Assuntos
Bezafibrato/uso terapêutico , Citocinas/efeitos dos fármacos , Ácidos Graxos Ômega-3/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Monócitos/efeitos dos fármacos , Adulto , Idoso , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Bezafibrato/uso terapêutico , Ácidos Graxos Ômega-3/farmacologia , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Linfócitos/efeitos dos fármacos , Citocinas/metabolismo , Quimioterapia Combinada , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Linfócitos/metabolismo , MasculinoRESUMO
AIM: To evaluate a new series of 16 hydantoin derivatives for activity against the intrinsic and overexpressed efflux pumps of the ATTC 25923 Staphylococcus aureus and the clinical Staphylococcus aureus HPV-107 strain, respectively. MATERIALS AND METHODS: The hydantoin compounds were evaluated for activity against the efflux pumps of the ATTC 25923 S. aureus and the clinical S. aureus HPV-107 strains by the aid of the automated ethidium bromide method. Compounds that inhibited the efflux pumps of either strain were evaluated for ability to reduce or reverse resistance of these strains to oxacillin. RESULTS: Although most of the hydantoins inhibited the efflux pumps of the ATTC strain, none reduced the resistance of this strain to oxacillin. In contrast, the inhibition of the Qac efflux pump present in HPV-107 was inhibited to some degree, by much higher concentrations of the hydantoin compounds than that needed for similar activity against the ATTC strain; only hydantoin PI8a significantly reduced the minimum inhibitory concentration of oxacillin against the HPV-107 strain. CONCLUSION: Hydantoin compound PI8a may have potential for therapy of a methicillin-resistant S. aureus infection whose multidrug-resistant phenotype is due to overexpression of an efflux pump.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Hidantoínas/farmacologia , Oxacilina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Sistemas Computacionais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Etídio/metabolismo , Corantes Fluorescentes/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxacilina/metabolismo , Resistência às Penicilinas/efeitos dos fármacos , Plasmídeos/genética , Staphylococcus aureus/metabolismoRESUMO
BACKGROUND: Multidrug resistance (MDR) is one of the major concerns in the treatment of cancer and one of the major causes of therapy failure. The overexpression of an ABC transporter, the ABCB1, is often associated with MDR in cancer. Previously it was observed that hydantoin compounds can modulate the activity of the ABCB1 pump. MATERIALS AND METHODS: Fourteen hydantoin derivatives were synthesized and studied for their capacity to increase accumulation of ethidium bromide (EB) by mouse lymphoma cancer cells that were transfected with the human ABCB1 gene and overexpress the human ABCB1 pump. RESULTS: It was observed that the accumulation of EB by the cells in the presence of four of the newly synthesized hydantoins was strongly increased. Similar but milder effects were also observed for the other seven hydantoins; the remaining three had no activity. CONCLUSION: The 14 hydantoin compounds studied belong to three different structural groups. Structure-activity relationships were studied and important molecular substituents that were possibly responsible for increased the activity of the molecules were identified. This important information may lead to the continuation of our work and to the future synthesis of more active compounds.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Hidantoínas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Etídio/análise , Etídio/metabolismo , Corantes Fluorescentes/análise , Corantes Fluorescentes/metabolismo , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Transporte de Íons/efeitos dos fármacos , Leucemia L5178/patologia , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , TransfecçãoRESUMO
This study aimed to compare the effects of ω-3 fatty acids and fibrate treatment on plasma levels and activities of hemostatic risk factors on glucose and lipid metabolism in subjects with isolated hypertriglyceridemia. Seventy-three subjects with elevated triglyceride levels were allocated into one of the following treatment options: bezafibrate (200 mg twice daily), ω-3 fatty acids (1 g twice daily) or placebo. Plasma lipids, glucose homeostasis markers (fasting and 2-h post-glucose load plasma glucose levels and HOMA), as well as plasma levels/activities of fibrinogen, factor VII and PAI-1 were determined at baseline, on the day of randomization, and after 4 and 12 weeks of the treatment. Not only did bezafibrate improve plasma lipids, but it also increased glucose sensitivity and tended to reduce post-glucose loads of plasma glucose. Except for the reduction in plasma triglycerides, ω-3 fatty acids produced no effect on the lipid profile and insulin sensitivity. Both treatment options reduced, to similar extents, plasma levels of fibrinogen and PAI-1 and factor VII coagulant activity. Our study indicates that, although fibrates exhibit more-pronounced metabolic effects than do ω-3 fatty acids, both these treatment options are equipotent in producing a complex beneficial effect on hemostasis in isolated hypertriglyceridemic subjects.
Assuntos
Bezafibrato/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Glicemia/efeitos dos fármacos , Feminino , Hemostasia/efeitos dos fármacos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: The aim of this study was to compare the effects of fibrates and omega-3 fatty acids on lymphocyte secretory function and systemic inflammation in patients with isolated hypertriglyceridemia. METHODS: The study included 107 patients with isolated hypertriglyceridemia who received bezafibrate (200 mg twice daily), omega-3 fatty acids (1 g twice daily) or placebo for 12 weeks. The lipid profile, fasting and 2-h post-glucose load plasma glucose levels, homeostasis model assessment index (HOMA), plasma high-sensitivity C-reactive protein (hsCRP) levels and lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α were assessed at baseline, on the day of randomization, and after 4 and 12 weeks of treatment. RESULTS: Both bezafibrate and omega-3 fatty acids reduced plasma triglyceride levels. Bezafibrate additionally decreased total and low-density lipoprotein-cholesterol levels and the HOMA and insignificantly decreased post-glucose load plasma glucose, as well as increased high-density lipoprotein-cholesterol. Bezafibrate treatment was associated with a reduction in lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α, which was accompanied by a reduction in plasma hsCRP levels. Omega-3 fatty acid did not significantly reduce lymphocyte cytokine release and plasma hsCRP. The anti-inflammatory effects of both drugs did not correlate with their action on plasma lipids, but in the case of the former the effect was related to the improvement in insulin sensitivity. CONCLUSION: Our results indicate that bezafibrate is superior to omega-3 fatty acid in inhibiting systemic inflammation and lymphocyte secretory function.
Assuntos
Bezafibrato/uso terapêutico , Citocinas/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Inflamação/sangue , Linfócitos/efeitos dos fármacos , Adulto , Idoso , Bezafibrato/administração & dosagem , Bezafibrato/efeitos adversos , Proteína C-Reativa/metabolismo , Colesterol/sangue , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/efeitos adversos , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/imunologia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Inflamação/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
Fibrates and omega-3 fatty acids have been used for many years in the treatment of increased triglyceride levels. Unfortunately, pleiotropic effects of these agents in patients with isolated hypertriglyceridaemia are poorly understood. The aim of this study was to compare the effect of bezafibrate and omega-3 fatty acids on monocyte cytokine release and systemic inflammation in this type of dyslipidaemia. The study included eighty-seven hypertriglyceridaemic subjects randomly allocated to one of three groups, treated respectively with bezafibrate (200 mg twice daily), omega-3 fatty acids (1 g twice daily) or placebo for 90 days. Eighty-three subjects completed the study. Apart from improvement in lipid profile, bezafibrate treatment reduced plasma high-sensitivity C-reactive protein (hsCRP) levels and inhibited monocyte release of interleukin-6, interleukin-1ß, monocyte chemoattractant protein-1 and tumour necrosis factor-α. Bezafibrate action on plasma hsCRP and monocyte cytokine release was lipid-independent but correlated with drug-induced improvement in insulin sensitivity. Omega-3 fatty acids reduced plasma triglycerides, but did not induce any significant changes in monocyte secretory function and plasma hsCRP. Our study suggests that bezafibrate is superior to omega-3 fatty acids in reducing systemic inflammation and in producing monocyte-suppressing effects. Anti-inflammatory actions of bezafibrate may contribute to the clinical effectiveness of fibrates in the prevention and treatment of isolated hypertriglyceridaemia.