Effects of pravastatin on lipid transfer protein and lecithin cholesterol acyltransferase in heterozygous familial hypercholesterolemia.

The effects of HMG CoA reductase inhibitor PRAVASTATIN on plasma lipoprotein levels, lipid transfer protein (LTP) activity and lecithin cholesterol acyltransferase (LCAT) activity were investigated in 20 patients with heterozygous familial hypercholesterolemia. Plasma total cholesterol decreased from 299.2 +/- 45.2 to 245.9 +/- 45.1 (mean +/- SD in mg/dl) (p < 0.0001), low density lipoprotein (LDL) cholesterol from 221.1 +/- 47.6 to 164.9 +/- 48.1 (p < 0.0001) and LDL-triglycerides from 38.0 +/- 10.2 to 30.2 +/- 8.8 (p < 0.0001). High density lipoprotein (HDL) cholesterol increased from 60.1 +/- 13.9 to 63.1 +/- 17.0 (p = 0.0264). The HDL-cholesterol: HDL-triglycerides ratio increased from 3.91 +/- 1.14 to 4.91 +/- 1.65 (p = 0.0029). Lipid transfer protein (LTP) activity (as % of transferred cholesteryl ester (CE)) decreased from 4.68 +/- 2.47 to 3.70 +/- 2.31 (p = 0.0024) and LCAT activity decreased from 113.1 +/- 29.9 (U/L) to 97.0 +/- 22.7. There was a negative correlation between LTP/LCAT ratio and HDL-C levels. These results suggested that the changes in plasma HDL-cholesterol concentrations during treatment with pravastatin may be related to the decreases in LTP and LCAT activity due to this drug.

An improved method for removal of antithrombin III from post-heparin plasma lipase fractions with a high recovery rate.

Affinity chromatography on heparin-Sepharose has been widely used for the purification of post-heparin plasma triglyceride lipases, but this procedure alone yields lipase fractions with a high content of antithrombin III (AT), which also binds to heparin and coelutes with the lipases. A rapid procedure in which this major contaminant is reduced by the use of affinity chromatography on heparin-Sepharose with low affinity for AT and further removal by anti-AT IgG Affi-Gel 10 column chromatography is reported and the results are compared with these of the conventional heparin-Sepharose and Concanavalin A-Sepharose column chromatography two step method. While the AT contamination of hepatic lipase eluate from conventional heparin-Sepharose column chromatography was 92 mg/dl in 100 mg/dl protein, heparin-Sepharose with low affinity for AT yielded samples with 55 mg/dl in 100 mg/dl protein. A second passage on concanavalin A-Sepharose of the sample from conventional heparin-Sepharose reduced the AT content from 92 mg/dl to 42 mg/dl in 100 mg/dl protein, but passage of the sample from heparin-Sepharose with low affinity for AT through an anti-AT IgG Affi-Gel 10 column removed almost all of the AT contamination from the lipase sample. This hepatic triglyceride lipase (HTGL) sample had a specific activity 1,963-fold higher than that of post-heparin plasma with a yield of 17% of the starting material, showing an excellent recovery rate compared with similar methods in use.

Effects of carvedilol on serum lipids in patients with essential hypertension.

The purpose of this study was to investigate the effect of carvedilol on serum lipids in patients with mild-to-moderate essential hypertension. Twenty-one patients with blood pressure greater than or equal to 160/95 mm Hg after a 4-week placebo run-in period were initially given 10 mg of carvedilol once daily. The dose was increased to 20 mg after 4 weeks if the target blood pressure was not achieved. The duration of treatment was 12 weeks. After 12 weeks of administration, blood pressure and the pulse rate (PR) declined significantly (blood pressure from 173/105 to 142/91 mm Hg, p less than 0.001; PR from 74 to 67 beats/min, p less than 0.001); however, serum lipids [total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein (HDL), HDL2, and HDL3], lipoprotein fraction (alpha, pre-beta, and beta), apoprotein fraction (A-I, A-II, CII, CIII, and E), and atherogenic index [(total cholesterol - HDL cholesterol) divided by HDL cholesterol] were not altered significantly. There were no side effects reported during the trial. From these results, it can be concluded that carvedilol has no adverse effect on the coronary risk profile as reflected by lipid measurements, and is an efficacious, safe, well-tolerated antihypertensive drug in patients with mild-to-moderate hypertension.

Hepatic lipase activity and high density lipoproteins in familial hypercholesterolemia: adaptational mechanisms for LDL-receptor deficient state.

With a view toward elucidating the poorly understood high density lipoprotein (HDL) metabolism in familial hypercholesterolemic (FH) patients, the activities of the plasma enzymes involved in HDL metabolism; hepatic triglyceride lipase (HTGL), lipoprotein lipase (LPL) and lecithin-cholesterol acyltransferase (LCAT) with concomitant determination of HDL particle size, were analyzed in 50 age-matched hypercholesterolemic patients (26 FH and 24 non-FH patients). The activity of HTGL in FH patients was significantly higher (p less than 0.02) than in non-FH patients. The analysis of HDL size by gradient gel electrophoresis showed significantly smaller HDL particles in FH patients. Analysis of the correlation between HTGL activity and HDL particle size confirmed that the variation in HDL particle size was related to HTGL activity. Those results suggest that the differences in HTGL activity and HDL size between the familial and non-familial types of hypercholesterolemia may be due to differences in their pathophysiology. The high HTGL activity and small HDL particles in FH probably are the consequences of an adaptational mechanism used by LDL-receptor-deficient hepatocytes to increase the intracellular pool of cholesterol.

The effect of CS-514 on serum lipids and apolipoproteins in hypercholesterolemic subjects.

CS-514 is a metabolic product of compactin and has a potent cholesterol-lowering effect in vitro and in animal studies by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The efficacy and adverse effects of the agent were studied in 41 hypercholesterolemic subjects by administering daily doses of 5, 20, or 40 mg for four weeks under double-blind conditions. Mean total serum cholesterol level was reduced by 11.1% in the 5-mg group, 18.8% in the 20-mg group, and 25.3% in the 40-mg group. Marked reduction of total serum cholesterol level was also observed in heterozygous familial hypercholesterolemics. Mean low-density lipoprotein cholesterol level and apolipoprotein B concentration decreased by 38.5% and 28.8%, respectively, in the 40-mg group, while high-density lipoprotein cholesterol level increased by 11.8%. No serious clinical and laboratory abnormalities were observed. Plasma cortisol and testosterone levels were not significantly affected. These results suggest that CS-514 will be a useful agent in the treatment of nonfamilial and heterozygous familial hypercholesterolemia.

Comparison of selectivity of LDL removal by double filtration and dextran-sulfate cellulose column plasmapheresis, and changes of subfractionated plasma lipoproteins after plasmapheresis in heterozygous familial hypercholesterolemia.

The possibility of selective removal of low density lipoprotein (LDL) by double filtration (DF) and dextran-sulfate cellulose (DSC) column plasmapheresis in hypercholesterolemia and the acute recovery process of the subfractionated plasma lipoproteins after plasmapheresis in heterozygous familial hypercholesterolemia were investigated. Sixty-six percent of the LDL cholesterol and 42% of the HDL cholesterol were removed by 2.5 L DF plasmapheresis with the second filters having average pore diameters of 30 nm and 40 nm. Fifty-nine percent of the LDL cholesterol was removed by 2.5 L DSC column plasmapheresis, while HDL cholesterol did not change. Therefore, DSC column plasmapheresis could remove LDL much more specifically than DF plasmapheresis. VLDL increased rapidly and reached the preplasmapheresis level within four days after plasmapheresis. IDL returned to the preplasmapheresis level in 2 weeks. The LDL1 level was approximately 80% of the preplasmapheresis level on the 14th day. LDL2 reached the peak at the seventh day. HDL2 and HDL3 moved in the same manner and reached the peak on the seventh day after DF plasmapheresis.

Lecithin:cholesterol acyltransferase-induced modifications of liver perfusate discoidal high density lipoproteins from African green monkeys.

The role of lecithin:cholesterol acyltransferase (LCAT) in the formation of plasma high density lipoproteins (HDL) was studied in a series of in vitro incubations in which perfusates from isolated African green monkey livers were incubated at 37 degrees C with partially purified LCAT for between 1 and 13 hr. The HDL particles isolated from monkey liver perfusate stored at 4 degrees C and not exposed to added LCAT contained apoA-I and apoE, were deficient in neutral lipids, and were observed by electron microscopy as discoidal particles. Particle sizes, measured as Stokes' diameters by gradient gel electrophoresis (GGE), ranged between 7.8 nm and 15.0 nm. The properties of perfusate HDL were unchanged following incubation at 37 degrees C in the presence of an LCAT inhibitor. However, HDL subfractions derived from incubations at 37 degrees C with active LCAT contained apoA-I as the major apoprotein, appeared round by electron microscopy, and possessed chemical compositions similar to plasma HDL. The HDL isolated from perfusate incubations at 37 degrees C with low amounts of LCAT had a particle size and chemical composition similar to plasma HDL3a. In three of four perfusates incubated with higher levels of LCAT activity, the HDL products consisted of two distinct HDL subpopulations when examined by GGE. The major subpopulation was similar in size and composition to plasma HDL2a, while the minor subpopulation demonstrated the characteristics of plasma HDL2b. The data indicate that the discoidal HDL particles secreted by perfused monkey livers can serve as precursors to three of the major HDL subpopulations observed in plasma.

The effect of CS-514, an inhibitor of HMG-CoA reductase, on serum lipids in healthy volunteers.

CS-514 is a competitive inhibitor of HMG-CoA reductase. The effect of this agent on serum lipids and lipoproteins was studied in 10 healthy normocholesterolemic male volunteers by giving 20 mg of CS-514 or placebo twice a day for 7 days under double-blind conditions. The mean total serum cholesterol level decreased by 18.6% in the CS-514 group, whereas it increased by 7.4% in the placebo group and the difference between the two groups was statistically significant (P less than 0.01). LDL cholesterol and LDL apo B values were reduced by 22.6% and 23.2%, respectively. Serum triglyceride level did not change significantly. No clinical or laboratory abnormalities were observed.

Comparison of selectivity of LDL removal by double filtration and dextran-sulfate cellulose column plasmapheresis.

The possibility of selective removal of VLDL, IDL and LDL by double filtration (DF) and dextran-sulfate cellulose (DSC) column plasmapheresis was investigated in hypercholesterolemia. Two and a half liters of plasma were treated. Sixty six percent of TC and 68% of LDL-C were removed by DF plasmapheresis. The removal rate of HDL-C was 50% which was significantly lower than that of LDL-C. The removal rate of apoprotein A-I and A-II was also significantly lower than that of apoprotein B. Sixty percent of LDL-C and 61% of apoprotein B were removed by DSC column plasmapheresis while the decrease of HDL-C, apoprotein A-I and A-II was minimal. Therefore, DSC column plasmapheresis could remove atherogenic lipoproteins more selectively than DF plasmapheresis.

The changes in plasma lipoproteins in a case of heterozygous familial hypercholesterolemia after plasmapheresis.

The changes in plasma lipoproteins after plasmapheresis were estimated in a case of heterozygous familial hypercholesterolemia. Two and a half liters of plasma were exchanged with the same volume of Plasmanate. The effects of cholestyramine on the changes in plasma lipoproteins were also studied after the second plasmapheresis. Fasting plasma was collected serially, and plasma VLDL, IDL, LDL1 (1.019 less than d less than 1.045), LDL2 (1.045 less than d less than 1.063), HDL2 (1.063 less than d less than 1.125) and HDL3 (d greater than 1.125) were separated by ultracentrifugation. The cholesterol and apoprotein contents in these lipoprotein fractions were analyzed. Apoprotein AI, AII, B, CII and E were measured by single radial immunodiffusion. VLDL-C and plasma apoprotein CII and E increased very rapidly. The IDL-C increase was slightly slower than that of VLDL-C. LDL1-C continued to increase for three weeks, but LDL2-C reached a plateau around a week after plasmapheresis and declined thereafter. The change of apoprotein B was similar to that of cholesterol in VLDL, IDL, LDL1 and LDL2. Cholesterol amounts in HDL2 and HDL3 changed in a parallel manner, as did apoprotein AI and AII. HDL2 and HDL3 reached their preplasmapheresis levels in a week. Cholestyramine did not inhibit the increase of VLDL, IDL, LDL1 or LDL2 in this case.

Diseases and cancer rate of AMHTS examines in the Tokai University Hospital.

Studies were conducted on 10,261 subjects who had undergone checkups in an AMHTS (Automated Multiphasic Health Testing and Services) Center in the Tokai University Hospital. The breakdown of the screening at the time of the examinations was 48% abnormal and 52% borderline or normal. The disease ratio obtained in follow-up survey averaged 16% and increased as the subjects became older. There were 68 cancer patients, 0.7% of the total number of examinees, and it was found that 88% of the cancer cases definitely diagnosed as cancer within one year after the examinations received these diagnoses within three months from the day of the examinations.