Effects of gamma-oryzanol on serum lipids and apolipoproteins in dyslipidemic schizophrenics receiving major tranquilizers

The subjects were 20 chronic schizophrenic patients with dyslipidemia (total cholesterol levels greater than or equal to 220 mg/dl, triglycerides greater than or equal to 150 mg/dl, or high-density lipoprotein cholesterol less than or equal to 40 mg/dl) who had been receiving neuroleptics for a mean of ten years. Each patient was given 100 mg of gamma-oryzanol three times daily for 16 weeks. Total cholesterol and low-density lipoprotein cholesterol levels, respectively, decreased significantly, from 204 and 124 mg/dl at baseline to 176 and 101 mg/dl at week 12. High-density lipoprotein cholesterol levels were 36.1 mg/dl at baseline and 35.9 mg/dl at week 12. Apolipoprotein (apo) B levels decreased significantly from 116 mg/dl to 101 mg/dl at week 16; apo A-II levels increased significantly from 31.7 mg/dl to 34.7 mg/dl; and the apo B/apo A-I ratio declined significantly from 0.99 to 0.84. No treatment side effects were recorded. It is concluded that gamma-oryzanol is safe and effective in the treatment of dyslipidemia.     

Efficacy and tolerability of lovastatin in elderly hypercholesterolemic patients.

In a previously published multicenter study (Kannel and associates, 1990), the effects of six months' treatment with lovastatin were evaluated in patients with hypercholesterolemia. In the present report the results from the 144 elderly patients (aged 65 to 83 years) are presented and compared with those from the 343 patients aged less than 65 years. The initial dose of lovastatin was 20 mg daily and could be increased to a maximum of 80 mg/day. After one month of treatment, in both the elderly and younger patients, levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein cholesterol, and triglycerides, and the total cholesterol: high-density lipoprotein (HDL) cholesterol and LDL:HDL [corrected] cholesterol ratios were significantly lower and high-density lipoprotein cholesterol levels were significantly higher. These improvements in the lipid profile were maintained for six months in both patient groups. LDL cholesterol goals of less than 130 mg/dl in patients with coronary heart disease (CHD) or two CHD risk factors and less than 160 mg/dl among the other patients were achieved by 53% of the elderly patients and 40% of the younger patients at one month (P less than 0.01) and by 62% and 47% at six months (P less than 0.01). By the end of the study, the mean daily dose of lovastatin was 35.4 mg for the elderly and 38.4 mg for the younger patients. The drug was generally well tolerated by all patients. The results indicate that both elderly and younger hypercholesterolemic patients respond well to treatment with lovastatin.     

Role of simvastatin as an immunomodulator in type 2 diabetes

OBJECTIVE: To test the hypothesis that simvastatin reduces the levels of circulating immune complexes (ICs) containing modified lipoproteins (mLDLs; mLDL-ICs), which may represent an additional mechanism for the reduced incidence of cardiovascular events in patients treated with simvastatin. RESEARCH DESIGN AND METHODS: A total of 26 patients with type 2 diabetes and triglyceride levels <400 mg/dl who were not receiving lipid-lowering medications or CYP 3A4 inhibitors were enrolled in the study. After 2 weeks on a lipid-lowering diet and exercise, the patients were started on simvastatin 20 mg/day. The dose of simvastatin was adjusted until the levels of LDL cholesterol were < or =100 mg/dl. Blood was collected at baseline, 3 and 6 months after LDL cholesterol levels reached target, and 3 months after stopping simvastatin to measure advanced glycation end product LDL and oxidized LDL antibodies, mLDL-IC, intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), E-selectin, metalloproteinase-1 (MMP-1), lipid profile, liver function tests, creatinine kinase, glucose, and HbA(1c). RESULTS: Twenty-one patients completed the study. Their HbA(1c) remained within 1% of baseline levels. There was a highly significant decrease in mLDL-IC levels after 3 and 6 months of treatment with simvastatin, with a return to near baseline levels after discontinuation. CONCLUSIONS: Simvastatin significantly reduced the concentration of mLDL-IC, probably as a consequence of both a decrease in the formation of mLDL and to a reduction in the titers of mLDL antibodies. This effect is likely to have a beneficial impact in the inflammatory reaction associated with atherosclerosis.     

Low-dose effect of simvastatin (MK-733) on serum lipids, lipoproteins, and apolipoproteins in patients with hypercholesterolemia

The effects of simvastatin (MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum lipids, lipoproteins, and apolipoproteins were investigated in 29 patients (12 men, 17 women, aged 37 to 73) with moderate to severe hypercholesterolemia. It was given in doses of 2.5 mg/day for four months and 5 mg/day for the succeeding four months. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B decreased by 18% (263 +/- 7 mg/dl to 216 +/- 7 mg/dl, P less than 0.01), 24% (180 +/- 7 mg/dl to 136 +/- 7 mg/dl, P less than 0.01), and 21% (133 +/- 4 mg/dl to 104 +/- 3 mg/dl, P less than 0.01), respectively, four months after treatment. Similar reductions (17%, 24%, and 23%, respectively, P less than 0.01) were observed at eight months. A significant reduction in triglyceride (TG) was observed (173 +/- 15 mg/dl to 136 +/- 11 mg/dl at eight months, P less than 0.01), as was a significant increase in serum high-density lipoprotein cholesterol (HDL-C) (48 +/- 2 mg/dl to 52 +/- 2 mg/dl at eight months, P less than 0.01). However, apo AI and apo AII remained unchanged. Atherogenic indices of (TC--HDL-C)/ HDL-C, LDL-C/HDL-C, and apo B/Apo AI ratios were significantly (P less than 0.01) reduced after treatment. No significant changes were observed in lipoprotein lipase, hepatic TG lipase, and lecithin: cholesterol acyltransferase (LCAT) activities. Simvastatin was well tolerated and no critical side effects were noted in the eight-month study period. These data indicate that simvastatin, even at a low dose of 2.5 to 5 mg daily, causes consistent reductions in serum TC, LDL-C, apo B, and TG, and a rise in HDL-C and antiatherogenic lipoproteins.     

Effect of simvastatin on apoprotein B—containing lipoproteins in patients with diabetic nephropathy

Background: Diabetic patients with nephropathy usually have a more atherogenic lipoprotein profile than those without nephropathy, which may be associated with the substantially higher incidence of coronary heart disease (CHD) in this population. Simvastatin has been shown to significantly reduce the incidence of CHD events in diabetic patients.Objective: The purpose of this study was to evaluate the effect of simvastatin (10 mg/d) on atherogenic apoprotein (apo) B—containing lipoproteins in type 2 diabetic patients with nephropathy.Methods: Diabetic patients with nephropathy and a group of healthy control subjects matched for age, sex, and body weight were enrolled. Diabetic patients were administered simvastatin 10 mg/d for 6 months. Apo B—containing lipoproteins were sequentially separated by ultracentrifugation to yield very low-density lipoprotein (VLDL) (density <1.006 g/mL), intermediate-density lipoprotein (IDL) (1.006-1.019 g/mL), light low-density lipoprotein (LDL) (1.019-1.044 g/mL), and dense LDL (1.044-1.063 g/mL) fractions. Apo B in lipoproteins was measured by a sensitive enzyme-linked immunosorbent assay at baseline and after 6 months of simvastatin treatment.Results: A total of 18 patients with diabetic nephropathy and 36 matched controls were enrolled. The diabetic patients had significantly higher levels (P < 0.01) of total cholesterol, LDL cholesterol, triglycerides, and apo B compared with age- and weight-matched control subjects at baseline. The diabetic patients also had significantly higher levels (P < 0.05) of cholesterol and apo B in the VLDL, light LDL, and dense LDL fractions. Treatment with simvastatin for 6 months significantly reduced plasma total cholesterol by 21%, LDL cholesterol by 30%, and apo B by 25% (P < 0.001), but did not affect urinary albumin excretion. Simvastatin significantly decreased both triglyceride and cholesterol levels in VLDL by 18% (P < 0.05), and cholesterol and apo B in IDL by 22% (P < 0.05) and 26% (P < 0.01). Simvastatin decreased both the light and dense LDL subfractions to a similar extent, reducing cholesterol and apo B in light LDL by 27% (P < 0.001) and in dense LDL by 28% (P < 0.01) and 18% (P < 0.05), respectively. The light LDL/dense LDL ratio for apo B and for cholesterol were not altered by simvastatin therapy.Conclusions: The results of this study suggest that simvastatin may reduce levels of atherogenic apo B—containing lipoproteins and small dense LDL in diabetic patients with nephropathy.     

Effects of a new calcium channel blocker, TA 3090, on serum lipoprotein levels in mild to moderate essential hypertension

The 25 hypertensive patients received 20 to 40 mg of TA 3090 daily for 12 weeks. Blood pressures declined significantly during treatment, from a mean of 162/98 to 145/88 mmHg. There were no significant changes in levels of total or very low-density lipoprotein cholesterol or triglyceride, in levels of low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, or in levels of apolipoprotein (apo) B, C-II, C-III, or E. Apo A-I and A-II levels increased significantly from 130 and 29.2 mg/dl before treatment to 152 and 31.4 mg/dl at 12 weeks. Mean serum creatinine levels decreased significantly from 0.92 to 0.80 mg/dl. No other drug-related changes in laboratory test results or side effects were noted. It is concluded that TA 3090 is a safe and effective treatment for mild to moderate hypertension.     

Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss.

In subjects with hypertriglyceridemia, plasma concentrations of low density lipoprotein (LDL) cholesterol are often normal or reduced. Perturbations that alter plasma very low density lipoprotein (VLDL) concentrations are associated with opposite changes in plasma LDL levels. To determine the mechanisms regulating plasma LDL levels, we used 131I-VLDL and 125I-LDL to measure the fractional catabolic rates (FCR), production rates (PR), and rates of interconversion of apoprotein B (apo B) in VLDL, intermediate density lipoprotein, and LDL in six hypertriglyceridemic subjects pre- and post-weight reduction. [2-3H]glycerol was used to quantitate VLDL triglyceride PR. All data are presented as mean +/- SD. Percent ideal body weight fell from 132 +/- 17.9 to 119 +/- 15.9% in the group, P less than 0.05. After weight loss, plasma VLDL triglyceride (486.0 +/- 364.1 vs. 191.3 +/- 65.4 mg/dl, P less than 0.05) and VLDL apo B (32.2 +/- 12.0 vs. 14.8 +/- 6.8 mg/dl, P less than 0.05) concentrations were reduced. VLDL triglyceride PR also fell after weight reduction (56.6 +/- 39.0 vs. 28.6 +/- 23.1 mg/kg per h, P less than 0.05), as did VLDL apo B PR (47.9 +/- 41.4 vs. 19.0 +/- 14.1 mg/kg per d, P less than 0.05). Pre-weight loss, plasma LDL cholesterol and apo B levels were low-normal or reduced (64.0 +/- 12.6 and 58.4 +/- 11.9 mg/dl, respectively) despite normal or elevated LDL apo B PR (17.4 +/- 7.2 mg/kg per d). The reduced cholesterol and apo B levels were associated with increased FCRs (0.68 +/- 0.29 d-1) and reduced cholesterol/protein ratios (1.01 +/- 0.18) in LDL. The plasma levels of LDL cholesterol and apo B rose after weight reduction (84.8 +/- 24.9, P less than 0.05; and 69.5 +/- 14.3 mg/dl, P less than 0.05, respectively, vs. base line). These increased concentrations resulted from a combination of events. First, the FCR for LDL apo B fell in five of six subjects with a significant reduction for the group as a whole (0.48 +/- 0.11 d-1, P less than 0.05 vs. base line). Second, the cholesterol/protein ratio increased in all six subjects with a significantly greater mean after weight loss (1.25 +/- 0.27, P less than 0.05 vs. base line). In contrast, the LDL apo B PR fell or was essentially unchanged in the six subjects after weight loss (mean, 14.4 +/- 2.8 mg/kg per d; NS vs. pre-weight loss). The changes in LDL catabolism and composition were associated with changes in the source of LDL apo B. Pre-weight loss, 73.3% of LDL was derived from VLDL, while 26.7% was directly secreted into plasma. Post-weight reduction, VLDL-derived LDL fell to 46.8% of total, while direct secretion accounted for 53.2% of LDL production. These changes were significant; P < 0.95. Thus, all subjects had direct secretion of LDL apo B and the magnitude of this source of VLDL triglyceride secretion. These results indicate that the regulation of plasma LDL levels in hypertriglyceridemic subjects is quite complex and that the rise in LDL levels after weight loss results from reduction in the fractional catabolism of this lipoprotein. The fall in the FCR is associated with changes in the source of LDL and in its composition.     

Effect of lovastatin on serum lipids in patients with nonfamilial primary hypercholesterolemia

The effect of lovastatin on serum lipids and its tolerability in patients with non-familial primary hypercholesterolemia (type II-A and type II-B) during a six-month period were evaluated in this open-label study. Thirty-eight patients were enrolled in the study; tolerability was assessed in all 38 patients. Thirty patients completed the study, and the effect of lovastatin on serum lipids in these patients was assessed. Some patients had been treated for hypercholesterolemia with long-term dietary and other non-pharmacologic means before entry into the study. All patients were unresponsive to a six-week program of intensive dietary therapy and other nonpharmacologic treatment to lower their blood cholesterol levels before receiving lovastatin. While maintaining intensive dietary therapy, administration of lovastatin was instituted at a dosage of 20 mg/day, which was increased by 20-mg increments monthly, as necessary, to a maximum of 80 mg/day. In an effort to achieve goal levels of low-density lipoprotein cholesterol (LDL-C), ten patients received a daily dosage of 20 mg, 12 patients received 40 mg, seven patients 60 mg, and one patient 80 mg. Twenty-nine of the 30 patients achieved significant lowering of serum levels of total cholesterol (TC), LDL-C, and apolipoprotein (apo) B-I; this was demonstrated after the first month of therapy with lovastatin and was maintained throughout the six-month treatment period. One patient failed to demonstrate lowering of these serum lipids, despite receiving the maximum recommended dosage of lovastatin of 80 mg/day. Comparative measurements of serum lipids during dietary therapy alone and after six months of diet plus lovastatin therapy were as follows: TC, 289 +/- 5 versus 216 +/- 9 mg/dl (P less than 0.0005); LDL-C, 206 +/- 4 versus 141 +/- 5 mg/dl (P less than 0.0005); and apo B-I, 112 +/- 3 versus 89 +/- 2 mg/dl (P less than 0.0005). Serum levels of very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides decreased slightly during lovastatin therapy, but the changes were not statistically significant. There were slight but statistically insignificant increases in serum levels of high-density lipoprotein cholesterol (HDL-C), apo A-I, and apo A-II.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia.

BACKGROUND: Simvastatin 40 to 80 mg/d has been found to increase high-density lipoprotein cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent doses (ie, 20-80 mg/d). Data on the effects of lower doses of the 2 drugs on HDL-C levels are conflicting. OBJECTIVE: The purpose of this study was to investigate the effects of simvastatin 20 mg/d and atorvastatin 10 mg/d on HDL-C levels in patients with hypercholesterolemia. METHODS: Patients with primary hypercholesterolemia (total cholesterol [TC] >250 mg/dL) who were not taking any lipid-lowering agents and who were following a low-fat diet were randomized to receive 1 of 2 treatments: simvastatin 20 mg/d or atorvastatin 10 mg/d. Serum TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and HDL-C levels were measured using standard methods after 2 months of therapy. In a secondary analysis, lipids and lipoprotein cholesterol were measured after 1 year in patients who continued treatment. RESULTS: Of the 240 patients enrolled (108 men and 132 women; age range, 23-77 years, mean [SEM] 56.7 [0.69]), 235 completed the study. After 2 months of therapy, TC, LDL-C, and serum TG levels decreased significantly versus baseline in both groups (P < 0.001), with no significant differences between treatment groups. HDL-C levels increased by 9.0% (P < 0.001 vs baseline) in the simvastatin group and by 4.3% (P < 0.02) in the atorvastatin group. The difference between the 2 groups in the percentage increase in HDL-C was statistically significant (P < 0.05). In 113 patients who continued treatment, HDL-C levels at 1 year were still significantly higher than baseline levels in the simvastatin group (6.3%, P = 0.034), but not in the atorvastatin group (2.8%, P = 0.587). CONCLUSIONS: The findings from this study suggest that the HDL-C-increasing effect of simvastatin 20 mg is significantly greater than that of atorvastatin 10 mg. Since increasing HDL-C levels is thought to lower the risk for atherosclerosis and coronary heart disease, these results warrant further investigation.     

Decreases in apolipoprotein(a) after renal transplantation: implications for lipoprotein(a) metabolism.

Serum concentrations of apolipoprotein(a) [apo(a)], the unique glycoprotein of lipoprotein(a), are increased in patients with end-stage renal failure. We prospectively studied serum apo(a) and other lipoproteins in 20 consecutive patients, ages 46 +/- 11 years, before and for six months after successful renal transplantation. All patients received cyclosporine, and no patient was treated for hyperlipidemia. The mean creatinine clearance increased from 7.5 mL/min before transplant surgery to 40.9 mL/min six months afterwards (P less than 0.001). Apo(a) decreased from a median of 403 units/L before transplantation to 184 units/L at one week (P less than 0.001) and was 170 units/L (P less than 0.001) at six months. For the assay used, 1 unit of apo(a) is equivalent to 1 mg of lipoprotein(a). In contrast, from baseline to six months, increases were found for low-density lipoprotein (LDL) cholesterol (P = 0.03), high-density lipoprotein cholesterol (P = 0.06), apo B (P = 0.07), and apo A-I (P = 0.01). The decrease in apo(a) in individual patients was significantly correlated with the increase in creatinine clearance (r = -0.48, P less than 0.001). The single patient who developed nephrotic syndrome after renal transplantation had marked increases in apo(a) (693-1595 units/L), apo B, and LDL cholesterol, which paralleled the degree of proteinuria. These findings suggest that abnormal renal function affects the regulation of lipoprotein(a) metabolism.     

Lipids, lipoproteins and apolipoproteins in the elderly

The lipoprotein components were studied in connection with a population study concerning the state of health and living habits of the elderly people in Turku, Finland. Serum levels of total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 (apo A1) and apolipoprotein B (apo B) of the 347 elderly people (aged 65 years or over) were measured and those of low density lipoprotein (LDL) cholesterol were calculated. The levels of total cholesterol, LDL cholesterol and apo B were significantly higher in females than in males, and the concentrations decreased with advancing age. The concentrations of HDL cholesterol and apo A1 were significantly higher in females than in males but age had no effect. Serum triglycerides behaved differently in males and females; in females age had a significant increasing effect whereas in males no age effect was observed. The apo A1/apo B ratio did not differ between males and females. Reference values of serum lipids, lipoproteins and apolipoproteins of the elderly are suggested.     

Effects of low dosage progestin-only administration upon plasma triglycerides and lipoprotein metabolism in postmenopausal women.

Oral administration to five postmenopausal women of dl-norgestrel (0.075 mg/d for 7 wk) reduced mean fasting plasma levels of triglycerides by 29% (P < 0.001), VLDL triglycerides by 39% (P < 0.01), and VLDL apo B by 26% (P < 0.05), while lowering mean total cholesterol by 7% (P < 0.06). To explain these observations the kinetics of VLDL and LDL apo B turnover were studied by injecting autologous 125I-labeled VLDL and 131I-labeled LDL under control conditions and again in the fourth week of a 7-wk course of dl-norgestrel. VLDL apo B pool size fell by an average of 27% (1.2 vs 1.7 mg/kg, P < 0.06) and production of apo B by 18% (18 vs 22 mg/kg per d, P < 0.05) with unchanged fractional catabolic rate. Production of LDL apo B increased 36% with dl-norgestrel (12 vs 9.4 mg/kg per d, P < 0.05), but this was compensated by a 36% increase in fractional catabolic rate of LDL apo B (0.33 vs 0.25 pools/d, P < 0.005), thereby maintaining pool size. Lipoprotein (a) fell by an average of 12% (16 vs 18 mg/dl, P < 0.06). dl-Norgestrel reduced VLDL triglycerides (40 vs 64 mg/dl, P < 0.05), intermediate density lipoprotein cholesterol (14 vs 19 mg/dl, P < 0.02), IDL apo B (5.3 vs 7.2 mg/dl, P < 0.05), and VLDL cholesterol (3.1 vs 5.1 mg/dl, 0.10 > P > 0.05), in parallel with the reductions in VLDL apo B production and pool size. dl-Norgestrel significantly lowered the production rate of VLDL apo B, thereby decreasing plasma VLDL and intermediate density lipoprotein concentrations.     

Comparison of the effects of guanabenz and hydrochlorothiazide on plasma lipids

The effects of hydrochlorothiazide (HCTZ) and guanabenz monotherapy on blood pressure and serum lipoprotein levels were compared in a 14-week, randomized, parallel, double-blind multicenter study of 218 outpatients with mild hypertension. Mean supine blood pressure decreased 13/9 mm Hg in the guanabenz group and 17/11 mm Hg in the HCTZ group, changes that were significantly (p less than 0.01) different from baseline but not significantly different between the two treatment groups. Significant (p less than 0.01) mean decreases in total cholesterol and low-density lipoprotein (LDL) cholesterol levels (of 9 mg/dl and 4 mg/dl from baseline values) occurred during guanabenz treatment; HDL cholesterol levels fell by an average of 4 mg/dl. In the HCTZ group, triglyceride levels were significantly (p less than 0.01) increased by 13 mg/dl, and HDL cholesterol levels fell by 2 mg/dl. The change in LDL cholesterol levels, but not HDL cholesterol levels, was significantly different between guanabenz and HCTZ periods. The results show that guanabez, although providing effective blood pressure control that is comparable to that of HCTZ, has more favorable effects on lipoproteins.     

Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100.

In 1979 Steinberg and colleagues recognized a unique kindred with normotriglyceridemic hypobetalipoproteinemia (1979. J. Clin. Invest. 64:292-301). We have undertaken an intensive reexamination of this kindred and have studied 41 family members in three generations. In this family we document the presence of two distinct apo B alleles associated with low plasma concentrations of apolipoprotein (apo) B and low density lipoprotein (LDL) cholesterol and we trace the inheritance of these two alleles over three generations. One of the alleles resulted in the production of an abnormal, truncated apo B species, apo B-37. The other apo B allele was associated with reduced plasma concentrations of the normal apo B species, apo B-100. H.J.B., the proband, and two of his siblings had both abnormal apo B alleles and were therefore compound heterozygotes for familial hypobetalipoproteinemia. Their average LDL-cholesterol level was 6 +/- 9 mg/dl. All of the offspring of the three compound heterozygotes had hypobetalipoproteinemia, and each had evidence of only one of the abnormal apo B alleles. In the entire kindred, we identified six heterozygotes for familial hypobetalipoproteinemia who had only the abnormal apo B-37 allele and their average LDL cholesterol was 31 +/- 12 mg/dl. We identified 10 heterozygotes who had only the allele for reduced plasma concentrations of apo B-100 and their LDL cholesterol level was 31 +/- 15 mg/dl. Unaffected family members (n = 22) had LDL cholesterol levels of 110 +/- 27 mg/dl. This report describes the first kindred in which two distinct abnormal apo B alleles have been identified, both of which are associated with familial hypobetalipoproteinemia.     

Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution,composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis.

Lipoprotein classes isolated from the plasma of two patients with apolipoprotein AI (apo AI) and apolipoprotein CIII (apo CIII) deficiency were characterized and compared with those of healthy, age- and sex-matched controls. The plasma triglyceride values for patients 1 and 2 were 31 and 51 mg/dl, respectively, and their cholesterol values were 130 and 122 mg/dl, respectively; the patients, however, had no measurable high density lipoprotein (HDL)-cholesterol. Analytic ultracentrifugation showed that patients'' S degrees f 0-20 lipoproteins possess a single peak with S degrees f rates of 7.4 and 7.6 for patients 1 and 2, respectively, which is similar to that of the controls. The concentration of low density lipoprotein (LDL) (S degrees f 0-12) particles, although within normal range (331 and 343 mg/dl for patients 1 and 2, respectively), was 35% greater than that of controls. Intermediate density lipoproteins (IDL) and very low density lipoproteins (VLDL) (S degrees f 20-400) were extremely low in the patients. HDL in the patients had a calculated mass of 15.4 and 11.8 mg/dl for patients 1 and 2, respectively. No HDL could be detected by analytic ultracentrifugation, but polyacrylamide gradient gel electrophoresis (gge) revealed that patients possessed two major HDL subclasses: (HDL2b)gge at 11.0 nm and (HDL3b)gge at 7.8 nm. The major peak in the controls, (HDL3a)gge, was lacking in the patients. Gradient gel analysis of LDL indicated that patients'' LDL possessed two peaks: a major one at 27 nm and a minor one at 26 nm. The electron microscopic structure of patients'' lipoprotein fractions was indistinguishable from controls. Patients'' HDL were spherical and contained a cholesteryl ester core, which suggests that lecithin/cholesterol acyltransferase was functional in the absence of apo AI. The effects of postprandial lipemia (100-g fat meal) were studied in patient 1. The major changes were the appearance of a 33-nm particle in the LDL density region of 1.036-1.041 g/ml and the presence of discoidal particles (12% of total particles) in the HDL region. The latter suggests that transformation of discs to spheres may be delayed in the patient. The simultaneous deficiency of apo AI and apo CIII suggests a dual defect in lipoprotein metabolism: one in triglyceride-rich lipoproteins and the other in HDL. The absence of apo CIII may result in accelerated catabolism of triglyceride-rich particles and an increased rate of LDL formation. Additionally, absence of apo CIII would favor rapid uptake of apo E-containing remnants by liver and peripheral cells. Excess cellular cholesterol would not be removed by the reverse cholesterol transport mechanism since HDL levels are exceedingly low and thus premature atherosclerosis occurs.     

Effects of manidipine and delapril on serum lipids, lipoproteins, and apolipoproteins in patients with mild to moderate essential hypertension: a randomized trial with one-year follow-up.

Forty-five patients with mild to moderate essential hypertension were randomly assigned to receive 10 to 40 mg of manidipine HCl or 15 to 60 mg of delapril daily for 12 months. In the manidipine-treated group were 13 women and 5 men (mean age, 48.2 years) and in the delapril-treated group 11 women and 11 men (mean age, 53.7 years). Blood samples were taken at baseline and after 6 and 12 months of treatment and again at 2 months after treatment discontinuation. Significant reductions in blood pressure were observed in both treatment groups. The reduction in diastolic blood pressure was significantly greater in the manidipine-treated patients than in the delapril-treated patients; no significant between-groups differences in systolic blood pressure were noted. Heart rate increased significantly in the manidipine group. No changes in serum levels of total cholesterol, triglycerides, and high-density and low-density lipoprotein cholesterol were noted during or after treatment. In the manidipine group, a small but significant decrease in apolipoprotein (apo) A-I and an increase in lipoprotein(a) were found at 6 months and a significant increase in apo A-II and apo E at 12 months; in the delapril group a significant decrease in apo A-I was found at 6 months. The results indicate that both manidipine and delapril are lipid-neutral antihypertensive drugs, since neither drug greatly affected serum lipid metabolism.     

Lipoproteins and apolipoproteins in human pleural effusions.

We investigated the lipoproteins and apoproteins in human serum and pleural effusions of different origin: transudates, inflammatory exudates, and malignant exudates. Transudates had a low cholesterol content of 35 +/- 12 mg/dl (mean +/- SD) because of low levels of low-density lipoprotein (LDL) cholesterol--representing 16% of serum levels--whereas inflammatory exudates (cholesterol 92 +/- 26 mg/dl) and malignant exudates (cholesterol 86 +/- 6 mg/dl) exhibited high levels of LDL, with 67% and 69% of serum levels. Apolipoprotein (apo) B level corresponded with LDL and presented with multiple split-products in sodium dodecyl sulfate-polyacrylamide gel electrophoresis in exudative effusions. LDL levels in effusions correlated with serum levels in exudates but did not correlate with those in transudates. In contrast, lipoprotein(a) appeared in all effusions from patients with detectable serum levels. The isoforms were similar as demonstrated by immunoblotting. Differences were found in the composition of the high-density lipoprotein (HDL) fraction: transudates had cholesterol-rich HDL when compared with serum. HDL particles of malignant exudates were poor in cholesterol, and isoelectric focusing demonstrated more sialized apolipoprotein E. A strongly abnormal HDL level with accumulation of cholesterol was found in a long-standing tuberculous effusion. In conclusion, cholesterol in acute effusions is bound to lipoproteins and derived from the blood. The difference in total cholesterol levels between transudates and exudates is based on the lack of LDL in transudates. Transudates show the lipoprotein characteristics of interstitial fluid. Alterations of lipoproteins occur in chronic inflammation and in malignancy with possible de novo synthesis of apolipoprotein E by tumor cells. Lipoprotein(a) accumulates independently from LDL in the pleural space, a finding that supports the view that the physiologic function of lipoprotein(a) is located in the interstitial space.     

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.     

Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia

The safety and efficacy of combined bezafibratesimvastatin therapywas evaluated in 49 patients with diet-resistant mixed hyperlipidaemia(type Mb). After a two-month placebo phase, patients were randomizedto receive either Bezafibrate Slow Release (SR) 400 mg maneor simvastatin 20 mg nocte followed by three months combinationtherapy. Total cholesterol, triglycerides and high-density lipoprotein(HDL) cholesterol were measured at monthly intervals. Apolipoproteins(apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen weremeasured before and after each treatment. Simvastatin was moreeffective than Bezafibrate SR in reducing total cholesterol(2.0 vs. 1.1 mmol/l, p=0.003) and lowering LDL cholesterol (1.7vs. 0.4 mmol/l, p= 0.0001) whereas Bezafibrate SR was more effectivein reducing triglycerides (by 41% vs. 17%, p= 0.001) and fibrinogen(by 23% vs. 3%, p= 0.004). Compared with simvastatin monotherapy,combined drug therapy induced further reductions in triglycerides(by 26%, p= 0.0003) and apoB (by 11 mg/dl, p=0.03) and an increasein apoA1 (by 21 mg/dl, p= 0.0008). Symptomatic and biochemicaladverse events did not occur more frequently on combined drugtherapy than on monotherapy. The combination of bezafibrateand simvastatin was more effective in controlling mixed hyperlipidaemiathan either drug alone and did not provoke more adverse events.     

Effects of polydextrose on serum lipids, lipoproteins, and apolipoproteins in healthy subjects

The subjects were 61 healthy volunteers who received 15 gm of polydextrose daily for two months. A significant increase in the incidence of soft feces and diarrhea and in the volume of feces was reported during polydextrose treatment. These had returned to normal one month after treatment. Serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol did not change during treatment. Levels of apolipoprotein (apo) A-I and A-II were significantly lowered at one month and high-density lipoprotein cholesterol (HDL-C) and apo A-I were significantly decreased at two months; these returned to normal after treatment. Levels of HDL2-C decreased and HDL3-C levels increased significantly during treatment. The results indicate that polydextrose selectively affected the metabolism of HDL and its major proteins, apo A-I and A-II.