RESUMO
OBJECTIVES: The aim of this study was to investigate the relation among atherosclerosis, antibodies against oxidized LDL (anti-oxLDL), and inflammation in rheumatoid arthritis (RA) patients treated with biological (b) disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Fifty-nine patients who were receiving conventional synthetic DMARDs and were eligible for treatment with a biological agent were included in the study. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and IgG antibodies against oxidized LDL (anti-oxLDL) as well as carotid intima-media thickness (cIMT) were determined before and after 6 months of treatment. Thirty-one healthy individuals were used as a control group. RESULTS: At baseline, RA patients had lower TC and HDL-C levels and increased cIMT compared to controls. After a 6-month follow-up, the re-evaluation of carotids revealed a statistically important decrease of cIMT values. This observation was accompanied by a statistically important elevation of HDL-C levels and a reduction of the titer of anti-oxLDL antibodies regardless of the bDMARD that was administered. No statistically significant association was found between the cIMT and anti-oxLDL, HDL-C, CRP, or DAS28 score neither before nor 6 months after treatment using linear regression analyses adjusted for age and gender. CONCLUSIONS: We provide evidence that atherogenic lipid profile and ongoing atherosclerosis which characterize RA patients appear to improve after biological therapy, and we also suggest a possible atherogenic effect of IgG anti-ox LDL antibodies.
Assuntos
Antirreumáticos , Artrite Reumatoide , Aterosclerose , Humanos , Espessura Intima-Media Carotídea , Estudos Prospectivos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Aterosclerose/complicações , LDL-Colesterol , HDL-Colesterol , Antirreumáticos/uso terapêutico , Imunoglobulina G/uso terapêuticoRESUMO
Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials. The aim of the present study was to elucidate the molecular requirements involving the PAR-4 mechanism of activation by peptide analogues of its tethered-ligand. Eight synthetic PAR-4 tethered-ligand peptide analogues were synthesized and studied for their agonistic/antagonistic potency and selectivity toward human washed platelet aggregation, using light transmittance aggregometry. In addition, in silico studies were conducted to describe the receptor-peptide interactions that are developed following PAR-4 exposure to the above analogues. To provide a first structure-activity relationship rationale on the bioactivity profiles recorded for the studied analogues, molecular docking was applied in a homology model of PAR-4, derived using the crystal structure of PAR-1. The following peptide analogues were synthesized: AYPGKF-NH2 (1), GYPGKF-NH2 (2), Ac-AYPGKF-NH2 (3), trans-cinnamoyl-AYPGKF-NH2 (4), YPGKF-NH2 (5), Ac-YPGKF-NH2 (6), trans-cinnamoyl-YPGKF-NH2 (7), and caffeoyl-YPGKF-NH2 (8). Peptide (1) is a selective PAR-4 agonist inducing platelet aggregation with an IC50 value of 26.2 µM. Substitution of Ala-1 with Gly-1 resulted in peptide (2), which significantly reduces the agonistic potency of peptide (1) by 25-fold. Importantly, substitution of Ala-1 with trans-cinnamoyl-1 resulted in peptide (7), which completely abolishes the agonistic activity of peptide (1) and renders it with a potent antagonistic activity toward peptide (1)-induced platelet aggregation. All other peptides tested were inactive. Tyr-2, residue, along with its neighboring environment was a key determinant in the PAR-4 recognition mode. When the neighboring residues to Tyr-2 provided an optimum spatial ability for the ligand to enter into the binding site of the transmembrane receptor, a biological response was propagated. These results were compared with the predicted binding poses of small molecule antagonists of PAR-4, denoted as YD-3, ML-354, and BMS-986120. π-π stacking interaction with Tyr-183 appears to be critical and common for both small molecules antagonists and the peptide trans-cinnamoyl-YPGKF-NH2. Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.
Assuntos
Plaquetas/metabolismo , Receptores de Trombina/metabolismo , Sequência de Aminoácidos , Humanos , Ligantes , Estrutura Molecular , TrombinaRESUMO
Atherothrombosis and its clinical manifestations are among the leading causes of death in the developed world. The current standard-of-care antiplatelet therapy for the treatment of such events comprises aspirin and a thienopyridine or ticagrelor. However, recurrent ischemic events due to residual cardiovascular risk are a common phenomenon in these patients. It is believed that this residual risk is caused, at least in part, by thrombin, which signals through protease-activated receptors (PARs) and especially PAR-1. Thus, PAR-1 antagonism could represent an effective approach in the treatment of atherothrombotic disease. In this context, two potent and selective agents have been developed, vorapaxar and atopaxar. However, only vorapaxar has completed phase 3 clinical trials. In the present review, the main pharmacodynamic and pharmacokinetic properties of the PAR-1 antagonists are briefly described and the latest clinical data on vorapaxar are presented.
Assuntos
Iminas/farmacologia , Lactonas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Piridinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Ensaios Clínicos como Assunto , Ponte de Artéria Coronária , Quimioterapia Combinada , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea , Doença Arterial Periférica/tratamento farmacológico , Receptores de Trombina/antagonistas & inibidores , Stents/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/prevenção & controle , Trombose/prevenção & controleAssuntos
Medicamentos Genéricos/farmacocinética , Inibidores da Agregação Plaquetária/farmacocinética , Ticlopidina/análogos & derivados , Química Farmacêutica , Clopidogrel , Medicamentos Genéricos/administração & dosagem , Humanos , Inibidores da Agregação Plaquetária/administração & dosagem , Equivalência Terapêutica , Ticlopidina/administração & dosagem , Ticlopidina/farmacocinéticaRESUMO
Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. Organic anion-transporting polypeptide 1B1 (OATP1B1) encoded by SLCO1B1 gene (solute carrier organic anion transporter family member 1B1) facilitates hepatic uptake of simvastatin and atorvastatin. SLCO1B1 polymorphisms are strongly associated with statin-induced myopathy whereas few studies have assessed their effect on statin differential response. In the present study, we analyzed the association of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms with response to atorvastatin and simvastatin in 386 adults (201 atorvastatin-treated and 185 simvastatin-treated) with primary hypercholesterolemia, all of Greek origin. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. Genetic polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A novel RFLP protocol was developed for the simultaneous identification of 388A>G and 411G>A polymorphisms. SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms were not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed on the effect of the analyzed SLCO1B1 polymorphisms in statin lipid lowering response in either statin-treated patient cohort. Further studies in different populations are required to draw firm conclusion on the potential association of SLCO1B1 polymorphisms with statin lipid-lowering response.
Assuntos
Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Pirróis/uso terapêutico , Sinvastatina/uso terapêutico , Adulto , Idoso , Alelos , Atorvastatina , LDL-Colesterol/sangue , Esquema de Medicação , Feminino , Frequência do Gene , Interação Gene-Ambiente , Haplótipos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/sangue , Polimorfismo de Fragmento de RestriçãoRESUMO
OBJECTIVES: Patients with rheumatoid arthritis (RA) have increased cardiovascular risk. The aim of the present study was the assessment of low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass distribution in patients with early RA (ERA, n = 30) compared with age- and sex-matched healthy subjects (n = 30), as well the effect of treatment for 12 months with the disease-modifying anti-rheumatic drugs (DMARDs) methotrexate and prednisone in this distribution. METHOD: LDL and HDL subclass distribution was determined using a polyacrylamide gel-tube electrophoresis method. RESULTS: ERA patients exhibited increased levels of inflammatory markers and high disease activity score. ERA patients had higher serum levels of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG) whereas their serum HDL cholesterol (HDL-C) levels were significantly lower compared with controls. ERA patients exhibited significantly higher plasma levels of small dense LDL-C (sdLDL-C), leading to a significantly decreased mean LDL diameter. ERA patients had significantly decreased small HDL particles (HDL-3) concentration whereas serum levels of large HDL particles (HDL-2) did not differ compared with controls. Treatment with DMARDs resulted in a significant decrease in inflammatory markers and disease activity, along with a significant increase in HDL-C serum levels. The concentration of sdLDL-C did not change significantly during treatment. We observed a significant increase in the levels of large HDL-2 whereas the concentration of small HDL-3 did not significantly change. CONCLUSIONS: Patients with ERA have increased sdLDL-C levels and decreased HDL-C levels because of decreased concentration of the small HDL-3 subclass. The administration of DMARDs induced a significant increase in HDL-C levels, which was attributed to the increase in large HDL-2 serum concentration.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Metotrexato/uso terapêutico , Idoso , Antirreumáticos/farmacologia , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Projetos Piloto , Prednisona/farmacologia , Prednisona/uso terapêuticoRESUMO
The effect of antihypertensive drugs on lipoprotein subfraction profile is still under investigation. In this study the effects of fixed combination of valsartan with either amlodipine (V-A) or hydrochlorothiazide (V-H) on low-density-lipoprotein (LDL) and high-density-lipoprotein (HDL) subfraction profile of patients with stage 2 or 3 hypertension were assessed. A total of 60 drug-naive patients were randomized to either V-A (160/5 mg, n=30) or V-H (160/12.5 mg, n=30). At baseline as well as 16 weeks post-treatment analysis of the LDL and HDL subfraction profile was conducted by using LDL Lipoprint System. Both V-A and V-H effectively reduced blood pressure (BP) to similar levels. An increase in the cholesterol concentration of small-dense LDL subfractions (by 18.2%, P<0.05) was observed in the V-H group, whereas this parameter remained unchanged in the V-A group. Therefore, mean LDL particle size was decreased in the V-H group (from 267 ± 5 to 266 ± 5Å, P<0.05). HDL-Cholesterol (HDL-C) levels were reduced by 4.7% (P<0.05) in the V-H group, mirrored by a reduction in the cholesterol mass of small and intermediate HDL particles. In conclusion, despite similar reductions in BP, V-H combination may adversely affect serum lipids as well as LDL and HDL subfraction profile as compared with V-A.
Assuntos
Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Tetrazóis/administração & dosagem , Valina/análogos & derivados , Adulto , Idoso , Anlodipino/efeitos adversos , Colesterol/sangue , Feminino , Humanos , Hidroclorotiazida/efeitos adversos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Tetrazóis/efeitos adversos , Triglicerídeos/sangue , Valina/administração & dosagem , Valina/efeitos adversos , ValsartanaRESUMO
BACKGROUND AND AIMS: Visfatin is associated with atherosclerosis-related diseases. We assessed in non-diabetic individuals the association of plasma visfatin levels with cardiovascular disease (CVD) risk and the atherosclerosis-related metabolic variables. METHODS AND RESULTS: When study population (n = 179, age 49 ± 11 years) was divided according to visfatin tertiles, the 10-year CVD Framingham risk scores were significantly increased in the top visfatin tertile. We observed a positive association between visfatin tertiles with waist circumference and blood pressure, as well as with total cholesterol and triglyceride levels, but not with apolipoprotein C-III, fibrinogen or pre-beta1 high density lipoprotein (HDL). The percentage of large HDL subclasses was significantly lower and the percentage of small HDL subclasses over the HDL-C concentration was significantly higher in the top visfatin tertile compared with the other tertiles. The atherogenic small dense low density lipoprotein subclasses (sdLDL-C) were significantly increased in the top visfatin tertile compared with the lower tertiles. High sensitivity C-reactive protein (hsCRP) concentration was significantly increased in the top visfatin tertile compared with the lower tertiles. Although age and sex distribution did not differ between visfatin tertiles, the simultaneous adjustment for these parameters attenuated the significance of the differences observed in sdLDL-C and hsCRP levels. Similarly, after adjustment for hsCRP or waist circumference, only triglycerides and blood pressure levels, as well as the distribution of HDL subclasses, remained significantly different between visfatin tertiles. CONCLUSIONS: Our results support a role for visfatin in the detection of subjects with many metabolic abnormalities, which result in increased CVD risk.
Assuntos
Aterosclerose/sangue , Citocinas/sangue , Nicotinamida Fosforribosiltransferase/sangue , Adulto , Idoso , Análise de Variância , Aterosclerose/diagnóstico , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Pressão Sanguínea , Proteína C-Reativa/análise , Distribuição de Qui-Quadrado , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Triglicerídeos/sangue , Regulação para Cima , Circunferência da CinturaRESUMO
BACKGROUND: Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). OBJECTIVE: To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. METHODS: We previously randomised patients with low-density lipoprotein cholesterol (LDL-C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. RESULTS: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL-C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. CONCLUSIONS: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.
Assuntos
Dislipidemias/tratamento farmacológico , Ácidos Graxos Ômega-3/administração & dosagem , Fenofibrato/administração & dosagem , Fluorbenzenos/administração & dosagem , Hipolipemiantes/administração & dosagem , Síndrome Metabólica/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Apolipoproteínas/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Quimioterapia Combinada , Dislipidemias/sangue , Feminino , Humanos , Masculino , Adesão à Medicação , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Rosuvastatina CálcicaRESUMO
Retinol binding protein 4 (RBP(4)) is regarded as a novel cardiometabolic risk factor, which is secreted mainly by the hepatocytes and also by the adipose tissue. RBP(4) has been shown to induce insulin resistance, and plasma RBP(4) values are increased in type 2 diabetes mellitus, obesity, metabolic syndrome, and cardiovascular disease. Moreover, it has been found that circulating RBP(4) decreases during medical interventions that result in amelioration of the metabolic profile, such as diet, exercise, oral antidiabetic drugs, and hypolipidemic agents. However, only few of the RBP(4)-related studies have investigated whether RBP(4) constitutes a causal factor of the above-mentioned metabolic conditions. Importantly, circulating RBP(4) is influenced by some nonmetabolic conditions, such as renal failure, acute illness, injury, and liver failure. Thus, further studies investigating the metabolic roles of RBP(4) should be carefully planned, taking into account the effects of nonmetabolic conditions on circulating RBP(4).
Assuntos
Proteínas de Ligação ao Retinol/metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Resistência à Insulina , Síndrome Metabólica/metabolismo , Obesidade/metabolismoRESUMO
BACKGROUND: The paraoxonase activity of the enzyme paraoxonase-1 (PON-1) associated with high-density lipoprotein (HDL) may significantly influence clopidogrel's antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON-1 activities and the Q192R genotype with clopidogrel's antiplatelet efficacy in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The platelet aggregation, P-selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON-1 Q192R genotype and to serum HDL-cholesterol levels, and PON-1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL-cholesterol levels and PON-1 activities at baseline (before clopidogrel loading) were not altered at 5- and 30-day post-clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non-responders (PRI: 64.2 ± 11.1%). HDL-cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non-responders. Similarly, the platelet activation markers were significantly higher in PON-1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. CONCLUSIONS: PON-1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.
Assuntos
Síndrome Coronariana Aguda/sangue , Arildialquilfosfatase/sangue , Lipoproteínas HDL/sangue , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Arildialquilfosfatase/genética , Sequência de Bases , Moléculas de Adesão Celular/metabolismo , Clopidogrel , Primers do DNA , Feminino , Citometria de Fluxo , Genótipo , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Fosfoproteínas/metabolismo , Fosforilação , Ticlopidina/uso terapêuticoRESUMO
The aim of the study was to compare the efficacy of high-dose rosuvastatin, low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega-3 fatty acids with regard to the lipid profile in patients with mixed hyperlipidemia. The primary endpoint was changes in non-high density lipoprotein-cholesterol (non-HDL-C) levels. Study participants were randomly allocated to receive rosuvastatin 40 mg (n = 30, R group), rosuvastatin 10 mg plus fenofibrate 200 mg (n = 30, RF group) or rosuvastatin 10 mg plus n-3 fatty acids 2 g (n = 30, RN group). Non-HDL-C levels were reduced in all groups: in R group by 54%, in RF group by 42% and in RN group by 42%. Significant reductions in total cholesterol (TC), low density lipoprotein (LDL)-C and triglyceride levels were observed in all groups. The reductions in total and LDL-C were greatest in the R group while a more pronounced reduction of triglycerides in the RF group compared with that in the R and the RN group was observed. HDL-C levels were significantly increased only in the RF group. In conclusion, high doses of rosuvastatin and small doses of rosuvastatin plus either fenofibrate or n-3 fatty acids exhibit favorable effects on both LDL-C and non-HDL-C levels. However, rosuvastatin monotherapy more potently reduces these parameters. The combination of rosuvastatin plus fenofibrate leads to a greater decrease in triglyceride levels and a greater increase in HDL-C levels compared with the other two treatments. While awaiting the results of ongoing trials high doses of rosuvastatin may represent the treatment of choice in individuals with mixed dyslipidemia.
Assuntos
Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Fenofibrato/uso terapêutico , Fluorbenzenos/uso terapêutico , Hipolipemiantes/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Feminino , Humanos , Masculino , Rosuvastatina CálcicaAssuntos
Síndrome Coronariana Aguda/fisiopatologia , Plaquetas/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Trombose/tratamento farmacológico , Ticlopidina/análogos & derivados , Síndrome Coronariana Aguda/complicações , Idoso , Plaquetas/fisiologia , Clopidogrel , Feminino , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/complicações , Trombose/fisiopatologia , Ticlopidina/farmacologia , Ticlopidina/uso terapêuticoRESUMO
BACKGROUND: Adipose tissue-derived leptin and adiponectin control hunger, energy expenditure, insulin sensitivity, endothelial function, reproduction and immunity and are thought to play a role in autoimmune diseases. However, their role in ankylosing spondylitis (AS) is not clearly defined. Tumour necrosis factor ΤNF-α is a potential modulator of adipocytokines. The effect of longterm anti-TNF-α treatment on plasma levels of leptin and adiponectin has not been assessed so far. OBJECTIVES: To assess the effect of a 6-month anti-TNF-α treatment on serum leptin and adiponectin levels in AS patients. METHODS: Thirty men with AS were included in the study. Thirty age- and weight-matched men served as controls. Clinical and biochemical parameters were assessed and serum levels of leptin and adiponectin were measured with enzyme immunoassay methods prior to and after the 6-month treatment with infliximab. RESULTS: Mean age and disease duration of AS patients were 40.6±13.7 and 13.4±8.4 years, respectively. At baseline, AS patients exhibited significantly higher adiponectin (15.4±8.3 vs. 8.6±4.2 µg/ml, p<0.05), but no difference in leptin levels (7.2±2.9 vs. 8.9±6.4 ng/ml, p=NS). Adipocytokines did not correlate with any disease parameter. Body weight of the patients did not change significantly over the 6-month period. Serum levels of leptin and adiponectin did not change significantly after the 6-month treatment. CONCLUSIONS: Adiponectin levels were significantly higher in AS patients compared with controls. Infliximab treatment did not change serum levels of leptin and adiponectin suggesting that the anti-TNF-α treatment may not modulate significantly their levels.
Assuntos
Adiponectina/sangue , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Leptina/sangue , Espondilite Anquilosante/sangue , Espondilite Anquilosante/tratamento farmacológico , Adulto , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To evaluate the effects of acute infection with Epstein-Barr virus (infectious mononucleosis, IM) on lipids and lipoproteins. METHODS: Fasting serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), apolipoproteins (apo) A-I, B, E, C-II, C-III and lipoprotein (a) [Lp(a)] were determined in patients with IM on diagnosis and 4 months after the resolution of febrile illness and in age- and sex-matched controls. Activities of cholesteryl-ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) as well as levels of several cytokines were determined. LDL subclass analysis was performed with the Lipoprint LDL System. RESULTS: Twenty-nine patients (16 males, aged 24.3±14.6 years) and 30 controls were included. TC, HDL-C, LDL-C, apoA-I, apoB, apoC-III and Lp(a) levels were lower at baseline whereas apoB/apoA-I ratio, TG levels and CETP activity were elevated compared with 4 months later. At baseline, higher levels in cytokines and the cholesterol concentration of small-dense LDL particles (sdLDL-C) were noticed, whereas LDL particle size was lower compared with follow-up. Activities of Lp-PLA2 and PON1 were similar at baseline and 4 months later. Four months after the resolution of IM levels of TGs, apoE, apoC-III, Lp(a), sdLDL-C and cytokines as well as LDL particle size, apoB/apoA-I ratio, CETP and Lp-PLA2 activities were similar to controls. PON1 activities both at baseline and 4 months later were lower in patients compared with controls. CONCLUSIONS: IM is associated with atherogenic changes of lipids and lipoproteins that are partially restored 4 months after its resolution.
Assuntos
Aterosclerose/sangue , Infecções por Vírus Epstein-Barr/sangue , Lipídeos/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Adolescente , Adulto , Arildialquilfosfatase/sangue , Estudos de Casos e Controles , Criança , Proteínas de Transferência de Ésteres de Colesterol/biossíntese , Feminino , Febre , Humanos , Inflamação , Lipoproteínas/química , MasculinoRESUMO
Serum lipid changes during infection may be associated with atherogenesis. No data are available on the effect of Brucellosis on lipids. Lipid parameters were determined in 28 patients with Brucellosis on admission and 4 months following treatment and were compared with 24 matched controls. Fasting levels of total cholesterol (TC), HDL-cholesterol (HDL-C), triglycerides, apolipoproteins (Apo) A, B, E CII, and CIII, and oxidized LDL (oxLDL) were measured. Activities of serum cholesterol ester transfer protein (CETP), paraoxonase 1 (PON1), and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and levels of cytokines [interleukins (IL)-1beta, IL-6, and tumor necrosis factor (TNFa)] were also determined. On admission, patients compared with controls had 1) lower levels of TC, HDL-C, LDL-cholesterol (LDL-C), ApoB, ApoAI, and ApoCIII and higher LDL-C/HDL-C and ApoB/ApoAI ratios; 2) higher levels of IL-1b, IL-6, and TNFa; 3) similar ApoCII and oxLDL levels and Lp-PLA(2) activity, lower PON1, and higher CETP activity; and 4) higher small dense LDL-C concentration. Four months later, increases in TC, HDL-C, LDL-C, ApoB, ApoAI, and ApoCIII levels, ApoB/ApoAI ratio, and PON1 activity were noticed compared with baseline, whereas CETP activity decreased. LDL-C/HDL-C ratio, ApoCII, and oxLDL levels, Lp-PLA(2) activity, and small dense LDL-C concentration were not altered. Brucella infection is associated with an atherogenic lipid profile that is not fully restored 4 months following treatment.
Assuntos
Aterosclerose/sangue , Brucella melitensis/fisiologia , Brucelose/sangue , Brucelose/tratamento farmacológico , Lipídeos/sangue , Doença Aguda , Administração Oral , Brucella melitensis/efeitos dos fármacos , Brucelose/diagnóstico , Brucelose/microbiologia , Estudos de Casos e Controles , Doxiciclina/administração & dosagem , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rifampina/administração & dosagem , Rifampina/farmacologia , Rifampina/uso terapêuticoRESUMO
Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P < 0.001 and P < 0.05, respectively). As the number of MetS components increased, the HDL phenotype comprised of a greater percentage of small HDL-3 and less large HDL-2 subclasses, resulting in a decreased HDL-2/HDL-3 ratio (P < 0.001 for all trends). Multivariate analysis revealed that HDL-2 levels and the HDL-2/HDL-3 ratio significantly and independently correlated with HDL-C (positively) and TG (negatively) levels. HDL-3 concentration significantly and independently positively correlated with HDL-C and TG levels. HDL-LpPLA(2) activity was decreased in MetS patients (P < 0.01), a phenomenon that may contribute to the defective antiatherogenic activity of HDL in MetS. PON1 activity did not differ between groups. We conclude that MetS, in addition to the decrease in HDL-C concentration, is associated with alterations in the HDL phenotype, which is comprised of a greater percentage of small HDL subclasses. Furthermore, HDL-LpPLA(2) activity is decreased in MetS patients.
Assuntos
Lipoproteínas HDL/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/enzimologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Arildialquilfosfatase/metabolismo , Feminino , Humanos , Lipoproteínas HDL/classificação , Lipoproteínas LDL/sangue , Lipoproteínas LDL/classificação , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: High-density lipoprotein (HDL) includes discrete subfractions. HDL exhibits anti-atherogenic properties, which have been partly linked to the activity of HDL-associated enzymes, such as the lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1). OBJECTIVE: We assessed in an open-label randomised study the effect of orlistat and ezetimibe, alone or in combination, on plasma HDL subclasses and HDL-associated enzyme activities in overweight and obese subjects (body mass index > 28 kg/m(2)) with hypercholesterolemia [total cholesterol > 200 mg/100 ml (5.2 mmol/l)]. METHODS: Eighty-six people were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, three times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. HDL subfractions were determined using a polyacrylamide gel-tube electrophoresis method. RESULTS: Levels of HDL cholesterol (HDL-C) and apolipoprotein AI did not change significantly in any group. In group O the cholesterol concentration of HDL-2 subclass increased significantly, while the cholesterol of HDL-3 subclass decreased significantly. In groups E and OE HDL-2 subclass did not significantly change, while the cholesterol concentration of HDL-3 subclass decreased significantly. We observed a non-significant decrease in the HDL-LpPLA(2) and PON1 activity in all groups. However, the ratios of both enzyme activities to low-density lipoprotein cholesterol (LDL-C) levels (an index of atherogenicity) significantly increased in all groups. CONCLUSION: Although HDL-C levels did not change after treatment with orlistat and ezetimibe, alone or in combination, there were alterations of the HDL-2 and HDL-3 subclasses. The activity of HDL-LpPLA(2) and PON1 per mg LDL-C increased significantly in all groups.
Assuntos
Azetidinas/uso terapêutico , Hiperlipidemias/terapia , Lactonas/uso terapêutico , Obesidade/terapia , Adulto , Fármacos Antiobesidade/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Arildialquilfosfatase/metabolismo , Índice de Massa Corporal , HDL-Colesterol/sangue , Dieta com Restrição de Gorduras , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Ezetimiba , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/enzimologia , Modelos Lineares , Lipoproteínas HDL2/sangue , Lipoproteínas HDL3/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/enzimologia , Orlistate , Fosfolipases A2/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Increased concentrations of low density lipoprotein cholesterol (LDL-C), as well as of small dense LDL-C (sdLDL-C), are considered as cardiovascular risk factors. OBJECTIVE: An assessment of the effects of ezetimibe and orlistat administration, alone or in combination, on LDL-C and sdLDL-C levels (primary endpoint), as well as on anthropometric variables and metabolic parameters (secondary endpoints) in overweight and obese patients [body mass index (BMI)>28 kg/m(2)] with hypercholesterolaemia [total cholesterol>200 mg/dL (5.2 mmol/L)]. METHODS: Eighty six subjects were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, 3 times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. RESULTS: Significant reductions in LDL-C (-19%, -21%, -32% in groups O, E and OE, respectively, all p<0.01 vs. baseline) and sdLDL-C levels (-45%, -48%, -76% in groups O, E, OE, respectively, all p<0.01 vs. baseline) were observed. Group OE experienced a significantly greater reduction in LDL-C and sdLDL-C levels compared with groups O and E (p<0.05). Furthermore, significant reductions of BMI, homeostasis model assessment (HOMA) index, serum uric acid, transaminase activities and plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity were observed in the O and OE groups. Gamma-glutamyl transpeptidase activity and Lp-PLA(2) activity improved significantly more with the combination treatment compared with either orlistat or ezetimibe monotherapy. CONCLUSIONS: Orlistat and ezetimibe combination had a more favourable effect on LDL-C and sdLDL-C levels in overweight and obese hypercholesterolaemic patients than either drug alone. Furthermore, orlistat, alone or in combination with ezetimibe, additionally improved several anthropometric and metabolic variables.