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1.
J Community Psychol ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667012

RESUMO

The present study is one of few to investigate both anti-trans discrimination and anti-trans prejudice. It examined four individual factors (religiosity; political beliefs; affiliation with LGBTQ [lesbian, gay, bisexual, transgender, and queer] people; gender role beliefs) through a lens of hetero-cis-normativity to understand their association with anti-trans attitudes and reported behaviors. Using a sample of 302 cisgender college students from across the United States, hierarchical multiple regressions on bootstrap samples were used to analyze how these factors are associated with anti-trans attitudes and behaviors. More liberal political beliefs, affiliation with more LGBTQ friends and family members, and less traditional gender role beliefs were related to more positive attitudes toward transgender people. Less traditional gender role beliefs and more positive attitudes were associated with more positive reported behaviors toward transgender individuals. Interventions designed to challenge traditional gender role beliefs and approximate affiliation with LGBTQ persons may be most effective to reduce pervasive hetero-cis-normative prejudice and discrimination within schools.

2.
Bioorg Med Chem Lett ; 35: 127778, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33339773

RESUMO

INTRODUCTION: Acute myocardial infarction (AMI) is a common medical condition in our clinical practice that should be treated with appropriate revascularization in a timely manner. Percutaneous revascularization (PR) has been the first-line treatment option when feasible. Limited data is available comparing PR to surgical revascularization (SR) in the AMI setting. METHODS: Study population was extracted from the 2016 Nationwide Readmissions Data using International Classification of Diseases, tenth edition, clinical modifications/procedure coding system codes for AMI, PR, SR, and procedural complications. Study endpoints included in-hospital all-cause mortality, length of index hospital stay (LOS), stroke, acute kidney injury, bleeding, need for blood transfusion, acute respiratory failure, and total hospital charges. RESULTS: The study identified 45,539 discharges with a principal admission diagnosis of AMI (38.7% ST elevation and 61.3% non-ST elevation) who had either PR or SR as a principal procedure (79.1% PR versus 20.9% SR). Single vessel revascularization was performed in 67.8% (93.1% had PR versus 6.9% had SR, p < 0.01). Multivessel revascularization was performed in 32.2% (64.8% had PR versus 35.2% had SR, p < 0.01). 83% of SR was in the setting of non-ST elevation AMI (NSTEMI). In comparison to SR, PR was associated with higher in-hospital all-cause mortality (3.7% versus 2.2%, p < 0.01), shorter LOS (4.3 versus 11.6 days, p < 0.01), and lower incidence of post-procedural stroke (1.0% versus 1.8%, p < 0.01), acute kidney injury (14.9% versus 24.8%, p < 0.01), bleeding (4.3% versus 47.1%, p < 0.01), need for blood transfusion (2.9% versus 18.5%, p < 0.01), acute respiratory failure (10.7% versus 19.8%, p < 0.01), and total hospital charges (120,590$ versus 229,917$, p < 0.01). These results persist after adjustment for baseline characteristics. In a subgroup analysis, SR mortality benefit persisted in patients who had multivessel revascularization (in both ST and non-ST elevation AMI), but not in single vessel revascularization. CONCLUSIONS: In patients presented with AMI, PR was associated with higher in-hospital all-cause mortality but lower morbidity, shorter LOS, and lower total hospital charges than SR. However, the mortality benefit of SR was seen in multivessel revascularization only, and not in single vessel revascularization.

4.
ACS Appl Mater Interfaces ; 12(34): 38744-38750, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32805977

RESUMO

The controlled tunability of superconductivity in low-dimensional materials may enable new quantum devices. Particularly in triplet or topological superconductors, tunneling devices such as Josephson junctions, etc., can demonstrate exotic functionalities. The tunnel barrier, an insulating or normal material layer separating two superconductors, is a key component for the junctions. Thin layers of NbSe2 have been shown as a superconductor with strong spin orbit coupling, which can give rise to topological superconductivity if driven by a large magnetic exchange field. Here we demonstrate the superconductor-insulator transitions in epitaxially grown few-layer NbSe2 with wafer-scale uniformity on insulating substrates. We provide the electrical transport, Raman spectroscopy, cross-sectional transmission electron microscopy, and X-ray diffraction characterizations of the insulating phase. We show that the superconductor-insulator transition is driven by strain, which also causes characteristic energy shifts of the Raman modes. Our observation paves the way for high-quality heterojunction tunnel barriers to be seamlessly built into epitaxial NbSe2 itself, thereby enabling highly scalable tunneling devices for superconductor-based quantum electronics.

5.
J Pharmacol Exp Ther ; 375(1): 139-151, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32719071

RESUMO

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4ß-hydroxycholesterol (4ßHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4ßHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.

6.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

7.
Psychol Health ; 35(9): 1075-1094, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31818131

RESUMO

Objective: We examined the differential predictive powers of physical and psychological impacts of parental physical illness, as well as both instrumental and emotional aspects of parentification, on adolescent distress.Design: Forty-seven parents with chronic physical illness and 132 adolescent children completed separate questionnaires that measured parental health conditions and adolescents' parentification, peer attachment, and psychological distress.Main findings: Ill parents' energy/fatigue level was not related to adolescent distress, but ill parents' emotional well-being was directly associated with adolescent distress. Adolescents' household responsibilities were not linked to their distress level; however, higher levels of emotional parentification appeared to affect their psychological adjustment. Higher quality of peer attachment was related to lower adolescent distress.Conclusions: The results highlight the importance of addressing and fostering physically ill parents' psychosocial adjustment and emotional availability, restoring a sense of normalcy in family adaptation processes, and facilitating emotional support for adolescents, including positive parent-child relationship and peer attachment.


Assuntos
Filho de Pais Incapacitados/psicologia , Doença Crônica , Ajustamento Emocional , Relações Pais-Filho , Angústia Psicológica , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apego ao Objeto , Pais/psicologia , Grupo Associado , Inquéritos e Questionários
8.
NPJ Parkinsons Dis ; 5: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31453317

RESUMO

Both subthalamic nucleus (STN) and caudal zona incerta (cZI) have been implicated as the optimal locus for deep brain stimulation (DBS) in Parkinson's disease (PD). We present a retrospective clinico-anatomical analysis of outcomes from DBS targeting both STN and cZI. Forty patients underwent bilateral DBS using an image-verified implantable guide tube/stylette technique. Contacts on the same quadripolar lead were placed in both STN and cZI. After pulse generator programming, contacts yielding the best clinical effect were selected for chronic stimulation. OFF-medication unified PD rating scale (UPDRS) part III scores pre-operatively and ON-stimulation at 1-2 year follow up were compared. Active contacts at follow-up were anatomically localised from peri-operative imaging. Overall, mean UPDRS part III score improvement was 55 ± 9% (95% confidence interval), with improvement in subscores for rigidity (59 ± 13%), bradykinesia (58 ± 13%), tremor (71 ± 24%) and axial features (36 ± 19%). Active contacts were distributed in the following locations: (1) within posterior/dorsal STN (50%); (2) dorsal to STN (24%); (3) in cZI (21%); and (4) lateral to STN (5%). When contacts were grouped by location, no significant differences between groups were seen in baseline or post-operative improvement in contralateral UPDRS part III subscores. We conclude that when both STN and cZI are targeted, active contacts are distributed most commonly within and immediately dorsal to STN. In a subgroup of cases, cZI contacts were selected for chronic stimulation in preference. Dual targeting of STN and cZI is feasible and may provide extra benefit compared with conventional STN DBS is some patients.

9.
Phys Rev Lett ; 122(21): 217204, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31283322

RESUMO

We report a longitudinal spin Seebeck effect (SSE) study in epitaxially grown FeF_{2}(110) antiferromagnetic (AFM) thin films with strong uniaxial anisotropy over the temperature range of 3.8-250 K. Both the magnetic-field and temperature-dependent SSE signals below the Néel temperature (T_{N}=70 K) of the FeF_{2} films are consistent with a theoretical model based on the excitations of AFM magnons without any net induced static magnetic moment. In addition to the characteristic low-temperature SSE peak associated with the AFM magnons, there is another SSE peak at T_{N} which extends well into the paramagnetic phase. All the SSE data taken at different magnetic fields up to 12 T near and above the critical point T_{N} follow the critical scaling law very well with the critical exponents for magnetic susceptibility of 3D Ising systems, which suggests that the AFM spin correlation is responsible for the observed SSE near T_{N}.

10.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

11.
J Med Chem ; 62(5): 2265-2285, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.


Assuntos
Ensaios Clínicos como Assunto , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Tetra-Hidronaftalenos/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Naftalenos/química , Naftalenos/farmacocinética , Ratos , Ratos Endogâmicos Lew , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacocinética
12.
J Community Psychol ; 46(7): 871-884, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30565737

RESUMO

This study surveyed 347 lesbian, gay, bisexual, transgender, and questioning college students from across the United States concerning their bully victimization, depressive symptoms, and sources of support. Participants responded to an online survey that asked them about their victimization experiences during the 3 months prior to the survey. The results indicate that four types of bully victimization (verbal, relational, cyber, and physical) occur during the college years, and that victimization relates positively to depressive symptomatology in sexual minority college students. The 4 forms of bullying did not relate to depression in the same manner for each of the 5 sexual minority subgroups. Peer support, but not family and campus support, provided a buffer against depression for lesbian, gay, and bisexual students. This study involved a sample exclusively comprising sexual minority college students, and the findings show the need for colleges to address bully victimization and its effects in this population.


Assuntos
Bullying/psicologia , Vítimas de Crime/psicologia , Depressão/psicologia , Minorias Sexuais e de Gênero/psicologia , Estudantes/psicologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Fatores de Proteção , Apoio Social , Estados Unidos , Universidades , Adulto Jovem
13.
Drug Metab Dispos ; 44(2): 238-49, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26608080

RESUMO

Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 ± 0.38, 0.17 ± 0.04, and 0.25 ± 0.04 µM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 ± 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment.


Assuntos
Cátions/metabolismo , Rim/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Linhagem Celular , Interações Medicamentosas/fisiologia , Células HEK293 , Humanos , Cinética , Macaca fascicularis , Metformina/metabolismo , Pirimetamina/metabolismo
14.
Drug Metab Dispos ; 43(7): 984-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25904762

RESUMO

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.


Assuntos
Creatinina/metabolismo , Túbulos Renais/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Antiporters/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Indometacina/farmacologia , Túbulos Renais Proximais/metabolismo , Cinética , Macaca fascicularis , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Sulfobromoftaleína/farmacologia
15.
J Pharmacol Exp Ther ; 344(3): 673-85, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23297161

RESUMO

Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17ß-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC(50) values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K(m) and RIF IC(50)) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting.


Assuntos
Fígado/metabolismo , Macaca fascicularis/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Clonagem Molecular/métodos , Interações Medicamentosas , Fluorbenzenos/farmacologia , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Masculino , Modelos Animais , Transportadores de Ânions Orgânicos/genética , Pirimidinas/farmacologia , Rifampina/farmacologia , Rosuvastatina Cálcica , Sulfonamidas/farmacologia
16.
Drug Metab Dispos ; 40(9): 1698-711, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22648560

RESUMO

Six proton pump inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, and rabeprazole, were shown to be weak inhibitors of cytochromes P450 (CYP3A4, -2B6, -2D6, -2C9, -2C8, and -1A2) in human liver microsomes. In most cases, IC50 values were greater than 40 µM, except for dexlansoprazole and lansoprazole with CYP1A2 (IC50 = ∼8 µM) and esomeprazole with CYP2C8 (IC50 = 31 µM). With the exception of CYP2C19 inhibition by omeprazole and esomeprazole (IC50 ratio, 2.5 to 5.9), there was no evidence for a marked time-dependent shift in IC50 (IC50 ratio, ≤ 2) after a 30-min preincubation with NADPH. In the absence of preincubation, lansoprazole (IC50 = 0.73 µM) and esomeprazole (IC50 = 3.7 µM) were the most potent CYP2C19 inhibitors, followed by dexlansoprazole and omeprazole (IC50 = ∼7.0 µM). Rabeprazole and pantoprazole (IC50 = ≥ 25 µM) were the weakest. A similar ranking was obtained with recombinant CYP2C19. Despite the IC50 ranking, after consideration of plasma levels (static and dynamic), protein binding, and metabolism-dependent inhibition, it is concluded that omeprazole and esomeprazole are the most potent CYP2C19 inhibitors. This was confirmed after the incubation of the individual PPIs with human primary hepatocytes (in the presence of human serum) and by monitoring their impact on diazepam N-demethylase activity at a low concentration of diazepam (2 µM). Data described herein are consistent with reports that PPIs are mostly weak inhibitors of cytochromes P450 in vivo. However, two members of the PPI class (esomeprazole and omeprazole) are more likely to serve as clinically relevant inhibitors of CYP2C19.


Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Esomeprazol/farmacologia , Fígado/efeitos dos fármacos , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , 2-Piridinilmetilsulfinilbenzimidazóis/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Biotransformação , Células Cultivadas , Simulação por Computador , Citocromo P-450 CYP2C19 , Remoção de Radical Alquila , Dexlansoprazol , Diazepam/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Esomeprazol/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Cinética , Lansoprazol , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Modelos Biológicos , NADP/metabolismo , Omeprazol/farmacocinética , Pantoprazol , Inibidores da Bomba de Prótons/farmacocinética , Rabeprazol , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
17.
Xenobiotica ; 41(6): 476-85, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21381897

RESUMO

The purpose of this study was to assess the impact of interferon-α2b (IFN-α2b) on the expression of various drug-metabolizing enzymes and transporters in freshly prepared co-cultures (parenchymal and non-parenchymal cells) of human primary hepatocytes. At therapeutically relevant concentrations (from 1000 to 3000 IU/mL), IFN-α2b up-regulated STAT1 (signal transducer and activator of transcription factor 1) mRNA expression. Conversely, three cytochrome P450s (CYP1A2, CYP2B6, CYP2E1), a UDP-glucuronosyltransferase (UGT2B7), a sulphotransferase (SULT1A1) and organic anion transporter (OAT2) were significantly down-regulated (~50%; P < 0.05). Western blot analysis of CYP1A2, UGT2B7 and OAT2 protein supported the mRNA data. Two peroxisome proliferator activator receptor alpha (PPARα)-controlled genes (pyruvate dehydrogenase kinase 4 and adipose differentiation-related protein), CYP3A4 and multidrug resistance-associated protein 2 were significantly up-regulated (up to 223%; P < 0.05). On the other hand, SULT2A1, carboxylesterase 2, organic anion transporting peptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1, P-glycoprotein and breast cancer resistance protein mRNA expression was not significantly affected. Western blot analysis of CYP3A4 supported the mRNA data also. The present results demonstrated complex interactions between IFN-α2b and hepatocytes and the observed down-regulation of CYP1A2, OAT2 and UGT2B7 is consistent with reports of drug interactions between IFN-α2b and drugs such as theophylline, clozapine and gemfibrozil.


Assuntos
Antivirais/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Interferon-alfa/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Transporte Biológico/efeitos dos fármacos , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Células Cultivadas , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Família 2 do Citocromo P450 , Regulação para Baixo/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Hepatócitos/enzimologia , Humanos , Interferon alfa-2 , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Desentoxicação Metabólica Fase I/genética , Desintoxicação Metabólica Fase II/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Perilipina-2 , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Sulfotransferases/genética , Sulfotransferases/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Drug Metab Dispos ; 38(7): 1072-82, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20360302

RESUMO

17alpha-Ethinylestradiol (EE2), a component of oral contraceptives, is known to undergo considerable first-pass 3-O-sulfation in the intestine and liver. Once formed, the 3-O-sulfate conjugate (EE2-Sul) is detected in circulation at appreciable levels (versus parent EE2) and is present in bile. Therefore, hepatic uptake of EE2-Sul was assessed with suspensions of cryopreserved human primary hepatocytes. In this instance, there was evidence for active (temperature-dependent) uptake, which was described by a two-K(m) (Michaelis constant) model (K(m1) = 220 nM; K(m2) = 15.5 microM). Uptake was inhibited (approximately 90%) by bromosulfophthalein but not by tetraethylammonium or p-aminohippurate. In agreement, EE2-Sul was shown to be a substrate of recombinant organic anion transporter peptides (OATP1B1 and OATP2B1), and Na(+)/taurocholate-cotransporting polypeptide (NTCP), expressed individually in human embryonic kidney (HEK) 293 cells. Transport by OATP1B1 was described by two K(m) values (87 nM and 141 microM), whereas OATP2B1- and NTCP-mediated uptake into HEK-293 cells conformed to single K(m) kinetics (10.7 and 2.6 microM, respectively). EE2-Sul was also assessed as an efflux transporter substrate using membrane vesicles expressing bile salt export pump, breast cancer resistance protein (BCRP), and individual forms of multidrug resistance-associated protein (MRP1, MRP2, and MRP3). Transport studies were also conducted with a cell line expression P-glycoprotein. Only vesicles that contained BCRP exhibited ATP-dependent uptake of EE2-Sul (K(m1) = 2.9 and K(m2) = 307 microM). Collectively, the data show that hepatic uptake of EE2-Sul can be mediated by three transporters (OATP1B1, OATP2B1, and NTCP), whereas biliary excretion of EE2-Sul into bile likely involves BCRP.


Assuntos
Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/biossíntese , Etinilestradiol/análogos & derivados , Hepatócitos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Transporte Biológico Ativo/genética , Proteínas de Transporte/genética , Linhagem Celular Transformada , Etinilestradiol/metabolismo , Humanos , Cinética , Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/biossíntese , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/biossíntese , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/biossíntese , Simportadores/genética , Transfecção/métodos
19.
Drug Metab Dispos ; 38(7): 1064-71, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20360303

RESUMO

17alpha-Ethinylestradiol (EE2), a synthetic and potent estrogen receptor agonist, is extensively metabolized in both intestine and liver and is largely excreted in bile and urine as the 3-O-sulfate (EE2-Sul) and 3-O-glucuronide. In the present study, EE2-Sul was evaluated as a substrate of various transporters known to be expressed in the kidney. Uptake studies were performed with human epithelial cells [human embryonic kidney (HEK)-293] that contained individually expressed organic cation transporter 2 (OCT2), organic anion transporter (OAT) forms 3 and 4, and multidrug and toxin extrusion 1 (MATE1). The transporter phenotyping studies were extended to include insect cell (Sf9) membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and Madin-Darby canine kidney cells that expressed OAT1. Based on the results obtained, we concluded that EE2-Sul serves as a substrate of OAT3 and OAT4, but not OCT2, OAT1, MATE1, and MRP4. First, EE2-Sul uptake was highly increased in OAT3/HEK-293 cells (versus mock/HEK-293 cells) and was inhibited by OAT3 inhibitors such as bromosulfophthalein (BSP), cimetidine, and probenecid. OAT3-mediated uptake also conformed to single-K(m) (Michaelis constant) kinetics (K(m) = 21.1 microM). Second, EE2-Sul uptake was also significantly higher in OAT4/HEK-293 cells and was inhibited by BSP, methotrexate, and probenecid. In contrast to OAT3, OAT4-dependent uptake was characterized by a two-K(m) model (K(m1) = 1.6 microM; K(m2) = 195 microM). Based on the results of this study, we hypothesize that EE2-Sul is taken up into renal proximal tubule cells by OAT3, and OAT4 plays a role in its secretion into the renal brush border lumen.


Assuntos
Transporte Biológico/efeitos dos fármacos , Proteínas de Transporte/biossíntese , Etinilestradiol/análogos & derivados , Rim/metabolismo , Animais , Transporte Biológico/genética , Proteínas de Transporte/genética , Linhagem Celular Transformada , Cães , Etinilestradiol/metabolismo , Humanos , Insetos , Cinética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteína 1 Transportadora de Ânions Orgânicos/biossíntese , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/biossíntese , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , Especificidade por Substrato , Transfecção/métodos
20.
Mol Cancer Ther ; 8(12): 3341-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19996272

RESUMO

BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.


Assuntos
Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administração & dosagem , Triazinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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