RESUMO
Inflammation is a well-documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C-reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (≥20 µg/L) (OR: 1.29; 95% CI: 1.06-1.56, 1.32; 1.05-1.65 and 1.51; 1.26-1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10-1.74, 1.50; 1.17-1.93 and 1.25; 1.00-1.56, respectively). Albumin was positively associated with Gleason 4 + 3 tumour (1.38; 1.02-1.86) and overall death (HRunit increase in log : 1.60; 95% CI: 1.11-2.30), but inversely associated with high risk PCa and high PSA levels (≥20 µg/L) (0.71; 0.56-0.89 and 0.72; 0.5 9-0.90). WBC was associated with increased odds of T3-T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity.
Assuntos
Biomarcadores/sangue , Mediadores da Inflamação/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Idoso , Proteína C-Reativa , Haptoglobinas , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mortalidade , Gradação de Tumores , Razão de Chances , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Sistema de Registros , Índice de Gravidade de Doença , Suécia/epidemiologiaRESUMO
Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, 'decontaminated' of the effects of informative censoring, and which includes Cox, random effects and latent class models as special cases. Simulated data confirm that our approach can map a cohort's substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Modelos Estatísticos , Medição de Risco , Apolipoproteínas/sangue , Teorema de Bayes , Neoplasias da Mama/complicações , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Feminino , Humanos , Estudos Longitudinais , Masculino , Modelos de Riscos Proporcionais , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Análise de Sobrevida , Suécia/epidemiologiaRESUMO
BACKGROUND AND AIMS: Both high and low fasting glucose has been associated with an increased mortality among individuals without diabetes. This J-shaped association has also been shown for HbA1c in relation to all-cause mortality. High fructosamine is associated with increased mortality. In this study we aim to evaluate if low fructosamine is also associated with increased mortality in non-diabetic subjects. METHODS AND RESULTS: We included 215,011 subjects from the AMORIS cohort undergoing occupational health screening or primary care in Stockholm, Sweden. Cause specific mortality was obtained from the Swedish Cause-of-Death Register by record linkage. Hazard ratios for the lowest decile of fructosamine were estimated by Cox regression for all-cause (n = 41,388 deaths) and cause-specific mortality during 25 years of follow-up. We observed gradually increased mortality with lower fructosamine in a large segment of the population. In the lowest decile of fructosamine the sex, age, social class and calendar adjusted hazard ratio was 1.20 (95% CI; 1.18-1.27) compared to deciles 2-9. This increased mortality was attenuated after adjustment for six other biomarkers (HR = 1.11 (95% CI; 1.07-1.15)). Haptoglobin, an indicator of chronic inflammation, made the greatest difference in the point estimate. In sensitivity analyses we found an association between low fructosamine and smoking and adjustment for smoking further attenuated the association between low fructosamine and mortality. CONCLUSION: Low levels of fructosamine in individuals without diabetes were found to be associated with increased mortality. Smoking and chronic inflammation seem to at least partially explain this association but an independent contribution by low fructosamine cannot be excluded.
Assuntos
Frutosamina/sangue , Inflamação/mortalidade , Fumar/mortalidade , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Causas de Morte , Regulação para Baixo , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Fumar/efeitos adversos , Fumar/sangue , Suécia , Fatores de TempoRESUMO
BACKGROUND AND AIMS: Glycation is linked to microvascular complications of diabetes and also to macrovascular events. Fructosamine is a biomarker of glycation but its associations to macrovascular complications are not well documented. The aim of this study was to evaluate fructosamine as a predictor of myocardial infarction and all-cause mortality in a large population based cohort. METHODS AND RESULTS: Information on glucose and fructosamine was obtained from subjects of the AMORIS cohort (n = 338,443) followed for 19 years on average. Incident cases of myocardial infarction and death from any cause were identified from national patient and cause of death register respectively. The incidence of myocardial infarction (n = 21,526 cases) and all-cause mortality (n = 73,458 deaths) increased at a fructosamine of 2.30 mmol/L or above. For myocardial infarction, the sex-age- fasting- and entry period adjusted hazard ratio in subjects above 2.70 mmol/L vs. reference range subjects was 2.88 (95% CI: 2.70-3.07). The corresponding hazard ratio for all-cause mortality was 2.31 (95% CI: 2.21-2.41). These associations remained basically unchanged after adjustment for total cholesterol, triglycerides, albumin, social class, smoking and hypertension. When additional adjustment for glucose was performed the associations were attenuated but remained. In a sub cohort with simultaneous measurements of fructosamine, HbA1c and fasting glucose respectively similar associations were observed (n = 9746). CONCLUSION: There is a strong association between fructosamine and myocardial infarction and death from any cause when major cardiovascular risk factors are accounted for. In addition, this association could only partly be explained by glucose levels.
Assuntos
Frutosamina/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/mortalidade , Biomarcadores/sangue , Glicemia/análise , Causas de Morte , Estudos de Coortes , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Chronic kidney disease predicts mortality in the general population, but less is known about the association with incidence of first myocardial infarction. We evaluated glomerular filtration rates (GFR) estimated by the Modification of Diet in Renal Disease study (GFR-MDRD) equation and the Mayo formula (GFR-Mayo) as predictors of myocardial infarction and death. METHODS: In 571 353 Swedish men and women, undergoing health controls, with mean age 45 years, and no previous myocardial infarction, hazard ratios were calculated to assess the association between renal function and incidence of myocardial infarction and all-cause mortality, respectively. Glomerular filtration rate 60-90, 30-60 and <30 mL per minute per 1.73 m(2), was defined as mildly, moderately and severely decreased GFR, respectively. RESULTS: There were 19 510 myocardial infarctions and 56 367 deaths during 11.6 years of follow-up. Hazard ratios (and 95% confidence intervals) for myocardial infarction, using GFR-Mayo were 1.11 (1.06-1.16) for mildly, 1.32 (1.18-1.48) for moderately and 2.54 (1.90-3.40) for severely decreased GFR. The corresponding figures for GFR-MDRD were 1.01 (0.96-1.05), 1.23 (1.14-1.32) and 2.49 (1.85-3.35). Mortality was increased at all levels of reduced GFR-Mayo and at moderately or severely decreased GFR-MDRD. CONCLUSIONS: Already mildly decreased GFR increase the risk of myocardial infarction and death in the general population. The association with adverse outcomes is stronger when GFR-Mayo rather than GFR-MDRD is used to assess renal function.
Assuntos
Algoritmos , Taxa de Filtração Glomerular/fisiologia , Nefropatias/complicações , Nefropatias/fisiopatologia , Infarto do Miocárdio/epidemiologia , Adulto , Causas de Morte , Creatinina/sangue , Feminino , Humanos , Incidência , Nefropatias/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Valor Preditivo dos Testes , SuéciaRESUMO
OBJECTIVES: To examine the rates of acute myocardial infarction (AMI) and ischaemic stroke (IS) and to examine the predictive value of total cholesterol (TC) and triglycerides (TG) for AMI and IS in patients with rheumatoid arthritis (RA) and people without RA. METHODS: In the Apolipoprotein MOrtality RISk (AMORIS) Study 480 406 people (including 1779 with RA, of whom 214 had an AMI and 165 an IS) were followed for 11.8 (range 7-17) years. Cox regression analysis was used to calculate HR per SD increase in TC or TG with 95% CI. All values were adjusted for age, diabetes and hypertension. RESULTS: The levels of TC and TG were significantly lower in patients with RA than in people without RA. Despite this, the rate of AMI and IS per 1000 years was at least 1.6 times higher in RA than non-RA. TC was nearly significantly predictive for AMI (HR/SD 1.13 (95% CI 0.99 to 1.29), p=0.07) and significantly predictive for future IS in RA (HR/SD 1.20 (95% CI 1.03 to 1.40), p=0.02). TG had no relationship to development of AMI (1.07, 0.94 to 1.21, p=0.29), but was weakly related to IS (1.13, 0.99 to 1.27, p=0.06). In contrast, both TC and TG were significant predictors of AMI and IS in people without RA. CONCLUSIONS: Patients with RA had 1.6 times higher rate of AMI and IS than people without RA. TC and TG were significant predictors of AMI and IS in people without RA, whereas the predictive value in RA was not consistent.
Assuntos
Artrite Reumatoide/complicações , Lipídeos/sangue , Infarto do Miocárdio/etiologia , Acidente Vascular Cerebral/etiologia , Adulto , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/epidemiologia , Biomarcadores/sangue , Colesterol/sangue , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Prognóstico , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologia , Triglicerídeos/sangueRESUMO
OBJECTIVES: To compare lipoprotein components associated with ischaemic and haemorrhagic stroke by age and gender in the Apolipoprotein MOrtality RISk (AMORIS) Study (n=148 600). DESIGN: Prospective follow-up study (11.8, range 7-17 years) of fatal and nonfatal ischaemic and haemorrhagic stroke through linkage with Swedish hospital discharge and mortality registers. SETTING: Measurements of lipoprotein components from health check-ups in the larger Stockholm area. RESULTS: Ischaemic stroke was more common than haemorrhagic stroke (5 :1), but case fatality was higher in haemorrhagic stroke. An elevated apoB/apoA-1 ratio and triglycerides, non-HDL cholesterol, low HDL cholesterol, and the total cholesterol to high-density cholesterol (TC/HDL-C) ratio were associated with increased incidence of nonfatal and fatal ischaemic stroke as well as all cerebrovascular events (n=7480) in both genders. The associations were somewhat stronger for nonfatal than fatal events. In ischaemic stroke the apoB/apoA-1 ratio was a stronger predictor than the TC/HDL-C ratio in all subjects, in those below 65 years of age and in those with LDL-C below 3 mmol L(-1). Haemorrhagic stroke was not associated with elevated atherogenic lipoproteins except for increased risk of fatal haemorrhagic stroke in women with a high apoB/apoA-I ratio. CONCLUSIONS: Dyslipidaemia is associated with an increased risk of ischaemic stroke but few relations were seen in haemorrhagic stroke. Use of the apoB/apoA-I ratio as a marker of dyslipidaemia is at least as efficient as conventional lipids, for the identification of subjects at increased risk of stroke, especially ischaemic stroke. Practical advantages, fasting is not needed, speak in favour of using apoB and apoA-1 in stroke risk prediction.
Assuntos
Apolipoproteínas/sangue , Colesterol/sangue , Hemorragias Intracranianas/sangue , Isquemia/sangue , Acidente Vascular Cerebral/sangue , Triglicerídeos/sangue , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Hemorragias Intracranianas/mortalidade , Isquemia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/mortalidadeRESUMO
OBJECTIVES: Few studies have simultaneously analysed the influence of elevated serum uric acid (UA) on acute myocardial infarction (AMI), ischaemic and haemorrhagic stroke (IS, HS) and congestive heart failure (CHF) in large healthy populations. We, here, examine UA as a risk factor for AMI, stroke and CHF by age and gender in the Apolipoprotein MOrtality RISk (AMORIS) Study. DESIGN: Prospective study (11.8 years, range 7-17) of fatal and nonfatal acute myocardial infarction, stroke and CHF through linkage with Swedish hospital discharge and mortality registers. SETTINGS: Measurements of uric acid in 417,734 men and women from health check-ups in Stockholm area. RESULTS: There was a gradual increase in risk of AMI, stroke and CHF by increasing UA levels. Women had a stronger relationship between UA and both AMI and IS than men. Predictions of AMI were at least as powerful in the elderly as in the young, but not so for IS. Associations were markedly attenuated when adjusted for total cholesterol, triglycerides, hospital hypertension and diabetes status. The association between UA and HS was U-shaped in both genders. CHF was more strongly related to UA than AMI and stroke and less affected by the adjustment factors. CONCLUSIONS: Already moderate levels of UA appear to be associated with an increased incidence of AMI, stroke and CHF in middle-aged subjects without prior cardiovascular disease. These associations seem to increase gradually from lower to higher levels of UA. UA may be an important complementary indicator of cardiovascular risk in the general population.
Assuntos
Insuficiência Cardíaca/sangue , Infarto do Miocárdio/sangue , Acidente Vascular Cerebral/sangue , Ácido Úrico/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Intervalos de Confiança , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologiaRESUMO
OBJECTIVES: Examine and compare lipoprotein components associated with fatal and nonfatal acute myocardial infarction (AMI) by time period in the Apolipoprotein MOrtality RISk (AMORIS) Study. DESIGN: Prospective follow-up study of nonfatal and fatal myocardial infarction through linkage with Swedish hospital discharge and Swedish mortality registers. SETTING: Measurements of lipoprotein components from health check-ups in the larger Stockholm area. SUBJECTS: The AMORIS subjects (n = 149 121) free of AMI at blood sampling were followed from 1985 to 2002 with respect to n = 6794 first cases of AMI. RESULTS: Hazard ratios of nonfatal and fatal AMI by lipoprotein parameters were highly significant and about equally strong in both genders. Apolipoprotein B (apoB), nonhigh density cholesterol and low density cholesterol predicted nonfatal AMI (NFAMI) better than fatal AMI, but high density cholesterol or apolipoprotein A-1 did not. Atherogenic components were weaker predictors after 1997 than before. In multivariate analyses apoB/apoA-1 was a better predictor than TC/HDL-C. ApoB/apoA-1 added clinically significant information to TC/HDL-C in men as reflected by a net reclassification improvement (NRI) of 9.4% (P < 0.0001). CONCLUSION: ApoB, apoB/apoA-1 and non-HDL-C were found about equally predictive with LDL-C being slightly less, but multivariate analyses showed apoB/apoA-1 to be the strongest predictor. Attenuation of prediction ability between nonfatal and fatal AMI may be due to modern treatment of CHD after a NFAMI and attenuation of hazard ratios after 1997 may be due to selection of lower risk subjects surviving to 1997.
Assuntos
Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Colesterol/sangue , Infarto do Miocárdio/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Métodos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Fatores Sexuais , Suécia/epidemiologiaRESUMO
Twelve male patients with advanced alcoholic cirrhosis of the liver were found to have markedly low serum lipid and lipoprotein concentrations. Serum triglyceride and cholesterol concentrations were about 50% of matched control values. The very low density lipoprotein-triglyceride concentration was only one-third of control values and the cholesterol concentrations in very low density and low density lipoproteins were far below control values. The mean high density lipoprotein cholesterol concentration was not significantly decreased, but in three of 12 patients extremely low values were found. These findings may reflect a failure of lipoprotein synthesis secondary to a bad nutritional state and metabolic disturbances in this advanced stage of liver cirrhosis. By means of the intravenous fat tolerance test with Intralipid it could be shown that substantial amounts of triglycerides could be cleared from the plasma in these patients. However, studies on the long-term Intralipid clearance capacity have to be performed before any general recommendations about the inclusion of fat emulsions in parenteral nutrition of these patients can be made.
Assuntos
Emulsões Gordurosas Intravenosas/metabolismo , Lipoproteínas/sangue , Cirrose Hepática Alcoólica/metabolismo , Idoso , Colesterol/sangue , Ácidos Graxos não Esterificados/sangue , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Cirrose Hepática Alcoólica/complicações , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
In two adolescent patients with acrodermatitis enteropathica fatty acid spectra in serum lipids and adipose tissue and serum lipoprotein concentrations were followed for about 7 yr. One patient was treated by diet and iv infusions of high amounts of linoleic acid and later by different doses of zinc. The other boy was given only varying doses of zinc. Extra supply of linoleic acid raised its concentrations in serum triglycerides, cholesterol esters, phospholipids, and adipose tissue lipids from low to normal or high levels. In both patients linoleic acid in serum lipids was sensible to the dose of zinc, decreasing when it was low and increasing when it was high. Serum triglycerides increased when the supply was low and was normalized when high doses were given. High-density lipoprotein cholesterol, however, remained low throughout the study. We conclude that in acrodermatitis enteropathica zinc thus seems to be of importance in regulating linoleic acid and serum lipoprotein metabolism.
Assuntos
Acrodermatite/dietoterapia , Tecido Adiposo/metabolismo , Ácidos Graxos Insaturados/análise , Gastroenteropatias/dietoterapia , Metabolismo dos Lipídeos , Lipoproteínas/sangue , Zinco/uso terapêutico , Acrodermatite/metabolismo , Adolescente , Ésteres do Colesterol/sangue , Ácidos Graxos Insaturados/administração & dosagem , Gastroenteropatias/metabolismo , Humanos , Ácidos Linoleicos/metabolismo , Lipídeos/sangue , Masculino , Fosfolipídeos/sangue , Triglicerídeos/sangueRESUMO
Previous studies on the possible effects of ascorbic acid on lowering serum triglycerides have given conflicting results. We have treated 9 patients with stable type IV hyperlipoproteinaemia despite adequate dietary treatment with placebo for 1 month, followed by ascorbic acid at 1 g twice daily for another month. Ascorbic acid did not change either triglyceride or cholesterol in whole serum or in any lipoprotein fraction. We conclude that treatment for 1 month with 2 g of ascorbic acid per day has no effects on lowering triglyceride concentrations.
Assuntos
Ácido Ascórbico/uso terapêutico , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Lipoproteínas/sangue , Placebos/uso terapêutico , Adulto , Idoso , Colesterol/sangue , Eletroforese em Gel de Ágar , Humanos , Hiperlipoproteinemia Tipo IV/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
Concentrations of serum lipoprotein lipids and apolipoproteins A-I, A-II and B were determined 3-6 months after myocardial infarction in 116 males below the age of 45 and in 116 age-matched controls. Among single variables the sum of cholesterol concentration in VLDL and LDL divided by the HDL cholesterol level was the best discriminator between patients and controls. The concentrations of serum triglycerides, apolipoprotein B, VLDL triglycerides and cholesterol, serum cholesterol, HDL cholesterol and LDL triglycerides, in that order, were better discriminators than was LDL cholesterol level. Among variables reflecting HDL concentration and composition HDL cholesterol was the best discriminator followed by HDL2 cholesterol, apolipoprotein A-I and the HDL cholesterol/apolipoprotein A-I ratio. Multivariate analysis indicated independent significance of elevated VLDL lipid and LDL cholesterol concentrations, and a decreased HDL cholesterol concentration, in relation to MI. The present data suggest that a disturbed triglyceride metabolism, in addition to elevated LDL and decreased HDL cholesterol levels, has an independent and pathogenetic significance for MI at a young age.
Assuntos
Apolipoproteínas/sangue , Lipoproteínas/sangue , Infarto do Miocárdio/sangue , Adulto , Apolipoproteína A-I , Apolipoproteína A-II , Apolipoproteínas A/sangue , Apolipoproteínas B/sangue , Colesterol/sangue , HDL-Colesterol/sangue , Humanos , Lipoproteínas VLDL/sangue , Masculino , Infarto do Miocárdio/etiologia , Risco , Triglicerídeos/sangueRESUMO
Lipid accumulation in monocyte-originated macrophages in the subendothelial space is an important characteristic of atherosclerotic lesions. Several lines of evidence have indicated that this accumulation occurs as a result of lipid peroxidation. In the present study the ability of probucol to prevent oxidation of low density lipoprotein (LDL) was investigated in 20 hypercholesterolemic individuals taking part in the Probucol Quantitative Regression Swedish Trial (PQRST). The effect of Cu2(+)-induced oxidation of LDL on degradation by macrophages, binding to LDL receptors on fibroblasts and LDL TBARS content was analysed. With LDL isolated from patients on diet alone oxidation led to a 44.3% decreased binding to fibroblasts (P less than 0.001), a ninefold increased uptake in macrophages (P less than 0.001) and a twentyfold increase in TBARS content (P less than 0.001) as compared to native LDL. These values were essentially the same during treatment with cholestyramine alone. However, during treatment with probucol plus cholestyramine exposure of LDL to Cu2+ resulted in an increase in TBARS which was less than 50% (P less than 0.02) of that observed during the other two treatment periods. Furthermore, probucol treatment abolished more than 70% of the decrease in B,E receptor binding to fibroblasts (P less than 0.05) and more than 90% of the increased degradation by macrophages (P less than 0.001) of Cu2+ oxidatively modified LDL.
Assuntos
Hipercolesterolemia/tratamento farmacológico , Lipoproteínas LDL/sangue , Macrófagos/metabolismo , Fenóis/farmacologia , Probucol/farmacologia , Idoso , Células Cultivadas , Colesterol/sangue , Resina de Colestiramina/uso terapêutico , Ácidos Graxos/metabolismo , Feminino , Alimentos Formulados , Humanos , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Probucol/metabolismo , Probucol/uso terapêutico , Receptores de LDL/metabolismoRESUMO
The four-week lipoprotein lowering effect of 0.2 g t.i.d. of BM 15.075 and of 0.5 g t.i.d. of clofibrate was studied in 29 subjects with different types of hyperlipoproteinaemia in a single blind crossover fashion. BM 15.075 decreased very low density lipoproteins (VLDL), triglycerides (TG) and cholesterol concentration in all types of hyperlipoproteinaemia the effect being dependent on initial lipoprotein concentrations. BM 15.075 decreased VLDL triglyceride concentrations on average 20% more than did clofibrate. BM 15.075 decreased low density lipoproteins (LDL) cholesterol concentrations in Type IIA and IIB but did not significantly affect this lipoprotein lipid in type IV hyperlipoproteinaemia. Regression analysis showed that the drug tended to decrease LDL cholesterol if initial concentrations were above 157 mg/100 ml and to increase initially lower levels. No significant differences between BM 15.075 and clofibrate was found in the effect of LDL cholesterol. High density lipoproteins (HDL) cholesterol concentrations were not influenced by BM 15.075. No subjective side effects were noted on BM 15.075. S-ASAT increased and alcaline phosphatases decreased on both treatments.
Assuntos
Hiperlipidemias/metabolismo , Hipolipemiantes/farmacologia , Fenilbutiratos/farmacologia , Benzamidas/farmacologia , Colesterol/sangue , Clofibrato/farmacologia , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Triglicerídeos/sangue , Ácido Úrico/sangueRESUMO
Relatively little is known about the biological mechanisms by which lipoproteins promote atherogenesis. It has, however, been shown that structural modification of low density lipoprotein (LDL), such as by oxidation, results in their uptake and degradation by intimal macrophages and consequently leads to formation of lipid-rich atherosclerotic lesions. The aim of the present investigation was to study the influence of dietary intake of fat, lipoprotein lipid composition, smoking and gender on macrophage degradation of LDL before and after oxidation. The study group consisted of 48 males and 56 females with hyperlipidemia taking part in the open prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). Analysis including lipoprotein determinations, dietary and smoking habit interviews, LDL degradation by macrophages, LDL receptor binding and LDL thiobarbituric acid reactive substance (TBARS) levels before and after copper ion-induced oxidation was done during the pre-andomization phase of the study. Increased plasma and very low density lipoprotein (VLDL) triglyceride levels were associated with an increased macrophage degradation of native LDL, whereas no such association was found after oxidation of LDL. The dietary intake of polyunsaturated fatty acids (PUFA) was also inversely related to the degradation of native LDL by macrophages, but increased the rate at which oxidized LDL was degraded. Smoking and gender did not influence the rate of macrophage degradation of native or oxidized LDL. It is concluded that hypertriglyceridemia is associated with an increased macrophage degradation of LDL. This may represent a mechanism by which hypertriglyceridemia promotes atherosclerosis.
Assuntos
Gorduras na Dieta/metabolismo , Hipertrigliceridemia/fisiopatologia , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Fumar/metabolismo , Adulto , Idoso , Feminino , Humanos , Metabolismo dos Lipídeos , Macrófagos/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
The Probucol Quantitative Regression Swedish Trial (PQRST) investigated the effect of the lipid lowering and antioxidant drug probucol on the development of atherosclerosis in humans. 303 hypercholesterolemic patients were randomized to receive either probucol or placebo, in combination with dietary advice and cholestyramine for a three-year period. Probucol was not found to effect progression regression of femoral atherosclerosis significantly as assessed by quantitative arteriography. To evaluate the effectiveness of probucol as an antioxidant during the study period, detailed analyses were performed on 42 of the randomized patients. During the trial, probucol-treated patients (n = 26) had 15% lower total cholesterol (P < 0.01) and 35% lower high density lipoprotein (HDL) cholesterol (P < 0.0001) compared with controls (n = 16). Low density lipoprotein (LDL) from probucol treated individuals was more resistant to oxidation by Cu2+ as determined by the lag phase for the formation of conjugated dienes (220 +/- 8 vs. 82 +/- 7 min (mean +/- S.E)), showed a 13 times lower formation of lipid peroxides, a 97% reduction in macrophage degradation and close to 90% less decrease in LDL receptor binding following oxidation as compared with controls (P < 0.001 for all differences). The results demonstrate that although probucol provided a significant protection against Cu(2+)-induced oxidative modification of LDL, it lacked effect on the development of femoral atherosclerosis. The relevance of these observations for the proposed role of lipid oxidation in atherosclerosis is discussed.
Assuntos
Anticolesterolemiantes/farmacologia , Arteriosclerose/prevenção & controle , Artéria Femoral , Lipoproteínas LDL/metabolismo , Probucol/uso terapêutico , Adulto , Angiografia , Arteriosclerose/diagnóstico por imagem , Arteriosclerose/patologia , Progressão da Doença , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/efeitos dos fármacos , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Oxirredução/efeitos dos fármacos , Receptores de LDL/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.
Assuntos
Angina Pectoris/tratamento farmacológico , Angina Pectoris/fisiopatologia , Exercício Físico/fisiologia , Felodipino/farmacologia , Nifedipino/farmacologia , Análise de Variância , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Felodipino/uso terapêutico , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Nifedipino/uso terapêuticoRESUMO
The Probucol Quantitative Regression Swedish Trial is being performed to investigate the effects of probucol on atherosclerosis in the femoral artery. Probucol is combined with cholestyramine and dietary management in hypercholesterolemic patients, and the effects of atheroma developing in the femoral artery will be followed by a quantitative angiographic technique. A randomly selected control group is also being managed by dietary therapy and cholestyramine, but receives placebo instead of probucol. The treatment time in this double-blind trial is 3 years, and femoral angiography is performed yearly. Detailed lipoprotein and apolipoprotein analysis are performed at monthly intervals. The basic study design is described here, and some results from the open prerandomization phase of the study are presented.
Assuntos
Arteriosclerose/prevenção & controle , Resina de Colestiramina/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Fenóis/uso terapêutico , Probucol/uso terapêutico , Arteriosclerose/sangue , Arteriosclerose/etiologia , Ensaios Clínicos como Assunto , Terapia Combinada , Quimioterapia Combinada , Feminino , Artéria Femoral , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/dietoterapia , Lipídeos/sangue , Masculino , Placebos , Distribuição Aleatória , Indução de Remissão , Projetos de Pesquisa , SuéciaRESUMO
The Probucol Quantitative Regression Swedish Trial tested whether treatment of hypercholesterolemic persons with probucol for 3 years affected femoral atherosclerosis. The primary end point was the change in atheroma volume estimated as change in lumen volume of the femoral artery assessed by quantitative arteriography. Three hundred three patients with visible atherosclerosis were randomized to probucol 0.5 g, twice daily, or to placebo. All patients were given diet and cholestyramine, 8 to 16 g/day. Twenty-nine patients were excluded because of inadequate primary end point measurements. The mean age of the remaining 274 subjects (158 were men) was 55 years. Seventeen percent had intermittent claudication and 24% had angina pectoris. After 3 years, the probucol-treated patients had 17% lower serum cholesterol, 12% lower low-density lipoprotein cholesterol, 24% lower total high-density lipoprotein cholesterol, and 34% lower high-density lipoprotein2 cholesterol levels than control subjects. All lipoprotein differences between the treatment groups remained highly significant during the trial. There was no statistically significant change in lumen volume between the probucol and the control group. Furthermore, there was no difference between the treatment groups with regard to change in arterial edge roughness or amount of aorto-femoral atherosclerosis; neither were there any differences between the treatment groups with regard to change in ST-segment depressions on exercise tests or ankle/arm blood pressure (secondary end points). In the control group, lumen volume increased (p < 0.001) and roughness of the femoral artery decreased (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)