RESUMO
SCOPE: Fatty acids (FAs) may affect endothelial cell (EC) function, influencing atherogenesis and inflammatory processes. Palmitoleic acid (POA) has been described as an anti-inflammatory FA. However, its effects on ECs are underexplored. This study compares the effects of POA with those of palmitic acid (PA) and oleic acid (OA) on EC inflammatory responses. METHODS AND RESULTS: EAHy926 cells (EC lineage) are exposed to PA, OA, or POA, and stimulated with tumor necrosis factor (TNF)-α. Associated with the FA's own incorporation, PA induces a twofold increase in arachidonic acid, while POA increases the amount of cis-vaccenic acid. PA, but not OA, enhances the production of IL-6 and IL-8 in response to TNF-α. In contrast, POA decreases production of monocyte chemotactic protein (MCP)-1, IL-6, and IL-8 compared to PA. TNF-α increases surface intercellular adhesion molecule-1 expression previously decreased by POA. TNF-α stimulation increases the expression of NFκB, cyclooxygenase (COX)-2, MCP-1, and IL-6 genes and reduces the expression of peroxisome proliferator-activated receptor (PPAR)-α gene. PA enhances the expression of MCP-1, IL-6, and COX-2 genes, while POA downregulates these genes, decreases expression of NFκB, and upregulates PPAR-α gene expression. CONCLUSION: POA has anti-inflammatory effects on ECs stimulated with TNF-α and may counter endothelial dysfunction.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Células Endoteliais/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Ácido Oleico/farmacologia , Ácidos Palmíticos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Ácidos Graxos Monoinsaturados/farmacocinética , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ácido Oleico/farmacocinética , Ácidos Palmíticos/farmacocinética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoAssuntos
Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Claritromicina/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirimidinas/farmacocinética , Rabdomiólise/induzido quimicamente , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacocinética , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Monoinsaturados/uso terapêutico , Ácidos Graxos Monoinsaturados/farmacocinética , Pravastatina/metabolismo , Pravastatina/uso terapêutico , Pravastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Transportadores de Ânions Orgânicos , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado , Interações Medicamentosas , Injúria Renal Aguda/induzido quimicamente , Rosuvastatina Cálcica , Fluorbenzenos/metabolismo , Fluorbenzenos/uso terapêutico , Fluorbenzenos/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Fluvastatina , Hiperpotassemia/induzido quimicamente , Indóis/metabolismo , Indóis/uso terapêutico , Indóis/farmacocinéticaRESUMO
Hypertension and dyslipidemia are independent risk factors for cardiovascular mortality and are frequently present in the same patient. Fluvastatin (FV), used to reduce cholesterol levels, and lercanidipine (LER), used to control blood pressure, are marketed as racemic mixtures. Therapeutic activities are 30-fold higher for (+)-3R, 5S-FV and 100- to 200-fold higher for S-LER compared with their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in healthy volunteers. A crossover randomized study was conducted in 3 phases on 8 volunteers treated with a single oral racemic dose of LER (20 mg) or FV (40 mg) or LER plus FV. Serial blood samples were collected from 0 to 24 hours. Plasma concentrations of the LER and FV enantiomers were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann-Whitney tests (P < .05) were used to analyze enantiomer ratios and the pharmacokinetic drug interaction. Data are expressed as medians. In monotherapy, the kinetic disposition of both FV and LER was enantioselective. AUC values were significantly higher for (-)-3S,5R-FV than for (+)-3R,5S-FV (358.20 vs 279.68 ng.h/mL) and for S-LER compared with R-LER (13.90 vs 11.88 ng.h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (-)-3S,5R-FV: 325.21; (+)-3R,5S-FV: 316.44 ng.h/mL). There was a significant reduction in S-LER (8.06 vs 13.90 ng.h/mL) and R-LER (6.76 vs 11.88 ng.h/mL) AUC values when FV was coadministered. In conclusion, the interaction between FV-LER might be clinically relevant because AUC values of (+)-3R,5S-FV were increased when LER was coadministered, and AUC values of the 2 LER enantiomers were reduced when FV was coadministered.
Assuntos
Anticolesterolemiantes/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacocinética , Di-Hidropiridinas/farmacocinética , Ácidos Graxos Monoinsaturados/farmacocinética , Indóis/farmacocinética , Adulto , Anticolesterolemiantes/farmacologia , Área Sob a Curva , Bloqueadores dos Canais de Cálcio/farmacologia , Cromatografia Líquida , Estudos Cross-Over , Di-Hidropiridinas/farmacologia , Interações Medicamentosas , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Fluvastatina , Humanos , Indóis/farmacologia , Estatísticas não Paramétricas , Estereoisomerismo , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
BACKGROUND/AIMS: Dietary habits are considered to be responsible for a fatty liver. The aims of this work are to study the effects of different lipid sources on rat hepatic structure. METHODS: Twenty 21-day-old to 18-month-old male rats were fed one of the following diets: soybean oil, canola oil, lard and egg yolk (LE), or canola oil+lard and egg yolk (CA+LE). The blood serum triglyceride samples were analyzed. The following hepatic biometry and the stereology parameters were determined: densities of volume (V(v)) and surface (S(v)), absolute volume (V) and surface (S) of the hepatocytes (h), fat globules (g), and hepatic sinusoids (s), and numerical density of the hepatocytes (N(v)[h]). RESULTS: The largest values of V(v)[h], S(v)[h], V[h], and S[h] were found in the LE group. However, the largest values of V(v)[g], S(v)[g], and S[g] were found in the CA+LE group, and the smallest values of those parameters were found in the LE group. On the other hand, V[g] was larger in the CA+LE group. V(v)[s] and V[s] were larger in the LE group and smaller in the CA+ LE group. CONCLUSION: Long-term administration of canola oil or soybean oil resulted in similar effects on hepatocytes, hepatic sinusoids, and fat globules. Long-term administration of lard and egg yolk attenuates hepatic fat accumulation and increases hepatic sinusoids. The administration of the canola oil and lard and egg yolk mixture increases hepatic fat accumulation, reducing the hepatic sinusoids.
Assuntos
Gorduras na Dieta/farmacocinética , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Animais , Gema de Ovo , Ácidos Graxos Monoinsaturados/farmacocinética , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Óleo de Brassica napus , Ratos , Ratos Wistar , Óleo de Soja/farmacocinética , Triglicerídeos/sangueRESUMO
Fluvastatin, an inhibitor of cholesterol biosynthesis, is commercialized as a racemic mixture of the (+)-3R,5S and (-)-3S,5R stereoisomers, although inhibition of HMG-CoA reductase mainly resides in the (+)-(3R,5S)-fluvastatin isomer. The aim of the present study was to analyze fluvastatin isomers in human plasma with application to studies on kinetic disposition. Plasma samples of 1 ml were eluted into 3 ml LC-18 Supelclean (Supelco) columns equilibrated with methanol and water. The columns were washed with water and acetonitrile and then eluted with methanol containing 0.2% diethylamine. The (+)-3R,5S and (-)-3S,5R isomers were separated by HPLC on a Chiralcel OD-H chiral phase column and detected by fluorescence (lambda(ex) 305 nm; lambda(em) 390 nm). The quantification limit was 0.75 ng for each isomer/ml plasma and linearity was observed up to 625 ng/ml. The relative standard deviations obtained for intra- and inter-assay precision were lower than 10% and the recovery was higher than 80% for both enantiomers. Application of the method to a stereoselective study on the pharmacokinetics of fluvastatin administered as a single oral dose (Lescol, 20 mg) to a healthy volunteer revealed stereoselectivity, with the highest plasma concentrations being observed for the (-)-3S,5R isomer (Cmax 92.4 vs. 60.3 ng/ml, AUC(0-infinity) 133.3 vs. 97.4 ng h/ml, Cl/f 150.2 vs. 205.2 l h(-1) and Vd/f 4.4 vs. 6.0 l/kg).