation-related fibrosis.


Assuntos
Colangite Esclerosante/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Antibacterianos/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Colangite Esclerosante/microbiologia , Ensaios Clínicos como Assunto/métodos , Transplante de Microbiota Fecal , Ácidos Fíbricos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Terapia de Alvo Molecular/tendências , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Probióticos/uso terapêutico , Simportadores/antagonistas & inibidores , Ácido Ursodesoxicólico/uso terapêutico
16.
Can J Physiol Pharmacol ; 95(2): 215-223, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28051334

RESUMO

To investigate the protective effect of glutamine (Gln) against obstructive cholestasis in association with farnesoid X receptor (FXR) activation, an obstructive cholestasis model was established in male Sprague-Dawley rats by bile duct ligation (BDL). Serum biomarkers and hematoxylin plus eosin staining were used to identify the degree of hepatic injury in the rats with obstructive cholestasis after Gln treatment. Immunohistochemistry, real-time PCR, Western blot, cultured primary rat hepatocytes with FXR knockdown, and dual-luciferase reporter assay were performed to elucidate the mechanisms underlying Gln hepatoprotection. We found that Gln treatment protected against obstructive cholestasis induced by BDL through reducing hepatocyte injury. Upregulation of the hepatic efflux transporters small heterodimer partner (Shp), bile salt export pump (Bsep), and multidrug resistance-associated protein 2 (Mrp2), and inhibition of the hepatic uptake transporter Na+/taurocholate cotransporting polypeptide (Ntcp) and the bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) expression were observed in rats with BDL treated with Gln in vivo. Furthermore, the regulatory effect of Gln on Bsep and Mrp2 expression was abrogated after FXR knockdown in rat primary cultured hepatocytes. Luciferase assay HepG2 cells also illustrated FXR was a direct target for Gln treatment. In conclusion, the regulation of Bsep and Mrp2 expression mediated by FXR might be an important mechanism for Gln against obstructive cholestasis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Colestase/metabolismo , Glutamina/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Animais , Colestase/patologia , Colesterol 7-alfa-Hidroxilase/antagonistas & inibidores , Glutamina/efeitos adversos , Hepatócitos/metabolismo , Testes de Função Hepática , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Cultura Primária de Células , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/farmacologia , RNA Interferente Pequeno/farmacologia , Ratos , Simportadores/antagonistas & inibidores
17.
Chin J Nat Med ; 14(7): 549-60, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27507206

RESUMO

NTCP is specifically expressed on the basolateral membrane of hepatocytes, participating in the enterohepatic circulation of bile salts, especially conjugated bile salts, to maintain bile salts homeostasis. In addition, recent studies have found that NTCP is a functional receptor of HBV and HDV. Therefore, it is important to study the interaction between drugs and NTCP and identify the inhibitors/substrates of NTCP. In the present study, a LLC-PK1 cell model stably expressing human NTCP was established, which was simple and suitable for high throughput screening, and utilized to screen and verify the potential inhibitors of NTCP from 102 herbal medicinal ingredients. The results showed that ginkgolic acid (GA) (13 : 0), GA (15 : 1), GA (17 : 1), erythrosine B, silibinin, and emodin have inhibitory effects on NTCP uptake of TCNa in a concentration-dependent manner. Among them, GA (13 : 0) and GA (15 : 1) exhibited the stronger inhibitory effects, with IC50 values being less than 8.3 and 13.5 µmol·L(-1), respectively, than the classical inhibitor, cyclosporin A (CsA) (IC50 = 20.33 µmol·L(-1)). Further research demonstrated that GA (13 : 0), GA (15 : 1), GA (17 : 1), silibinin, and emodin were not substrates of NTCP. These findings might contribute to a better understanding of the disposition of the herbal ingredients in vivo, especially in biliary excretion.


Assuntos
Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Simportadores/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Células LLC-PK1 , Modelos Biológicos , Transportadores de Ânions Orgânicos Dependentes de Sódio/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Extratos Vegetais/química , Relação Estrutura-Atividade , Suínos , Simportadores/química , Simportadores/metabolismo
18.
BMC Gastroenterol ; 16(1): 71, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27431238

RESUMO

BACKGROUND: Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus. METHODS: This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA). DISCUSSION: BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus. TRIAL REGISTRATION: EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.


Assuntos
Cirrose Hepática Biliar/complicações , Metilaminas/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Prurido/tratamento farmacológico , Simportadores/antagonistas & inibidores , Tiazepinas/uso terapêutico , Adolescente , Adulto , Idoso , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colagogos e Coleréticos/farmacocinética , Colagogos e Coleréticos/uso terapêutico , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metilaminas/administração & dosagem , Metilaminas/efeitos adversos , Metilaminas/farmacocinética , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/uso terapêutico , Prurido/etiologia , Simportadores/uso terapêutico , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Tiazepinas/farmacocinética , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/uso terapêutico , Adulto Jovem
19.
Diabetes Obes Metab ; 18(7): 654-62, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26939572

RESUMO

AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D). METHODS: Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days. RESULTS: In both studies, GSK672 reduced circulating bile acids and increased serum 7-α-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was ∼40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Metilaminas/administração & dosagem , Tiazepinas/administração & dosagem , Adulto , Apolipoproteínas B/metabolismo , Área Sob a Curva , Ácidos e Sais Biliares/metabolismo , Glicemia/metabolismo , LDL-Colesterol , Estudos Cross-Over , Diarreia/induzido quimicamente , Método Duplo-Cego , Esquema de Medicação , Jejum/metabolismo , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metformina/efeitos adversos , Metformina/farmacologia , Metilaminas/efeitos adversos , Metilaminas/farmacologia , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Tiazepinas/efeitos adversos , Tiazepinas/farmacologia , Resultado do Tratamento
20.
Acta Pharmacol Sin ; 37(3): 415-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26806301

RESUMO

AIM: Leflunomide is an immunosuppressive agent marketed as a disease-modifying antirheumatic drug. But it causes severe side effects, including fatal hepatitis and liver failure. In this study we investigated the contributions of hepatic metabolism and transport of leflunomide and its major metabolite teriflunomide to leflunomide induced hepatotoxicity in vitro and in vivo. METHODS: The metabolism and toxicity of leflunomide and teriflunomide were evaluated in primary rat hepatocytes in vitro. Hepatic cytochrome P450 reductase null (HRN) mice were used to examine the PK profiling and hepatotoxicity of leflunomide in vivo. The expression and function of sodium/bile acid cotransporter (NTCP) were assessed in rat and human hepatocytes and NTCP-transfected HEK293 cells. After Male Sprague-Dawley (SD) rats were administered teriflunomide (1,6, 12 mg · kg(-1) · d(-1), ig) for 4 weeks, their blood samples were analyzed. RESULTS: A nonspecific CYPs inhibitor aminobenzotriazole (ABT, 1 mmol/L) decreased the IC50 value of leflunomide in rat hepatocytes from 409 to 216 µmol/L, whereas another nonspecific CYPs inhibitor proadifen (SKF, 30 µmol/L) increased the cellular accumulation of leflunomide to 3.68-fold at 4 h. After oral dosing (15 mg/kg), the plasma exposure (AUC0-t) of leflunomide increased to 3-fold in HRN mice compared with wild type mice. Administration of leflunomide (25 mg·kg(-1) · d(-1)) for 7 d significantly increased serum ALT and AST levels in HRN mice; when the dose was increased to 50 mg·kg(-1) · d(-1), all HRN mice died on d 6. Teriflunomide significantly decreased the expression of NTCP in human hepatocytes, as well as the function of NTCP in rat hepatocytes and NTCP-transfected HEK293 cells. Four-week administration of teriflunomide significantly increased serum total bilirubin and direct bilirubin levels in female rats, but not in male rats. CONCLUSION: Hepatic CYPs play a critical role in detoxification process of leflunomide, whereas the major metabolite teriflunomide suppresses the expression and function of NTCP, leading to potential cholestasis.


Assuntos
Antirreumáticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Isoxazóis/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Animais , Antirreumáticos/metabolismo , Antirreumáticos/farmacocinética , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/patologia , Crotonatos/metabolismo , Crotonatos/farmacocinética , Crotonatos/toxicidade , Inibidores das Enzimas do Citocromo P-450/farmacologia , Feminino , Células HEK293 , Humanos , Isoxazóis/metabolismo , Isoxazóis/farmacocinética , Leflunomida , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Ratos Sprague-Dawley , Simportadores/antagonistas & inibidores , Toluidinas/metabolismo , Toluidinas/farmacocinética , Toluidinas/toxicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA