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










Base de dados
Intervalo de ano de publicação
1.
Regul Toxicol Pharmacol ; 118: 104801, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33039518

RESUMO

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

2.
J Thromb Thrombolysis ; 50(1): 20-29, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32323192

RESUMO

Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit-risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30-49 mL/min) or dose-adjusted warfarin (median follow-up: 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure-response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (Ctrough) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. Ctrough was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median]: 1.26 [95% confidence interval 1.13-1.40]) but not with major bleeding alone. The exposure-response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than Ctrough. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.

3.
Regul Toxicol Pharmacol ; : 104859, 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33388367

RESUMO

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

4.
Ther Adv Cardiovasc Dis ; 13: 1753944719863641, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364490

RESUMO

BACKGROUND: This analysis aimed to evaluate the impact of rivaroxaban exposure and patient characteristics on efficacy and safety outcomes in patients with acute coronary syndrome (ACS) and to determine whether therapeutic drug monitoring might provide additional information regarding rivaroxaban dose, beyond what patient characteristics provide. METHODS: A post hoc exposure-response analysis was conducted using data from the phase III ATLAS ACS 2 Thrombolysis in Myocardial Infarction (TIMI) 51 study, in which 15,526 randomized ACS patients received rivaroxaban (2.5 mg or 5 mg twice daily) or placebo for a mean of 13 months (maximum follow up: 31 months). A multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event clinical outcomes. RESULTS: For the incidence of myocardial infarction (MI), ischemic stroke, or nonhemorrhagic cardiovascular death, hazard ratios (HRs) for steady-state maximum plasma concentration (Cmax) in the 5th and 95th percentiles versus the median were statistically significant but close to 1 for both rivaroxaban doses. For TIMI major bleeding events, a statistically significant association was observed with Cmax [HR, 1.08; 95% CI, 1.06-1.11 (95th percentile versus median, 2.5 mg twice daily)], sex [HR, 0.56; 95% CI, 0.38-0.84 (female versus male)], and previous revascularization [HR, 0.62; 95% CI, 0.44-0.87 (no versus yes)]. CONCLUSIONS: The shallow slopes of the exposure-response relationships and the lack of a clear therapeutic window render it unlikely that therapeutic drug monitoring in patients with ACS would provide additional information regarding rivaroxaban dose beyond that provided by patient characteristics.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Modelos Biológicos , Rivaroxabana/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Isquemia Encefálica/mortalidade , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Acidente Vascular Cerebral/mortalidade , Resultado do Tratamento
5.
CPT Pharmacometrics Syst Pharmacol ; 8(11): 805-814, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31276324

RESUMO

Prothrombin time (PT) is a measure of coagulation status and was assessed in the majority of patients in the rivaroxaban phase II and III clinical trials as a pharmacodynamic marker. In the absence of sufficient phase III pharmacokinetic (PK) data to provide individual exposure measures for input into rivaroxaban exposure-response analyses, the aim of the present study was to investigate the use of PT-adjustment approaches (i.e., the use of observed individual PT measurements) to enhance the prediction of individual rivaroxaban exposure metrics (derived using a previously developed integrated population PK model) based on the observed linear relationship between PT and rivaroxaban plasma concentrations. The PT-adjustment approaches were established using time-matched PK and PT measurements, which were available from 1,779 patients across four phase II trials and one phase III trial of rivaroxaban. PT-adjusted exposure estimates improved the identification of statistically significant effects when compared with covariate-only exposure estimates.

6.
Br J Clin Pharmacol ; 76(6): 917-31, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23594227

RESUMO

AIMS: To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODS: Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [(13)C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [(13)C4]cortisone. RESULTS: Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11ß-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated. CONCLUSIONS: These findings indicate that 11ß-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Triazóis/farmacologia , Triazóis/farmacocinética , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Adulto Jovem
7.
Physiol Genomics ; 45(1): 47-57, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23170035

RESUMO

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11ß-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE-/- mice. However, the molecular mechanism underlying the atheroprotective effect was not clear. In this study, we tested whether and how 11ß-HSD1 inhibition affects vascular inflammation, a major culprit for atherosclerosis and its associated complications. ApoE-/- mice were treated with an 11ß-HSD1 inhibitor for various periods of time. Plasma lipids and aortic cholesterol accumulation were quantified. Several microarray studies were carried out to examine the effect of 11ß-HSD1 inhibition on gene expression in atherosclerotic tissues. Our data suggest 11ß-HSD1 inhibition can directly modulate atherosclerotic plaques and attenuate atherosclerosis independently of lipid lowering effects. We identified immune response genes as the category of mRNA most significantly suppressed by 11ß-HSD1 inhibition. This anti-inflammatory effect was further confirmed in plaque macrophages and smooth muscle cells procured by laser capture microdissection. These findings in the vascular wall were corroborated by reduction in circulating MCP1 levels after 11ß-HSD1 inhibition. Taken together, our data suggest 11ß-HSD1 inhibition regulates proinflammatory gene expression in atherosclerotic tissues of ApoE-/- mice, and this effect may contribute to the attenuation of atherosclerosis in these animals.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Vasculite/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Apolipoproteínas E/genética , Aterosclerose/etiologia , Colesterol/metabolismo , Perfilação da Expressão Gênica , Genes MHC da Classe II/genética , Glucocorticoides/metabolismo , Microdissecção e Captura a Laser , Lipídeos/sangue , Camundongos , Camundongos Knockout , Análise em Microsséries , Vasculite/complicações
8.
J Am Soc Hypertens ; 5(3): 166-76, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21419745

RESUMO

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11ß-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11ß-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Drogas em Investigação , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/administração & dosagem , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/efeitos adversos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adolescente , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/metabolismo , Índice de Massa Corporal , Método Duplo-Cego , Monitoramento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Feminino , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Am Heart J ; 158(4): 513-519.e3, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19781408

RESUMO

BACKGROUND: Residual cardiovascular (CV) risk often remains high despite statin therapy to lower low-density lipoprotein cholesterol (LDL-C). New therapies to raise high-density lipoprotein cholesterol (HDL-C) are currently being investigated. Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that raises HDL-C and reduces LDL-C when administered alone or with a statin. Adverse effects on blood pressure, electrolytes, and aldosterone levels, seen with another drug in this class, have not been noted in studies of anacetrapib to date. METHODS: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHD risk equivalents (clinical trials.gov NCT00685776). Eligible patients at National Cholesterol Education Program-Adult Treatment Panel III LDL-C treatment goal on a statin, with or without other lipid-modifying medications, are treated with anacetrapib, 100 mg, or placebo for 18 months, followed by a 3-month, poststudy follow-up. The primary end points are percent change from baseline in LDL-C and the safety and tolerability of anacetrapib. Comprehensive preplanned interim safety analyses will be performed at the 6- and 12-month time points to examine treatment effects on key safety end points, including blood pressure and electrolytes. A preplanned Bayesian analysis will be performed to interpret the CV event distribution, given the limited number of events expected in this study. RESULTS: A total of 2,757 patients were screened at 153 centers in 20 countries, and 1,623 patients were randomized into the trial. Lipid results, clinical CV events, and safety outcomes from this trial are anticipated in 2010.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , LDL-Colesterol/sangue , Doença das Coronárias/tratamento farmacológico , Oxazolidinonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transferência de Ésteres de Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Doença das Coronárias/sangue , Doença das Coronárias/fisiopatologia , Método Duplo-Cego , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Obesity (Silver Spring) ; 16(6): 1178-85, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18388900

RESUMO

OBJECTIVE: Our main objective was to compare the regulation of cortisol production within omental (Om) and abdominal subcutaneous (Abd sc) human adipose tissue. METHODS AND PROCEDURES: Om and Abd sc adipose tissue were obtained at surgery from subjects with a wide range of BMI. Hydroxysteroid dehydrogenase (HSD) activity ((3)H-cortisone and (3)H-cortisol interconversion) and expression were measured before and after organ culture with insulin and/or dexamethasone. RESULTS: Type 1 HSD (HSD1) mRNA and reductase activity were mainly expressed within adipocytes and tightly correlated with adipocyte size within both depots. There was no depot difference in HSD1 expression or reductase activity, while cortisol inactivation and HSD2 mRNA expression (expressed in stromal cells) were higher in Om suggesting higher cortisol turnover in this depot. Culture with insulin decreased HSD reductase activity in both depots. Culture with dexamethasone plus insulin compared to insulin alone increased HSD reductase activity only in the Om depot. This depot-specific increase in reductase activity could not be explained by an alteration in HSD1 mRNA or protein, which was paradoxically decreased. However, in Om only, hexose-6-phosphate dehydrogenase (H6PDH) mRNA levels were increased by culture with dexamethasone plus insulin compared to insulin alone, suggesting that higher nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) production within the endoplasmic reticulum (ER) contributed to the higher HSD reductase activity. DISCUSSION: We conclude that in the presence of insulin, glucocorticoids cause a depot-specific increase in the activation of cortisone within Om adipose tissue, and that this mechanism may contribute to adipocyte hypertrophy and visceral obesity.


Assuntos
Cortisona/metabolismo , Hidrocortisona/metabolismo , Omento/metabolismo , Gordura Subcutânea/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adulto , Dexametasona/farmacologia , Feminino , Glucocorticoides/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Omento/citologia , Oxirredutases/metabolismo , RNA Mensageiro/metabolismo , Gordura Subcutânea/citologia
12.
Bioorg Med Chem Lett ; 18(11): 3412-6, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18440812

RESUMO

3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Triazóis/síntese química , Triazóis/farmacologia , Administração Oral , Animais , Técnicas de Química Combinatória , Cortisona/análise , Cortisona/sangue , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Hidrocortisona/análise , Hidrocortisona/sangue , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/farmacocinética
13.
Bioorg Med Chem Lett ; 18(9): 2799-804, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18434143
16.
Assay Drug Dev Technol ; 3(4): 377-84, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16180992

RESUMO

11beta-Hydroxysteroid dehydrogenase type-1 (11beta-HSD1) is a potential target for the treatment of diabetes, obesity, and hyperlipidemia. This enzyme is mainly responsible for reactivating glucocorticoid hormone inside cells such as adipose cells and liver cells by converting the inactive cortisone to active cortisol. Enzyme assays for 11beta-HSD1 involve either a thin-layer chromatography or high-performance liquid chromatography step to separate cortisol from the substrate cortisone. This additional step is labor intensive and increases the assay time, which limits assay throughput. A homogenous scintillation proximity assay-based method has been recently developed that enables high-throughput screening of 11beta-HSD1 inhibitors. We have applied this novel 11beta-HSD1 assay to screening a large-size compound collection and identified several structural classes of lead compounds that selectively inhibit the activity of 11beta-HSD1.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Contagem de Cintilação/métodos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Anticorpos Monoclonais , Células CHO , Técnicas de Química Combinatória , Cricetinae , Cricetulus , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidrocortisona/análise , Hidrocortisona/imunologia , Hidrocortisona/metabolismo , Microssomos/enzimologia , Transfecção , Trítio
17.
Expert Rev Cardiovasc Ther ; 3(5): 911-24, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16181035

RESUMO

The metabolic syndrome (syndrome X) is a cluster of risk factors and a common cause of cardiovascular disease in humans. Although the underlying mechanism for metabolic syndrome is still poorly understood, recent clinical data and studies with transgenic animals implicate elevated intracellular glucocorticoid tone in the etiology of metabolic syndrome. Development of selective inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 and their use in rodent animal disease models encompassing several aspects of metabolic syndrome indicate the possibility of therapeutic intervention. This review will focus on recent advances in our understanding of the role of 11beta-HSD1 in metabolic disorders and other disease processes.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Glucocorticoides/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Animais , Humanos , Camundongos
18.
J Exp Med ; 202(4): 517-27, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16103409

RESUMO

The enzyme 11beta-hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11beta-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11beta-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11beta-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11beta-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Arteriosclerose/tratamento farmacológico , Azepinas/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Resistência à Insulina , Triazóis/administração & dosagem , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/administração & dosagem , Animais , Aorta/metabolismo , Arteriosclerose/complicações , Arteriosclerose/enzimologia , Glicemia/efeitos dos fármacos , Cortisona/metabolismo , Dieta Aterogênica , Modelos Animais de Doenças , Ácidos Graxos/sangue , Hidrocortisona , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , Síndrome , Triglicerídeos/sangue
20.
Biochem Biophys Res Commun ; 294(1): 88-94, 2002 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-12054745

RESUMO

Secretory non-pancreatic phospholipase A(2) (sPLA(2)) has been implicated in inflammation and has been found in human atherosclerotic lesions. To test the effect of sPLA(2) deficiency on atherosclerosis, C57BL/Ks mice (apoE(+/+) and PLA(2)(++) were bred with C57BL/6 apoE knockout mice which are sPLA(2)(--) due to a spontaneous mutation. Sibling pairs of mice (apoE(--)/sPLA(2)(++) and apoE(--)/sPLA(2)(--)) on high fat Western diets were dissected at 22 weeks. In vitro enzyme assays confirmed higher serum sPLA(2) activity in the sPLA(2)(++) compared to sPLA(2)(--) for both sexes, while sPLA(2)(--) males had slightly higher serum cholesterol and phospholipids. Analysis of lipoprotein profiles by FPLC showed no effect of sPLA(2) genotype on any measured parameters. Atherosclerosis was quantitated by assaying cholesterol in aortic extracts. Male sPLA(2) trended slightly higher than sPLA(2)(++) with no statistical significance. Female sPLA(2)(++) and sPLA(2)(--) mice showed no significant differences in any of the measured parameters. These results suggest that the endogenous mouse sPLA(2) gene does not significantly affect HDL or atherosclerosis in mice.


Assuntos
Arteriosclerose/metabolismo , Lipoproteínas HDL/metabolismo , Fosfolipases A/deficiência , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/fisiologia , Cromatografia Líquida de Alta Pressão , Gorduras na Dieta/administração & dosagem , Feminino , Genótipo , Fosfolipases A2 do Grupo II , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfolipases A/metabolismo , Fatores Sexuais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA