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1.
Atherosclerosis ; 157(1): 137-44, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11427213

RESUMEN

Although acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce lipid levels in several animal models, the safety and lipid modifying activity of any single agent in this class has not been demonstrated in humans. The safety and efficacy of avasimibe (CI-1011), a new, unique, wholly synthetic ACAT inhibitor, was evaluated in the treatment of 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia (low levels of high-density lipoprotein cholesterol [HDL-C]). Following an 8-week placebo and dietary-controlled baseline period, patients were randomly assigned to double-blind treatment with placebo, 50, 125, 250, or 500 mg avasimibe administered as capsules once daily for 8 weeks. At all evaluated doses, avasimibe treatment resulted in prompt and significant reductions (P<0.05) in plasma levels of total triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-C) with mean reductions of up to 23% and 30% respectively, apparently independent of dose. No statistically significant changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C or apolipoprotein (apo) B were detected. ApoAI levels were also unchanged on all doses of avasimibe apart from the 500 mg dosage, which was associated with a significant decrease in plasma apoAI. The relevance of this latter finding in only one dosage group is not known. All doses of avasimibe were well tolerated with no resulting significant abnormalities of biochemical, hematological, or clinical parameters.


Asunto(s)
Acetatos/administración & dosificación , Hiperlipidemia Familiar Combinada/tratamiento farmacológico , Hipolipemiantes/administración & dosificación , Ácidos Sulfónicos/administración & dosificación , Acetamidas , Acetatos/efectos adversos , Adulto , Anciano , Método Doble Ciego , Femenino , Humanos , Hiperlipidemia Familiar Combinada/sangre , Hipolipemiantes/efectos adversos , Lípidos/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Esterol O-Aciltransferasa/antagonistas & inhibidores , Sulfonamidas , Ácidos Sulfónicos/efectos adversos , Resultado del Tratamiento
3.
Arterioscler Thromb Vasc Biol ; 19(6): 1512-7, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10364083

RESUMEN

The relationship between atheroma lipid composition and serum lipoprotein and oxidation measurements has not been fully explored. To address this question, we studied serum, plasma, and aortic wall specimens from 66 subjects undergoing coronary artery bypass graft surgery. The lipid composition of aortic specimens was characterized in terms of cholesterol ester and cholesterol crystal plus phospholipid by using hot-stage polarizing light microscopy; tissue oxidation status was assessed by measuring conjugated dienes. Serum lipoprotein-related measurements included total cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apolipoproteins B and AI, and lipoprotein(a). Oxidation status was assessed by measuring LDL mobility, thiobarbituric acid-reactive substances, LDL conjugated dienes, and IgG and IgM autoantibodies against oxidized LDL. Fasting blood glucose was also determined. Lesion cholesterol crystal plus phospholipid content was associated inversely with serum HDL cholesterol levels (r=-0.279, P=0.029) and positively with fasting blood glucose (r=0.359, P=0.016), LDL mobility (0.276, P<0.05), and IgM autoantibodies against oxidized LDL (r=0.272, P=0.037). There was also a significant relationship between the level of aortic tissue conjugated dienes and plasma LDL mobility (r=0.332, P=0.007). In multivariate analysis, IgM autoantibodies against oxidized LDL, fasting blood glucose, and LDL mobility, in descending order of significance, together accounted for 35% of the variability in aortic lesion cholesterol crystal plus phospholipid content. These data support direct and independent roles for oxidation and hyperglycemia in the pathophysiology of atherosclerosis.


Asunto(s)
Arteriosclerosis/metabolismo , Puente de Arteria Coronaria , Lípidos/análisis , Lipoproteínas/metabolismo , Anciano , Autoanticuerpos/sangre , Ésteres del Colesterol/metabolismo , Femenino , Humanos , Inmunoglobulina M/sangre , Lipoproteínas LDL/inmunología , Masculino , Persona de Mediana Edad , Oxidación-Reducción
4.
Circulation ; 94(12): 3239-45, 1996 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-8989135

RESUMEN

BACKGROUND: Heterozygous lipoprotein lipase (LPL) deficiency has been associated with familial hypertriglyceridemia and familial combined hyperlipidemia. Studies of heterozygotes with LPL gene defects at amino acid residues 188 and 207 showed higher triglycerides (TG) and lower HDL cholesterol (HDL-C), with no elevation in LDL cholesterol (LDL-C). Other LPL defects may reveal alternate clinical phenotypes. METHODS AND RESULTS: We evaluated three families with defects at amino acid residues 64, 194, and 188. Thirty-eight heterozygotes (8 with defect 64, 14 with defect 194, and 16 with defect 188) and 95 family members without defects were studied. Plasma lipid, lipoprotein, and apolipoprotein (apo) values were measured, as well as blood pressure. Pooled carriers demonstrated higher systolic blood pressure (SBP) (127 versus 116 mm Hg, P < .0001) and TG (160 versus 125 mg/dL, P = .004) and lower HDL-C (44 versus 52 mg/dL, P = .001) than did noncarriers. A comparison of the 188 carriers and noncarriers revealed the most striking phenotypic characteristics, with lower HDL-C (36 versus 51 mg/dL, P < .0001) and HDL-C/(apo A-I + apo A-II) (0.21 versus 0.24, P = .002) and higher TG (206 versus 123 mg/dL, P = .0003), SBP (132 versus 116 mm Hg, P = .0004), and apo B/LDL-C (1.12 versus 0.93, P < .0001). CONCLUSIONS: These data confirm past observations that LPL deficient heterozygotes trend toward lower HDL-C and higher TG levels while potentially expressing higher SBP. These data also implicate the specific LPL gene defect as a contributing factor to the variable expression of HDL-C, TG, and SBP.


Asunto(s)
LDL-Colesterol/sangre , Tamización de Portadores Genéticos , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/fisiopatología , Lipoproteína Lipasa/genética , Mutación Puntual , Sístole , Triglicéridos/sangre , Adulto , Presión Sanguínea , Índice de Masa Corporal , Exones , Ácido Glutámico , Glicina , Humanos , Hiperlipoproteinemia Tipo I/sangre , Isoleucina , Treonina , Triptófano
5.
Am J Cardiol ; 77(14): 1232-4, 1996 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-8651103

RESUMEN

Measurement of low-density lipoprotein cholesterol during acute myocardial infarction in nonfasting patients on initial presentation to an emergency room by any of 3 methods (ultracentrifugation, immunoseparation, or the Friedewald estimate), identifies patients eligible for antilipemic interventions. Although slightly less sensitive, the conventional Friedewald estimate of low-density lipoprotein cholesterol levels provides clinicians good correlation with ultracentrifugation.


Asunto(s)
LDL-Colesterol/sangre , Servicio de Urgencia en Hospital , Infarto del Miocardio/sangre , Análisis Químico de la Sangre/métodos , Humanos , Admisión del Paciente
6.
JAMA ; 275(15): 1161-4, 1996 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-8609682

RESUMEN

OBJECTIVE: To determine the extent to which geographic variation in invasive cardiac procedures can be explained by the variable use of diagnostic testing. DESIGN: A population-based cohort study using Medicare Part B data (physician services). SETTING AND SUBJECTS: Procedure data for all Medicare beneficiaries in northern New England. MAIN OUTCOME MEASURES: Twelve coronary angiography service areas were constructed for Medicare beneficiaries in northern New England. Age- and sex-adjusted utilization rates were developed for three procedure categories: total stress test, coronary angiography, and revascularization. Total stress tests were further stratified into nonimaging and imaging procedures (eg, thallium). Tests performed in follow-up to invasive procedures were excluded (eg, stress test following revascularizations). Linear regression was used to assess the relationship between procedure categories. RESULTS: A tight positive relationship was found between total stress test rates and the rates of subsequent coronary angiography (R2=0.61, P<.005). Most of the variance was explained by imaging stress tests (R2=0.50, P<.02). A strong relationship was found between coronary angiography and revascularization (R2=0.82, P<.001). Finally, a clear relationship between total stress tests and subsequent revascularizations was also found (R2=0.55, P<.006). CONCLUSION: The population-based rates of diagnostic testing largely explained the variance associated with subsequent therapeutic interventions. Our results suggest that local testing intensity is an important determinant of the variable use of invasive cardiac procedures.


Asunto(s)
Angiografía Coronaria/estadística & datos numéricos , Prueba de Esfuerzo/estadística & datos numéricos , Revascularización Miocárdica/estadística & datos numéricos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , Estudios de Cohortes , Diagnóstico por Imagen/estadística & datos numéricos , Humanos , Modelos Lineales , Medicare Part B/estadística & datos numéricos , New England , Estados Unidos , Revisión de Utilización de Recursos
7.
Ann Intern Med ; 124(4): 425-8, 1996 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-8554252

RESUMEN

OBJECTIVE: To explore genetic mechanisms for pregnancy-associated pancreatitis and hyperlipidemia in two sisters. DESIGN: Case history. SETTING: Tertiary care facility with outpatient follow-up. PATIENTS: Two sisters with acute pancreatitis and the acute respiratory distress syndrome were admitted (patient 1) or transferred (patient 2) to an intensive care setting with severely elevated triglyceride levels. Patient 1 was in the last trimester of pregnancy; patient 2 was 1 month postpartum. Both patients were of French Canadian ancestry. INTERVENTION: Acute treatment was directed at stabilizing both patients medically (with fat restriction) and one patient surgically (patient 2). Treatment with fat restriction, weight loss, and gemfibrozil was continued after hospitalization. RESULTS: Through DNA sequencing, we detected a mutation at amino acid residue 188 of lipoprotein lipase (LPL), reflecting product from one allele of the LPL gene in which a glutamine residue was substituted for a glycine (gly 188-->glu). CONCLUSION: LPL plays a key role in regulating triglyceride levels in pregnancy. Mutations of LPL may place the patient at risk for pancreatitis. This heterozygous LPL mutation, gly 188-->glu, is prevalent in certain ethnic groups and may be a common cause of pancreatitis associated with pregnancy.


Asunto(s)
Hiperlipidemias/genética , Lipoproteína Lipasa/genética , Pancreatitis/genética , Mutación Puntual , Complicaciones del Embarazo , Adulto , Femenino , Heterocigoto , Humanos , Embarazo
8.
JAMA ; 275(2): 128-33, 1996 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-8531308

RESUMEN

OBJECTIVE: To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements. DESIGN: Randomized double-blind, placebo-controlled, parallel-group, multicenter trial. SETTING: Community- and university-based research centers. PATIENTS: A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL). INTERVENTIONS: Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo. MAIN OUTCOME MEASURES: Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo. RESULTS: Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen. CONCLUSIONS: In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.


Asunto(s)
Anticolesterolemiantes/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipertrigliceridemia/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Anticolesterolemiantes/administración & dosificación , Atorvastatina , Dieta con Restricción de Grasas , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inhibidores Enzimáticos/uso terapéutico , Femenino , Ácidos Heptanoicos/administración & dosificación , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/dietoterapia , Modelos Lineales , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Triglicéridos/sangre
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