| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Pravastatin (mevalotin) restenosis trial after percutaneous transluminal coronary angioplasty. Cholesterol reduction rate determines the restenosis rate Yui, Y., C. Kawai, et al. (1995), Ann N Y Acad Sci 748: 208-16. Abstract: There is no consensus on lipids and restenosis after percutaneous transluminal coronary angioplasty (PTCA). We evaluated whether prevastatin could prevent restenosis after PTCA. In this study, pravastatin therapy was started one month before PTCA. The follow-up angiography was done three months later. Total cholesterol reduction rates one index of reduction rate is calculated between 1 M (month) before PTCA and at PTCA, and another done between 1 M before PTCA and at follow-up angiography proved to be good predictors of restenosis rate after PTCA; The greater the cholesterol reduction rate, the lower the rate of restenosis. The residual stenosis after PTCA correlated with the restenosis rate. The restenosis rate in the pravastatin group was lower than that in the control group, but the difference was not statistically significant. However, in the subgroup with pre-PTCA restenosis of 99% or more, the restenosis rate in the pravastatin group was significantly lower than that of the control group. Pravastatin seems to prevent intimal hyperplasia through the reduction of cholesterol level and to reduce restenosis. Many macrophages are present in the highly stenosed or occluded coronary arteries, and the reduction of the number and the activity of macrophages may prevent the restenosis. Pravastatin also has an antithrombotic action. In such regions, the occlusion by the thrombus formation is also considered to play a key role in restenosis in addition to the intimal hyperplasia. Thus, pravastatin may be useful especially for PTCA against highly stenosed or occluded coronary arteries. |
| Pravastatin and lovastatin similarly reduce serum cholesterol and its precursor levels in familial hypercholesterolaemia Vanhanen, H. and T. A. Miettinen (1992), Eur J Clin Pharmacol 42(2): 127-30. Abstract: The hypocholesterolaemic effect of pravastatin 40 mg and lovastatin 40 mg daily has been compared in patients with familial hypercholesterolaemia (FH). Administration of the two drugs was separated by a three-month washout period. The reduction in total serum cholesterol after 1,2 and 4 weeks of treatment was similar after pravastatin (-23%, -32% and -32%) and lovastatin (-23%, -30% and -31%). The serum concentrations of LDL cholesterol were similarly reduced, whilst triglycerides, other lipoproteins, cholestanol and squalene were not altered. The reductions in the serum levels of the cholesterol precursor sterols, delta 8-cholesterol, desmosterol and lathosterol were not significantly different after either drug. The lack of difference suggests that cholesterol synthesis was equally inhibited by the two agents. In addition, the serum content of the plant sterols campesterol and sitosterol tended to be equally increased. The comparability of the increases suggests that the absorption and biliary elimination of the two sterols were equally affected by the two statins. Thus, no difference was found between the effects of pravastatin and lovastatin on the serum levels and metabolic precursors of cholesterol in FH during four weeks of treatment. |
| Pravastatin and simvastatin differently inhibit cholesterol biosynthesis in human lens de Vries, A. C., M. A. Vermeer, et al. (1993), Invest Ophthalmol Vis Sci 34(2): 377-84. Abstract: PURPOSE. In the current study, the hypocholesterolemic drugs pravastatin and simvastatin were compared for their influence on cholesterol biosynthesis in the human lens. METHODS. For measurements of cholesterol and fatty acid synthesis rates, human lenses were incubated for 20 hr in the presence of 14C-acetate, and pravastatin or simvastatin. Radiolabeled 14C-cholesterol and 14C-fatty acids were determined. To avoid the influence of individual differences, one lens from each donor was incubated without drug (control) and the other lens was incubated in the presence of drug. For each lens pair, the percentage inhibition of the cholesterol synthesis caused by the drug was calculated. Fatty acid synthesis was not influenced by the drugs. By comparing the fatty acid synthesis rate of the drug-incubated with the control lens of a pair, a predefined exclusion criterion was used to eliminate lens pairs in which the lenses had no comparable biosynthetic capacities. RESULTS. Using various concentrations of the drugs, a dose-response curve was constructed for the inhibition of the cholesterol synthesis. The IC50 values (drug concentration give 50% inhibition) were 0.5 mumol/l and 0.004 mumol/l for pravastatin and simvastatin, respectively. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in microsomal membranes from human lens cortex was inhibited by simvastatin and pravastatin to the same extent. CONCLUSIONS. Under the conditions used in this study, cholesterol synthesis in human lenses is inhibited by simvastatin 100-fold more effectively than by pravastatin. This difference was likely due to differences in the intracellular exposure of the reductase to the drugs in intact human lenses. |
| Pravastatin attenuates cardiovascular inflammatory and proliferative changes in a rat model of chronic inhibition of nitric oxide synthesis by its cholesterol-lowering independent actions Egashira, K., W. Ni, et al. (2000), Hypertens Res 23(4): 353-8. Abstract: Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitors such as pravastatin may be through their cholesterol-lowering independent effects on the blood vessels. We have recently reported that chronic inhibition of nitric oxide (NO) synthesis with N(omega)nitro-L-arginine methyl ester (L-NAME) increases systolic blood pressure and induces coronary vascular inflammatory changes in rats. We designed this study to investigate whether treatment with pravastatin attenuates such proarteriosclerotic changes through their cholesterol-lowering independent effects. Several groups of Wistar-Kyoto rats were studied: the control group, L group received L-NAME in their drinking water (100 mg/kg per day) and L+Px group received L-NAME plus pravastatin (50, 100 or 250 mg/kg per day). We observed marked increases in monocyte infiltration into the coronary arteries, proliferative cell nuclear antigen-positive cells, and monocyte chemoattractant protein-1 (MCP-1) expression in the heart on day 3 after L-NAME administration began. Treatment with pravastatin did not affect serum cholesterol levels or systolic blood pressure but did reduce the L-NAME induced inflammatory and proliferative changes. Pravastatin also attenuated the MCP-1 gene expression induced by L-NAME. In summary, pravastatin inhibited the inflammatory and proliferative changes in the coronary vessels through their cholesterol-independent effects in this model, which may provide an insight into the mechanisms of anti-inflammatory or anti-arteriosclerotic actions of pravastatin. |
| Pravastatin decreases serum lipids and vascular cholesterol deposition in Watanabe heritable hyperlipidemic (WHHL) rabbits Khachadurian, A. K., T. Shimamura, et al. (1991), Jpn Heart J 32(5): 675-85. Abstract: The effects of long term administration of pravastatin (a competitive inhibitor of hydroxymethylglutaryl CoA reductase) were assessed by measuring serum lipids and aortic and coronary atherosclerosis in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Six-month-old WHHL rabbits were given either 50 mg/kg/day of the drug or vehicle. The rabbits were sacrificed following 6 or 12 months of treatment and serum cholesterol and triglycerides and aortic cholesterol and hydroxyproline were measured. Atherosclerotic plaques in the aorta and coronary arteries were quantified with morphometric methods. Mean serum cholesterol +/- SEM (n) in the control vs. pravastatin groups after 6 months were: 535 +/- 34 (11) vs. 411 +/- 22 (12) (p less than 0.005) and after 12 months 458 +/- 43 (9) vs. 309 +/- 29 mg/dl (12) (p less than 0.005). In the pravastatin group, percent aortic area covered with plaque and aortic cholesterol content were reduced 35% (ns) and 55% (p less than 0.05) at 6 months, and 26% (ns) and 44% (ns) at 12 months, respectively. Little difference was found in serum triglycerides and aortic hydroxyproline in the 2 groups. There was strong correlation of serum cholesterol with aortic cholesterol content (r = 0.61, p less than 0.003) and with the percent aortic plaque area (r = 0.67, p less than 0.001), at 12 months. Morphometric analysis of wall thickness and lumen area of major coronary arteries revealed no significant differences in the 2 groups. In conclusion, pravastatin effectively lowered the serum cholesterol level in an animal model defective in low density lipoprotein receptors; this reduction was strongly correlated with amelioration of such atherosclerotic processes as lipid deposition and plaque formation. |
| Pravastatin effectively lowers LDL cholesterol in familial combined hyperlipidemia without changing LDL subclass pattern Franceschini, G., M. Cassinotti, et al. (1994), Arterioscler Thromb 14(10): 1569-75. Abstract: Familial combined hyperlipidemia (FCHL) is the most common genetic lipid disorder among young survivors of myocardial infarction. Elevations of plasma total and low-density lipoprotein (LDL) cholesterol and the prevalence of small, dense LDL particles are both involved in the high coronary risk of FCHL patients. We investigated the ability of pravastatin to favorably correct plasma lipid and lipoprotein levels and LDL structure in FCHL patients. Twelve patients with FCHL, documented by studies of first-degree relatives, received pravastatin (40 mg/d) for 12 weeks. Pravastatin significantly lowered plasma total and LDL cholesterol levels by 21% and 32%, respectively. Triglyceride levels did not change, and apolipoprotein B (apoB) concentrations decreased by 9% (P = NS). High-density lipoprotein (HDL) cholesterol increased by 6% because of a significant 73% rise of HDL2 cholesterol. LDL were smaller (diameter, 24.5 +/- 0.5 nm), less buoyant, and apoB-rich (cholesteryl ester-apoB ratio, 1.64 +/- 0.46) in the selected patients compared with patients with familial hypercholesterolemia or healthy control subjects. LDL became even smaller (23.8 +/- 0.6 nm) and richer in apoB (cholesteryl ester-apoB ratio, 1.27 +/- 0.52) after pravastatin treatment. Although pravastatin favorably altered plasma lipid and lipoprotein levels in FCHL patients, the abnormal LDL particle distribution and composition were not affected. Because of the apparent resistance of the small, dense LDL to drug-induced modifications, a maximal lipid-lowering effect is needed to reduce coronary risk in FCHL patients. |
| Pravastatin has no effect on bile lipid composition, nucleation time, and gallbladder motility in persons with normal levels of cholesterol Sharma, B. C., D. K. Agarwal, et al. (1997), J Clin Gastroenterol 25(2): 433-6. Abstract: Pravastatin dissolves gallstones in patients with hypercholesterolemia by reducing the cholesterol saturation index (CSI) of bile. There are few reports on effect of pravastatin on bile lipids, CSI and nucleation time (NT) in patients with gallstones and normal plasma lipid levels, or on the effect of pravastatin on gallbladder motility. Therefore we studied the effect of pravastatin on bile lipids, CSI, NT, and gallbladder motility in persons with normal cholesterol levels. We included 10 patients (ages 32 +/- 8 years; 6 men) with symptomatic gallstones and normal plasma lipid profiles. Estimation of bile lipids, CSI, and NT in duodenal bile and gallbladder motility were done using standard methods. Subsequently each patient was given 40 mg pravastatin daily for 1 month. At completion of pravastatin therapy, bile lipids and gallbladder motility studies were repeated. After pravastatin therapy, we found no significant reduction in bile cholesterol (11.2 +/- 3.2 vs. 10.4 +/- 2.8 mmol/l), bile acids (114.6 +/- 7.4 vs. 133 +/- 16 mmol/l), phospholipids (23 +/- 3.5 vs. 24 +/- 6.2 mmol/l), CSI (1.28 +/- 0.4 vs. 1.22 +/- 0.3), and nucleation time (7 +/- 3 vs. 7 +/- 3 days). In addition, there was no significant change in gallbladder fasting volume (26 +/- 3 vs. 26.6 +/- 3 ml), residual volume (14.6 +/- 1.1 vs. 15.08 +/- 1.4 ml), ejection fraction (44% vs. 43%), and rate constant of gallbladder emptying (0.018/min vs. 0.022/min). One-month therapy with pravastatin does not alter bile lipids, CSI, NT, and gallbladder contractility in persons with normal levels of cholesterol. |
| Pravastatin in heterozygous familial hypercholesterolemia: low-density lipoprotein (LDL) cholesterol-lowering effect and LDL receptor activity on skin fibroblastS Gaddi, A., M. Arca, et al. (1991), Metabolism 40(10): 1074-8. Abstract: The cholesterol-lowering effect of provastatin, a new competitive inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, was studied in 10 patients with heterozygous familial hypercholesterolemia (FH). Residual low-density lipoprotein receptor (LDL-R) activity was also evaluated in cultured skin fibroblasts prior to treatment, and showed a wide range of reduction from 30% to 70% of the normal value. Treatment with pravastatin 40 mg once daily reduced total and LDL cholesterol (LDL-C) after 6 months by 19.7% and 25.4%, respectively (P less than.001). Serum apolipoprotein (apo) B levels decreased significantly by 29.1% (P less than.001). No significant changes were observed in mean serum total triglycerides or high-density lipoprotein cholesterol (HDL-C) levels. A positive correlation between residual LDL-R activity and maximum percent reduction of LDL-C levels was observed (r =.676, P less than.05). No clinically important side effects were recorded and the treatment was well tolerated. Thus, pravastatin effectively reduces LDL in heterozygous FH, and this effect appears to be related to LDL-R status. |
| Pravastatin inhibited the cholesterol synthesis in human hepatoma cell line Hep G2 less than simvastatin and lovastatin, which is reflected in the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and squalene synthase Cohen, L. H., A. van Vliet, et al. (1993), Biochem Pharmacol 45(11): 2203-8. Abstract: The possible difference between lovastatin (mevinolin, MK-803), simvastatin (MK-733) and pravastatin (CS-514), all chemically-related competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, were tested in the human hepatoma cell line Hep G2, which is often used as a model for the human hepatocyte. After an 18-hr incubation of the cells with the drugs, pravastatin (IC50 = 1900 nM) was less potent than simvastatin and lovastatin (IC50 = 34 and 24 nM, respectively) in inhibiting the sterol synthesis. As a consequence of this inhibition, the HMG-CoA reductase mRNA levels and squalene synthase activity, both negatively-regulated by sterols, were increased equally by simvastatin and lovastatin, whereas the induction by pravastatin was much less. In contrast, there were fewer differences between the compounds in inhibiting HMG-CoA reductase activity, when assayed directly in Hep G2 cell homogenates (IC50 values = 18, 61 and 95 nM for simvastatin, lovastatin and pravastatin, respectively). Moreover, in experiments with human hepatocytes in primary culture the IC50 values for inhibition of the cholesterol synthesis by simvastatin and pravastatin were of the same order of magnitude (23 and 105 nM, respectively). The results are therefore explained as follows: the three drugs act in the same way within the Hep G2 cell in terms of inhibiting HMG-CoA reductase and their subsequent effect on the feedback regulation of the cholesterol synthesis, i.e. increasing squalene synthase and HMG-CoA reductase mRNA. However, pravastatin seems to be less able to enter the cells compared with simvastatin and lovastatin, possibly because of the higher hydrophobicity of the latter compounds. The observation with human hepatocytes suggests that in Hep G2 cells a specific hepatic transporter is missing. On one hand the human hepatoma cell line Hep G2 has proved to be a good model for the study of the feedback regulation of enzymes of the cholesterol biosynthetic pathway such as HMG-CoA reductase and squalene synthase, but, on the other hand seems to be less suitable as a model for the study of specific uptake of drugs, e.g. the vastatins, in human hepatocytes. |
| Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies Keidar, S., M. Aviram, et al. (1994), Br J Clin Pharmacol 38(6): 513-9. Abstract: 1. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) inhibitor, is a highly selective inhibitor of hepatic cholesterol synthesis. We studied the in vivo and in vitro effects of pravastatin on macrophage cholesterol metabolism. 2. The effects of incubating pravastatin with human monocyte derived macrophages (HMDM), mouse peritoneal macrophages (MPM) and a J-774 A.1 macrophage-like cell line, on macrophage cholesterol synthesis, cellular degradation of native low density lipoprotein (LDL) and modified LDL, cholesterol efflux from these cells and the cholesterol esterification rate were determined. 3. Pravastatin was administered either as one 40 mg dose or 40 mg daily for 8 weeks to normocholesterolaemic and hypercholesterolaemic individuals. The effects on cholesterol synthesis and degradation in monocytes derived from these subjects were studied. 4. In vitro, pravastatin resulted in a dose-dependent inhibition of macrophage cholesterol synthesis. Cellular degradation of native LDL increased by 119% in the presence of 0.1 mg ml-1 pravastatin. Degradation of both acetyl LDL and oxidized LDL was unaffected. Small concentrations of pravastatin (up to 0.19 micrograms ml-1) increased the cellular cholesterol esterification rate after incubation with LDL, but higher concentrations resulted in an inhibition of the esterification. 5. Single dose pravastatin administration caused a reduction in cholesterol synthesis by the subjects own HMDM by 62% and 47% in normocholesterolaemic and hypercholesterolaemic individuals, respectively. Chronic administration resulted in a 55% inhibition of cholesterol synthesis and a 57% increase in LDL degradation. 6. The results indicate that the selective uptake of pravastatin shown for hepatocytes can be extended to macrophages.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Pravastatin lowers serum cholesterol, cholesterol-precursor sterols, fecal steroids, and cholesterol absorption in man Vanhanen, H., Y. A. Kesaniemi, et al. (1992), Metabolism 41(6): 588-95. Abstract: Serum lipids, and absorption, intestinal fluxes, fecal elimination, and synthesis of cholesterol were studied before and during 4 weeks of pravastatin treatment at a dose of 40 mg/d in heterozygous familial hypercholesterolemic (FH) patients without (control group, n = 7) and with an ileal bypass (IBP group, n = 6). The drug reduced serum total and low-density lipoprotein (LDL) cholesterol and LDL-apoprotein (apo)B levels up to 34%. Less-consistent decreases in intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL) cholesterol were also seen. None of the control patients and two of the IBP patients became normolipidemic (LDL less than 4 mmol/L). Marked transient reductions in serum free-methylated-cholesterol precursors, and more-constant decreases in the esterified and total fractions, suggested that cholesterol synthesis was reduced shortly after the start of treatment. The decreases in total lathosterol and methylsterols were more extensive in the IBP group than in the control group. Serum plant sterol levels were slightly increased, with inconsistent elevations of cholestanol. Reduced fecal elimination of cholesterol and its precursors suggests that decreased cholesterol synthesis was mainly due to lowered bile acid production, particularly in the IBP group with markedly enhanced basal bile acid and cholesterol synthesis. The serum and fecal levels of cholesterol precursors, lathosterol in particular, were related to each other and were proportionate to the serum level and fecal elimination of cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Pravastatin reduces serum cholesterol and low density lipoprotein concentrations following pancreas transplantation al'Halawani, M. H., J. L. Larsen, et al. (1994), Transplantation 58(11): 1204-9. Abstract: Hyperlipidemia is a significant risk factor for atherosclerotic vascular disease. We have shown previously that pancreas transplantation (PTX) improves but does not normalize lipids in most PTX recipients. We studied whether pravastatin was effective in treating 10 patients with elevated low density lipoprotein (LDL)-cholesterol (LDL-C) following PTX. Seven men and 3 women were studied. Six received combined kidney-pancreas transplantations, while 4 received PTX alone. Age at time of PTX was 37.2 +/- 2.2 years (mean +/- SEM), and 4 had established coronary artery disease before PTX. Mean cholesterol (C), LDL-C, triglycerides (TG), and high density lipoprotein (HDL)-cholesterol (HDL-C) were 236 +/- 12, 142 +/- 6, 222 +/- 50, and 49 +/- 4 mg/dl before PTX. The LDL to HDL ratio was 3.0 +/- 0.3. After PTX, excluding the first 45 days, mean C, LDL-C, and HDL-C increased to 278 +/- 10, 178 +/- 7, and 63 +/- 6 mg/dl (all P < or = 0.05), respectively. TG, LDL to HDL ratio, and weight were unchanged. Pravastatin (11.7 +/- 0.8 mg/day, mean +/- SEM) was initiated 250 +/- 53 days after PTX. During therapy, C and LDL-C decreased on average to 231 +/- 10 and 134 +/- 8 mg/dl, respectively (both P < 0.01), while HDL did not change. The decreases in C and LDL-C were unexplained by a decrease in weight, cyclosporine dose or concentration, or increase in serum creatinine. However, prednisone dose decreased over the same interval, so a contribution from this variable cannot be excluded. No evidence of toxicity was identified during therapy. This is one of the first reports demonstrating that pravastatin is a safe and effective treatment for elevated C and LDL-C in patients following PTX. However, pravastatin did not increase HDL or decrease TG, as observed in the nontransplantation setting. Whether pravastatin or any hypolipidemia therapy can prevent cardiovascular events or mortality following PTX remains to be established. |
| Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions Kaesemeyer, W. H., R. B. Caldwell, et al. (1999), J Am Coll Cardiol 33(1): 234-41. Abstract: OBJECTIVES: We tested the hypothesis that pravastatin (PRA) activates endothelial nitric oxide synthase (eNOS). BACKGROUND: Pravastatin has been found to have clinical benefits beyond those predicted by its actions in reducing plasma low density lipoprotein cholesterol (LDL). Both PRA and simvastatin (SIM) are equally effective in reducing LDL, but only PRA reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates. METHODS: We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using a NO electrode and by an assay for conversion of hemoglobin to methemoglobin. Specificity of NOS activation was tested by using the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 1 mmol/liter) in the presence or absence of excess L-arginine (L-ARG, 1 mmol/liter). RESULTS: Endothelium-dependent vasorelaxation was maximal with acetylocholine (ACH, 100%), followed by PRA (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PRA and ACH had similar dose-dependent effects on NO production, while SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these results and demonstrated their specificity for NOS activity. The L-NAME blunted the responses to 45% of initial values. Excess L-ARG reversed this effect and potentiated NO production to 133% of initial levels. CONCLUSIONS: Both PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation. |
| Pravastatin sodium, a competitive inhibitor of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases the cholesterol content of newly secreted very-low-density lipoprotein in Watanabe heritable hyperlipidemic rabbits Shiomi, M. and T. Ito (1994), Metabolism 43(5): 559-64. Abstract: We examined the secretion of very-low-density lipoprotein (VLDL) when hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis, was inhibited. To inhibit HMG-CoA reductase in liver, pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, was administered to homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, a low-density lipoprotein receptor-deficient animal model, at a dosage of 50 mg/kg per day for 5 weeks. Although triglyceride levels were not changed, total cholesterol levels of sera and each atherogenic lipoprotein were decreased by approximately 30%. As a result, the percentage of cholesterol concentration in newly secreted VLDL was significantly decreased by 24%. The VLDL secretion rate was determined by intravenous injection of Triton WR-1339. The VLDL secretion rate was significantly decreased by 23% using cholesterol as an index, but it did not change using triglyceride, phospholipid, or protein as an index. It is concluded that one of the mechanisms of serum total cholesterol decrease due to reduction of the putative cholesterol pool of the liver in homozygous WHHL rabbits is caused by a decrease of cholesterol content in newly secreted VLDL particles. |
| Pravastatin sodium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases serum total cholesterol in Japanese White rabbits by two different mechanisms Miyazaki, A. and T. Koga (2002), Atherosclerosis 162(2): 299-306. Abstract: Pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), when orally administered to male Japanese White (JW) rabbits at 1-30 mg/kg for 21 days, decreased the concentrations of total cholesterol, low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol in a dose-dependent manner. On the other hand, pravastatin did not change the concentration of serum triglycerides and very low density lipoprotein (VLDL)-cholesterol. On day 21, LDL-cholesterol was significantly decreased at doses higher than 3 mg/kg, whereas HDL-cholesterol was significantly reduced at doses higher than 10 mg/kg. The concentrations of hepatic LDL receptor proteins determined by immunoblot analysis increased at the same dose at which the concentrations of LDL-cholesterol decreased. The serum concentrations of HDL-cholesterol were decreased at the same dose at which VLDL-cholesterol secretion rates from the liver were reduced. The present study suggests that in JW rabbits, pravastatin decreases the serum concentration of LDL-cholesterol through an LDL receptor pathway, whereas the agent lowers the concentration of HDL-cholesterol by the mechanisms associated with a reduction of VLDL-cholesterol secretion from the liver. |
| Pravastatin sodium, an inhibitor of HMG-CoA reductase, decreases HDL cholesterol by transfer of cholesteryl ester from HDL to VLDL in Japanese white rabbits Miyazaki, A., T. Koieyama, et al. (2004), J Atheroscler Thromb 11(1): 22-8. Abstract: In a recent paper, we reported that pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme. A reductase, decreases the concentrations of low density lipoprotein (LDL) cholesterol through an LDL receptor pathway in Japanese White (JW) rabbits, whereas this agent lowers high density lipoprotein (HDL) cholesterol in a manner correlated with a reduction of very low density lipoprotein (VLDL) cholesterol secretion from the liver. In the present study, we administered pravastatin to JW rabbits at 30 mg/kg for 14 days and examined further the mechanisms for the reduction of HDL cholesterol. A striking finding was that the 4-day administration of pravastatin at 30 mg/kg selectively decreased the concentration of HDL cholesterol. Since 4-day administration of pravastatin to JW rabbits did not change the concentrations of hepatic LDL receptor proteins, these receptors were not likely to be involved in the reduction of HDL cholesterol. Another important finding was that pravastatin suppressed VLDL cholesteryl ester (CE) secretion from the liver, but not that of other VLDL lipids and VLDL proteins, indicating that the CE-poor VLDL particles were secreted by the consecutive administration of pravastatin. There were, however, no differences in the levels of VLDL cholesterol between the control and pravastatin-treated groups over the experimental period of 14 days. These observations raised the possibility that the reduction of HDL cholesterol in the pravastatin-treated group was due to the transfer of CE molecules from HDL particles to these CE-poor VLDL particles. Molecular species analysis supported this notion that the VLDL-CE in the pravastatin-treated group was rich in cholesteryl linoleate, indicating that the CE in this group mainly originated from HDL, whereas the VLDL-CE in the control group was rich in cholesteryl oleate, indicating that the CE in this group originated from the liver. The present study suggests that pravastatin lowers HDL cholesterol by transferring CE from these lipoproteins to VLDL in JW rabbits. |
| Pravastatin--(Pravachol)--a new inhibitor of cholesterol synthesis Haghfelt, T. (1993), Ugeskr Laeger 155(12): 903-6. |
| Pravastatin, a new cholesterol synthesis inhibitor for lowering increased serum cholesterol Hoppichler, F., M. Lechleitner, et al. (1992), Z Gesamte Inn Med 47(11): 523-7. Abstract: The association between increased risk for coronary artery disease (CAD) and elevated plasma cholesterol has been firmly established. The beneficial effect of cholesterol lowering treatment modalities was confirmed in both primary and secondary intervention trials. Because long-term treatment is usually required for lipid lowering therapies the drugs used for lipid reduction have to be not only efficacious but also safe. Inhibitors of cholesterol synthesis that have become clinically available during the last few years, can reduce plasma levels of total cholesterol and low density lipoprotein (LDL)-cholesterol very effectively. In the Familial Atherosclerosis Treatment Study (FATS) an intensive cholesterol lowering treatment modality consisting of a combination of an inhibitor of cholesterol synthesis and colestipol reduced the progression of coronary lesions and caused a partial regression of such lesions. Among the various inhibitors of cholesterol synthesis developed recently, pravastatin appears to be tissue-specific because of its hydrophilic property. |
| Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect Dangas, G., D. A. Smith, et al. (2000), Thromb Haemost 83(5): 688-92. Abstract: Lipid-lowering with statins reduces blood thrombogenicity. However, it is unknown whether this is purely due to LDL-cholesterol reduction, or it is related to a statin or agent specific effect. We investigated the relationship between reduction in blood thrombogenicity and the magnitude of low-density lipoprotein cholesterol (LDL-C) during pravastatin therapy. We prospectively followed for 6 months 57 hyperlipidemic patients who initiated therapy with pravastatin, and 36 patients who were randomized into placebo plus diet. Pravastatin-treated patients were grouped according to the LDL-C reduction at 6 months; (i) "adequate LDL-C reduction": LDL-C reduction >30% from baseline or LDL-C<125 mg/dl (n = 38; LDL-C reduction 74 +/- 4 mg/dl; 6-month LDL-C 119 +/- 5 mg/dl); (ii) "inadequate LDL-C reduction": neither of the above criteria (n = 19; LDL-C reduction 31 +/- 5 mg/dl; 6-month LDL-C 158 +/- 6 mg/dl). Placebo patients were divided into those "with LDL-C reduction" (n = 17, mean reduction 21 +/- 5 mg/dl) and those "without LDL reduction" (n = 19). The following parameters were altered at 6 months in both patients with "adequate" and "inadequate" LDL-C reduction: (1) tissue plasminogen activator decreased by 1.4 +/- 0.4 and 1.5 +/- 0.5 ng/ml respectively (p = NS); (2) plasminogen activator inhibitor-1 decreased by 8.7 +/- 2.0 and 10.1 +/- 2.7 ng/ml respectively (p = NS); (3) thrombus formation under dynamic flow conditions decreased by 3.5 +/- 0.9 and 2.8 +/- 1.2 microm2 x 10(3) respectively (p = NS). In contrast, no significant changes from baseline were noted in placebo-treated patients, regardless of their LDL-C reduction category, and multivariate analysis eliminated LDL-C reduction as an independent predictor of reduction in thrombogenicity. Therefore, the reduction in thrombogenicity was not proportional to the magnitude of LDL-C reduction suggesting that a class or agent specific property is primarily responsible for the pro-fibrinolytic/antithrombotic effects observed. |
| Prebeta1-high-density lipoprotein (prebeta1-HDL) concentration can change with low-density lipoprotein-cholesterol (LDL-C) concentration independent of cholesteryl ester transfer protein (CETP) Miida, T., K. Ozaki, et al. (2000), Clin Chim Acta 292(1-2): 69-80. Abstract: To clarify whether prebeta1-high-density lipoprotein (prebeta1-HDL) concentration changes with low-density lipoprotein-cholesterol (LDL-C) concentration independent of cholesteryl ester transfer protein (CETP), we determined prebeta1-HDL concentration by native two-dimensional gel electrophoresis in 58 subjects with normal triglyceride and HDL-cholesterol concentrations. We also measured LDL-C and CETP concentrations. In 17 subjects, a second blood sample was taken 1-6 months after the first. We found that prebeta1-HDL concentration was positively correlated with LDL-C concentration (r=0.529, P<0.0001) and with CETP mass (r=0.398, P<0.01). In 17 patients, Deltaprebeta1-HDL was positively correlated with DeltaLDL-C (r=0.635, P<0.01), but not with DeltaCETP mass (r=0.275). In conclusion, prebeta1-HDL concentration changes with LDL-C concentration independent of CETP. These results suggest that prebeta1-HDL concentration may reflect the balance between several regulatory factors, including LDL-C and CETP concentrations. |