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1.
J Lipid Res ; 54(2): 467-72, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23172660

RESUMO

Estimation of low-density lipoprotein cholesterol (LDL-C) using the Friedewald (FR) formula is often inaccurate when triglycerides are elevated or VLDL particle composition is altered. We hypothesized that LDL-C estimation by the FR formula and other measurement methods might also be inaccurate in individuals treated with a cholesteryl ester transfer protein (CETP) inhibitor. An assay comparison study was conducted using pre and posttreatment serum samples from 280 of the 811 patients treated with the CETP inhibitor anacetrapib in the DEFINE study (determining the efficacy and tolerability of CETP inhibition with anacetrapib). After 24 weeks of treatment with anacetrapib, mean LDL-C values by FR formula, Roche direct method (RDM) and Genzyme direct method (GDM) deviated from that measured by the ß-quantification (BQ) reference method by -12.2 ± 7.5, -10.2 ± 6.6, -10.8 ± 8.8 mg/dl, respectively. After treatment with anacetrapib, the FR formula and detergent-based direct methods provided lower LDL-C values than those obtained by the BQ reference method. The bias by the FR formula appeared to be due to an overestimation of VLDL-C by the TG/5 component of the formula. Evaluation of the clinical significance of these findings awaits comprehensive lipid and cardiovascular outcome data from ongoing Phase III clinical studies of anacetrapib.


Assuntos
Análise Química do Sangue/métodos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , LDL-Colesterol/sangue , Oxazolidinonas/farmacologia , Idoso , Análise Química do Sangue/normas , Precipitação Química , HDL-Colesterol/sangue , HDL-Colesterol/isolamento & purificação , LDL-Colesterol/isolamento & purificação , Ensaios Clínicos como Assunto , Sulfato de Dextrana/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Fatores de Tempo , Ultracentrifugação
2.
Int J Clin Pharmacol Ther ; 50(8): 584-94, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22578199

RESUMO

OBJECTIVE: To assess and validate the application of a non-radioactive assay for cholesteryl ester transfer protein (CETP) activity in clinical samples. DESIGN AND METHODS: In this Phase 0 study, CETP activity was measured following addition of the CETP inhibitor JNJ-28545595 to plasma samples from normolipidemic and three subgroups of dyslipidemic subjects with differing lipid profiles. RESULTS: CETP activity was elevated in plasma samples from dyslipidemic subjects compared to normolipidemic subjects. Increased triglyceride levels correlated with decreased CETP inhibition. The assay was found to have good analytical precision and high throughput potential as required for clinical trial sample analysis. CONCLUSIONS: The results demonstrate that pharmacological inhibition of CETP is affected by the dyslipidemic nature of plasma samples. In addition, since the optimal degree of CETP inhibition for maximal cardiovascular benefit in patients is not known, this assay may be used to help define optimal dosing of CETP inhibitors.


Assuntos
Bioensaio/métodos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Dislipidemias/sangue , Lipídeos/sangue , Adulto , Idoso , Proteínas de Transferência de Ésteres de Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue
3.
Clin Chem ; 57(3): 490-501, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21228254

RESUMO

BACKGROUND: Our objective was to evaluate the accuracy of cardiovascular disease (CVD) risk score classification by direct LDL cholesterol (dLDL-C), calculated LDL cholesterol (cLDL-C), and non-HDL cholesterol (non-HDL-C) compared to classification by reference measurement procedures (RMPs) performed at the CDC. METHODS: We examined 175 individuals, including 138 with CVD or conditions that may affect LDL-C measurement. dLDL-C measurements were performed using Denka, Kyowa, Sekisui, Serotec, Sysmex, UMA, and Wako reagents. cLDL-C was calculated by the Friedewald equation, using each manufacturer's direct HDL-C assay measurements, and total cholesterol and triglyceride measurements by Roche and Siemens (Advia) assays, respectively. RESULTS: For participants with triglycerides<2.26 mmol/L (<200 mg/dL), the overall misclassification rate for the CVD risk score ranged from 5% to 17% for cLDL-C methods and 8% to 26% for dLDL-C methods when compared to the RMP. Only Wako dLDL-C had fewer misclassifications than its corresponding cLDL-C method (8% vs 17%; P<0.05). Non-HDL-C assays misclassified fewer patients than dLDL-C for 4 of 8 methods (P<0.05). For participants with triglycerides≥2.26 mmol/L (≥200 mg/dL) and<4.52 mmol/L (<400 mg/dL), dLDL-C methods, in general, performed better than cLDL-C methods, and non-HDL-C methods showed better correspondence to the RMP for CVD risk score than either dLDL-C or cLDL-C methods. CONCLUSIONS: Except for hypertriglyceridemic individuals, 7 of 8 dLDL-C methods failed to show improved CVD risk score classification over the corresponding cLDL-C methods. Non-HDL-C showed overall the best concordance with the RMP for CVD risk score classification of both normal and hypertriglyceridemic individuals.


Assuntos
Doenças Cardiovasculares/classificação , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Triglicerídeos/sangue , Análise Química do Sangue/métodos , Análise Química do Sangue/normas , Análise Química do Sangue/estatística & dados numéricos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Interpretação Estatística de Dados , Dislipidemias/complicações , Jejum/sangue , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Ultracentrifugação
4.
Clin Chem ; 56(6): 977-86, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20378768

RESUMO

BACKGROUND: Methods from 7 manufacturers and 1 distributor for directly measuring HDL cholesterol (C) and LDL-C were evaluated for imprecision, trueness, total error, and specificity in nonfrozen serum samples. METHODS: We performed each direct method according to the manufacturer's instructions, using a Roche/Hitachi 917 analyzer, and compared the results with those obtained with reference measurement procedures for HDL-C and LDL-C. Imprecision was estimated for 35 runs performed with frozen pooled serum specimens and triplicate measurements on each individual sample. Sera from 37 individuals without disease and 138 with disease (primarily dyslipidemic and cardiovascular) were measured by each method. Trueness and total error were evaluated from the difference between the direct methods and reference measurement procedures. Specificity was evaluated from the dispersion in differences observed. RESULTS: Imprecision data based on 4 frozen serum pools showed total CVs <3.7% for HDL-C and <4.4% for LDL-C. Bias for the nondiseased group ranged from -5.4% to 4.8% for HDL-C and from -6.8% to 1.1% for LDL-C, and for the diseased group from -8.6% to 8.8% for HDL-C and from -11.8% to 4.1% for LDL-C. Total error for the nondiseased group ranged from -13.4% to 13.6% for HDL-C and from -13.3% to 13.5% for LDL-C, and for the diseased group from -19.8% to 36.3% for HDL-C and from -26.6% to 31.9% for LDL-C. CONCLUSIONS: Six of 8 HDL-C and 5 of 8 LDL-C direct methods met the National Cholesterol Education Program total error goals for nondiseased individuals. All the methods failed to meet these goals for diseased individuals, however, because of lack of specificity toward abnormal lipoproteins.


Assuntos
Análise Química do Sangue/métodos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Humanos , Padrões de Referência , Sensibilidade e Especificidade , Ultracentrifugação
5.
J Clin Endocrinol Metab ; 92(12): 4671-7, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17726081

RESUMO

CONTEXT: In preclinical models, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase have been shown to positively affect bone remodeling balance. Observational studies and secondary analyses from lipid-lowering trials have yielded inconsistent results regarding the effect of these agents on bone mineral density and fracture risk. OBJECTIVE: Our objective was to determine whether clinically significant skeletal benefits result from hydroxymethylglutaryl-coenzyme A reductase inhibition in postmenopausal women. DESIGN AND SETTING: We conducted a prospective, randomized, double-blind, placebo-controlled, dose-ranging comparative clinical trial at 62 sites in the United States. PARTICIPANTS: Participants included 626 postmenopausal women with low-density lipoprotein cholesterol levels of at least 130 mg/dl (3.4 mmol/liter) and less than 190 mg/dl (4.9 mmol/liter), and lumbar (L1-L4) spine bone mineral density T-score between 0.0 and -2.5. INTERVENTION: Once-daily placebo or 10, 20, 40, or 80 mg atorvastatin was administered. MAIN OUTCOME MEASURES: We assessed percent change from baseline in lumbar (L1-L4) spine bone mineral density with each dose of atorvastatin compared with placebo. RESULTS: At 52 wk, there was no significant difference between each atorvastatin and placebo group or change from baseline at any tested dose of atorvastatin or placebo in lumbar (L1-L4) spine bone mineral density. Nor did atorvastatin produce a significant change in bone mineral density at any other site. Changes in biochemical markers of bone turnover did not differ significantly between each atorvastatin and placebo group. All doses of atorvastatin were generally well tolerated, with similar incidences of adverse events across all dose groups and placebo. CONCLUSIONS: Clinically relevant doses of atorvastatin that lower lipid levels had no effect on bone mineral density or biochemical indices of bone metabolism in this study, suggesting that such oral agents are not useful in the prevention or treatment of osteoporosis.


Assuntos
Osso e Ossos/patologia , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pós-Menopausa/fisiologia , Pirróis/uso terapêutico , Absorciometria de Fóton , Adulto , Idoso , Atorvastatina , Biomarcadores , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Lipídeos/sangue , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/metabolismo
6.
Metabolism ; 53(2): 159-64, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14767866

RESUMO

In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 +/- 0.48 v 9.46 +/- 0.47 mmol/L, P <.001) and the combined SU and metformin therapy group (14.09 +/- 0.51 v 10.57 +/- 0.85 mmol/L, P =.001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 +/- 0.09 v 0.34 +/- 0.07 mmol/L, P =.02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 +/- 19 v 446 +/- 18 ng/mL, P =.02) and the combined SU and metformin therapy group (496 +/- 29 v 456 +/- 31 ng/mL, P =.05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Idoso , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/epidemiologia , Colesterol/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangue
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