Showing papers on "Lovastatin published in 1994"
TL;DR: In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality.
Abstract: BACKGROUND HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.
872 citations
TL;DR: Lovastatin slows the progression of coronary atherosclerosis and inhibits the development of new coronary lesions and in patients whose baseline total or LDL cholesterol levels were above the group median.
Abstract: BACKGROUND3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are widely prescribed for hyperlipidemia, yet their effect on the evolution of coronary atherosclerosis has not been defined.METHODS AND RESULTSTo address this issue, 331 patients with diffuse but not necessarily severe coronary atherosclerosis documented on a recent arteriogram and with fasting serum cholesterol between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial. All patients received intensive dietary counseling. Lovastatin or placebo was begun at 20 mg/d and was titrated to 40 and 80 mg during the first 16 weeks to attain a fasting low-density lipoprotein (LDL) cholesterol < or = 130 mg/dL. The mean lovastatin dose was 36 mg/d. Coronary arteriography was repeated after 2 years. In 299 patients (90%), 3858 coronary segments containing 2309 stenoses were measured blindly on pairs of films with an automated computerized quantitative system. Total and LDL cholesterol decreased by 21 +/- 11% and...
495 citations
TL;DR: Clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets, found that coronary lesions or = 50% S at baseline had different responses to therapy, are reported on.
Abstract: BACKGROUNDThe Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets.METHODS AND RESULTSTwo hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were trig...
316 citations
TL;DR: The BBB permeability correlates with the CNS side effects of the HMG-CoA reductase inhibitors, and is shown to be similar to that of the blood–brain barrier.
Abstract: Among the HMG-CoA reductase inhibitors, lovastatin and simvastatin have central nervous system (CNS) side effects, such as sleep disturbance, whereas pravastatin does not. This difference in CNS side effects may be due to a difference in blood-brain barrier (BBB) permeability among these inhibitors. To test this hypothesis, we compared the BBB transport ability of HMG-CoA reductase inhibitors by using an in vivo brain perfusion technique in rats and an in vitro culture system of bovine brain capillary endothelial cells. The in vivo BBB permeability coefficients of the lipophilic inhibitors, [14C]lovastatin and [14C]simvastatin, were high. In contrast, that of the hydrophilic inhibitor, [14C]pravastatin, was low and not significantly different from that of [14C]sucrose, an extracellular space marker. Similarly, the in vitro BBB permeability coefficients of [14C]lovastatin and [1C]simvastatin were high, while that of [14C]-pravastatin was low. The in vivo and in vitro transcellular permeabilities obtained for HMG-CoA reductase inhibitors were comparable. This study shows that the BBB permeability correlates with the CNS side effects of the HMG-CoA reductase inhibitors.
204 citations
TL;DR: Four inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia, three of which are fungal metabolites or derivatives thereof: lovastatin, simvastsatin, and pravastatin.
Abstract: Four inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia. Three of these are fungal metabolites or derivatives thereof: lovastatin, simvastatin, and pravastatin. The fourth, fluvastatin, is totally synthetic. Its structure, containing a fluorophenyl-substituted indole ring, is distinct from that of the fungal metabolites. Lovastatin and simvastatin are administered as prodrugs, which undergo in vivo transformation to active inhibitory forms; fluvastatin and pravastatin are administered as active agents. The HMG-CoA reductase inhibitors are all effective in reducing plasma concentrations of low density lipoprotein. They have differing pharmacokinetic properties, which may be of importance in some patients. All of these drugs are very well tolerated, and there do not appear to be major differences in toxicity or adverse effects. When LDL reductions > 30% are needed, simvastatin is the most cost-effective HMG-CoA reductase inhibitor. However, these drugs are most commonly used in dosages that reduce LDL-C by 20-30%. For this degree of LDL reduction, fluvastatin is the most cost-effective HMG-CoA reductase inhibitor.
200 citations
TL;DR: The data suggest that HMG-CoA reductase inhibitors such as lovastatin merit further investigation as potential therapeutic agents for the treatment of malignant gliomas.
183 citations
TL;DR: Lovastatin was better tolerated than niacin and both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins in patients with primary hypercholesterolemia.
Abstract: Background: Niacin and lovastatin are both effective drugs for the treatment of hypercholesterolemia and are among the drugs of first choice recommended by the adult treatment panel. To date, however, no studies have directly compared the lipoprotein-modifying effects and safety of lovastatin and niacin across their usual dosage range in patients with primary hypercholesterolemia. Methods: The efficacy and safety of lovastatin and niacin were compared in a controlled, randomized, open-label study of 26 weeks' duration that was conducted at five lipid clinics. One hundred thirty-six patients with primary hypercholesterolemia participated in the study. Entry criteria were a low-density lipoprotein (LDL) cholesterol level greater than 4.37 mmol/L (160 mg/dL) with coronary heart disease and/or more than two coronary heart disease risk factors or an LDL cholesterol level greater than 5.19 mmol/L (190 mg/dL) in patients without coronary heart disease or less than two coronary heart disease risk factors. The study consisted of a 4-week diet run-in period after which eligible patients were randomly assigned to receive treatment with either lovastatin (20 mg/d) or niacin (1.5 g/d) for 10 weeks. On the basis of the LDL cholesterol response and patient tolerance, the doses were sequentially increased to 40 and 80 mg/d of lovastatin or 3 and 4.5 g/d of niacin after 10 and 18 weeks of treatment, respectively. Results: In the two patient groups, 66% of patients treated with lovastatin and 54% of patients treated with niacin underwent full dosage titration. At all time points, lovastatin was significantly (P Conclusions: Lovastatin and niacin both exerted favorable dose-dependent changes on the concentrations of plasma lipids and lipoproteins. Lovastatin was more effective in reducing LDL cholesterol concentrations, whereas niacin was more effective in increasing high-density lipoprotein cholesterol concentrations and reducing the Lp(a) lipoprotein level. Lovastatin was better tolerated than niacin, in large part because of the common cutaneous side effects of niacin. (Arch Intern Med. 1994;154:1586-1595)
152 citations
TL;DR: It is shown that HL-60 cells treated with lovastatin, an inhibitor of mevalonate synthesis, exhibit alterations in growth and morphology, as well as changes in the subcellular distribution of isoprenylated proteins like nuclear lamin A and p21Ras.
143 citations
Journal Article•
TL;DR: Although the currently available HMG-CoA reductase inhibitors differ in their relative hypolipidemic effects, as a class they constitute the most effective agents available to maximally reduce elevated concentrations of LDL-cholesterol.
132 citations
TL;DR: It is indicated that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.
Abstract: The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations >3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.
126 citations
TL;DR: The effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses and the reversed antiproliferative effect of farnesol is assessed.
Abstract: Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.
TL;DR: It is demonstrated that plasma TFPI was associated with and regulated by LDL in plasma from healthy subjects and patients with familial hypercholesterolemia, and Gel filtration of plasma from these patients demonstrated a specific drop in apolipoprotein B-TFPI complexes, whereas T FPI not associated with lipoproteins was unchanged.
Abstract: Tissue-factor pathway inhibitor (TFPI) is a potent inhibitor of extrinsic coagulation, which is mainly associated with lipoproteins in circulating blood. Gel filtration of human plasma confirmed the presence of three peaks in which approximately 10%, 70%, and 20% of total TFPI activity was retained. Precipitation of very-low-density lipoproteins and low-density lipoproteins (LDLs) in plasma by polyethylene glycol almost completely abolished peaks and I and II. LDL isolated by ultracentrifugation revealed two peaks of TFPI after gel filtration that coeluted with peaks I and II, respectively, from gel filtration of total plasma. TFPI activity in peaks I and II was also precipitated by anti-apolipoprotein B antibodies. Fourteen patients with familial hypercholesterolemia had higher plasma TFPI activity than did age- and sex-matched normolipemic control subjects (1.45 +/- 0.27 U/mL versus 0.80 +/- 0.09 U/mL, P < .001). Plasma TFPI was correlated with LDL cholesterol (r = .73, P < .001) and apolipoprotein B (r = .69, P < .001). No association was found with high-density lipoprotein cholesterol or apolipoprotein A-I. In a double-blind, placebo-controlled trial among the familial hypercholesterolemia patients, lovastatin alone or in combination with fish oil concentrate lowered plasma TFPI in parallel with LDL cholesterol. Gel filtration of plasma from these patients demonstrated a specific drop in apolipoprotein B-TFPI complexes, whereas TFPI not associated with lipoproteins was unchanged. This study demonstrated that plasma TFPI was associated with and regulated by LDL in plasma from healthy subjects and patients with familial hypercholesterolemia.
TL;DR: Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia and it was suggested that changes in serum ubiqu inone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for Ubiquinone.
Abstract: Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia. The serum ubiquinone levels were determined after the patients had received simvastatin (20-40 mg per day) for 4.7 years, after a 4 week treatment pause and again after they had resumed treatment with lovastatin (20-40 mg per day) for 12 weeks. During the treatment pause the average serum ubiquinone levels increased by 32%; resumption of treatment caused a reduction of 25%. The changes in the levels of ubiquinone and serum total cholesterol as well as those of ubiquinone and low-density lipoprotein cholesterol were closely parallel. This suggested that changes in serum ubiquinone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for ubiquinone. After long-term simvastatin treatment and after short-term lovastatin treatment, average serum ubiquinone levels (1.16 and 1.22 mg.l-1, respectively) were similar to that observed in a group of apparently healthy middle-aged men (1.16 mg.l-1).
TL;DR: It is concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development.
TL;DR: Older subjects of both genders and a variety of racial and ethnic groups can be successfully recruited into a cholesterol-lowering trial and Lovastatin has effects similar to those reported in younger subjects in previous controlled trials.
Abstract: Background: Total and lipoprotein cholesterol levels continue to be predictors of coronary heart disease risk in men and women over 65 years old. Cholesterol-lowering trials, however, while sometimes including such subjects, have not concentrated on this age group. The Cholesterol Reduction in Seniors Program was a five-center pilot study to assess feasibility of recruitment and efficacy of cholesterol lowering in this age group. Methods: The study was a randomized, double-masked clinical trial with placebo, 20-mg lovastatin, and 40-mg lovastatin arms. Major efforts were made to recruit women and minorities. Participants were followed up for 1 year on a cholesterollowering diet plus placebo or study drug. End points were changes in blood lipid levels. Data on other blood chemistry values, as well as quality-of-life measures and coronary heart disease morbidity and mortality, were also collected. Results: Four hundred thirty-one subjects with low-density lipoprotein cholesterol levels greater than 4.1 and less than 5.7 mmol/L (159 and 221 mg/dL) were randomized, of whom 71% were women and 21% were African Americans; the mean age was 71 years. In the 20- and 40-mg lovastatin groups, total cholesterol levels fell 17% and 20%; lowdensity lipoprotein cholesterol levels fell 24% and 28%; triglyceride levels fell 4.4% and 9.9%, respectively. High-density lipoprotein cholesterol levels rose 7.0% and 9.0%, respectively. No changes were observed in the placebo group. Gender, race, and age did not significantly affect responses. Coronary heart disease morbidity and mortality data were collected but not analyzed for this study. Conclusion: Older subjects of both genders and a variety of racial and ethnic groups can be successfully recruited into a cholesterol-lowering trial. Lovastatin has effects similar to those reported in younger subjects in previous controlled trials. There is little advantage to the higher lovastatin daily dose. Side effects were remarkably low in all groups. (Arch Intern Med. 1994;154:529-539)
TL;DR: In patients with hypercholesterolemia, lovastatin and pravastatin have nearly identical effects on lipids and no significant effects on sleep and cognitive performance.
Abstract: Sleep disturbances and decrements of daytime performance have been attributed to HMG-CoA reductase inhibitors. As a rule, lipophilic compounds more readily cross the blood-brain barrier and are more likely to affect central nervous system function. The authors compared the effects of lovastatin (40 mg), a lipophilic compound, to pravastatin (40 mg), a hydrophilic compound, in a 6-week, double-blind, randomized, placebo-controlled, three-way Latin square design, cross-over study on 22 men with hypercholesterolemia. Patients had LDL cholesterol of more than 165 mg/dL and triglyceride of less than 350 mg/dL after 6 weeks of a low-fat (< 30%), low-cholesterol (< 300 mg/day) diet. Compared with placebo, there were no significant effects of lovastatin or pravastatin on the following subjective and polysomnographic sleep measures: changes in total sleep time, time in each sleep stage, sleep efficiency, sleep latency, REM density, REM activity, and number of arousals. Similarly, there were no effects of the two drugs on measures of cognitive performance. A significant increase in the duration of nocturnal tumescence (NPT) was observed after 2 weeks of treatment with both study drugs. This effect was not significant after 6 weeks of treatment. Both lovastatin and pravastatin caused significant (P < .05 compared with placebo) decreases in total cholesterol (by 20.9 and 20.6%, respectively), LDL cholesterol (by 27.8 and 29.9%), and triglycerides (by 13.6 and 3.7%). Subjects' HDL increased by 2.3% with lovastatin (NS) and by 3.1% with pravastatin (P < .05). Lipoprotein(a) increased by 20.5% with lovastatin and by 1.1% with pravastatin; these changes were not significantly different from placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The lipid composition of whole platelets and the fluidity of platelet membranes, as well as the sensitivity of the cell to aggregation, were studied in type IIA hypercholesterolemic human subjects before and after treatment with lovastatin.
Abstract: The lipid composition of whole platelets and the fluidity of platelet membranes, as well as the sensitivity of the cell to aggregation, were studied in type IIA hypercholesterolemic human subjects before and after treatment with lovastatin. Fourteen patients with primary hypercholesterolemia having initial cholesterol levels of 383 +/- 52 mg/dL (mean +/- standard deviation) were studied and compared with 21 control subjects having cholesterol levels of 187 +/- 32 mg/dL. Lovastatin was administered orally at a starting dose of 40 mg daily. The dose was increased to 80 mg daily for eight patients who did not achieve the target cholesterol level of 200 mg/dL at 6 weeks. Serum cholesterol level was decreased by 37% following 20 weeks' administration of the drug. The fluidity of platelet membranes expressed in terms of the fluorescence anisotropy parameter was determined using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). When compared with platelets obtained from normocholesterolemic controls, platelets from hypercholesterolemic patients had a higher molar ratio of cholesterol to phospholipids ([C/PL] 0.86 +/- 0.15 v 0.57 +/- 0.06 for controls) and of phosphatidylcholine to sphingomyelin ([PC/SM] 2.64 +/- 0.87 v 2.00 +/- 0.15 for controls), enhanced fluidity (anisotropy parameter at 37 degrees C of 0.892 +/- 0.066 v 0.977 +/- 0.065 for controls), and a greater tendency to aggregate (aggregation of 84.2% +/- 6.3% v 78.5% +/- 7.6% for controls).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutations.
Abstract: Lovastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of pancreatic cancer cells A possible mechanism of this inhibition is that lovastatin inhibits the activity of RAS protein by depleting farnesyl (an intermediate of cholesterol synthesis) The K-ras gene is frequently mutated in pancreatic cancers and RAS protein requires farnesyl to be bound to the cell membrane and thereby activated To investigate whether lovastatin inhibition of cell growth depends upon the presence of ras mutation, codons 12/13 and 61 of ras genes were examined by the dideoxynucleotide chain-terminating method in five pancreatic cell lines (human CAPAN2, CAV, MIA Paca2, PANCi, and hamster H2T) on which lovastatin exerted a growth-inhibitory effect These codons play a major role in tumorigenic mutation of ras genes Lovastatin inhibited cell growth by 99% (MIA), 97% (H2T), 78% (CAV), 41% (CAPAN2), and 23% (PANC1), respectively, when cells were treated with 25 micrograms/ml lovastatin for 6 days Activating point mutations were found in codon 12 of the K-ras gene (wild type:GGT) in MIA (GTT), H2T (GAT), CAPAN2 (TGT), and PANC1 (GAT) but not in CAV In addition, the CAV cell line did not have a mutation in either H- or N-ras genes Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutation
Journal Article•
TL;DR: The differential effect of lovastatin on normal and leukaemic progenitor cells may have value in the clinical management of AML and the possible use of Lovastatin, or related drugs, as adjuvants to conventional chemotherapy including in vitro BM purging, merits consideration.
Abstract: Primary human acute myeloid leukaemic (AML) cells from bone marrow (BM) and peripheral blood (PB), the human myeloblastic leukaemia cell line (HL60) and normal human BM mononuclear cells were cultured in serum-free medium. The survival of progenitor cells from normal BM, HL60 and AML cell populations was reduced over a range of concentrations of lovastatin. This dose response relationship was more pronounced in HL60 and AML cell cultures, indicating greater sensitivity of AML progenitor cells compared with normal BM progenitors. Short-term exposure (18 h) to a range of concentrations of lovastatin showed the same differential response between leukaemic and normal BM cells in terms of clonogenicity. At a concentration of 10 micrograms/ml progenitor cell survival remained above 65% for normal BM while at this concentration leukaemia progenitor cell survival fell below 25% of the untreated values. The differential effect of lovastatin on normal and leukaemic progenitor cells may have value in the clinical management of AML. The possible use of lovastatin, or related drugs, as adjuvants to conventional chemotherapy including in vitro BM purging, merits consideration.
TL;DR: This uncontrolled study requires further investigation to elucidate the independent relation between lovastatin, PAI-1, and fibrinogen.
Abstract: There are now extensive data suggesting that the progression of atherosclerosis can be altered by cholesterol-lowering therapy. The changes in stenosis severity, measured angiographically, are small relative to the clinical benefit noted. Other factors, in addition to changes in stenosis severity, are probably operative. Effects of cholesterol-lowering on endothelial function, perhaps mediated by reductions in PAI-1 levels, may be one of these mechanisms. This uncontrolled study requires further investigation to elucidate the independent relation between lovastatin, PAI-1, and fibrinogen.
TL;DR: A low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause.
Abstract: Objective. —To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality. Design. —In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placebo-controlled, randomized, double-blind study using lovastatin as the therapeutic agent. Setting. —The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex. Patients. —For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean±SD LDL cholesterol, 4.78±0.59 mmol/L [185 ±23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean±SD LDL cholesterol, 3.31 ±0.39 mmol/L [128±15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. Interventions. —In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo. Main Outcome Measures. —In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. Results. —In the LDL turnover study, mean (±SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [±3.2] mg/kg per day and 11.1 [±2.2] mg/kg per day, respectively). In contrast, mean (±SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [±0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [±0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (±SD) total cholesterol and LDL cholesterol from 7.03 (±1.16) mmol/L (272 [±45] mg/dL) and 4.42 (±0.80) mmol/L (171 [±31] mg/dL, respectively, to 5.70 (±1.03) mmol/L (221 [±40] mg/dL) and 3.46 (±0.85) mmol/L (134 [±33] mg/dL). Conclusions. —The turnover data suggest that hypercholesterolemia in postmenopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause. (JAMA. 1994;271:453-459)
TL;DR: It is concluded that LDL-apheresis stimulates cholesterol biosynthesis transiently despite concomitant therapy with an HMG-CoA reductase inhibitor, the degree of stimulation being inversely related to the level to which the LDL-cholesterol was reduced.
TL;DR: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit the in vitro intraerythrocytic development of Plasmodium falciparum and Babesia divergens, with concentrations inhibiting parasite growth by 50% in the ranges of 10 to 20 and 5 to 10 micrograms, respectively.
Abstract: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit the in vitro intraerythrocytic development of Plasmodium falciparum and Babesia divergens, with concentrations inhibiting parasite growth by 50% in the ranges of 10 to 20 and 5 to 10 micrograms.ml-1, respectively. For P. falciparum, the 50% inhibitory concentrations were in the same range whatever the chloroquine susceptibility of the strains tested (strain F32/Tanzania [chloroquine susceptible] or FcB.1/Columbia [resistant]). The stage-dependent susceptibility of P. falciparum to simvastatin was studied by subjecting synchronized cultures to 6-h pulses of drug throughout the 48-h erythrocytic life cycle. The most important inhibitory effects were observed between the 12th and 30th hours of the cycle, corresponding to the trophozoite stage. This period precedes the S phase and the nuclear divisions. Parasites in the newly formed ring stage (time zero to the 6th hour of the cycle) and the schizont stage (30th to 48th hour of the cycle) were weakly or not susceptible to simvastatin pulses.
TL;DR: Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease.
Abstract: Background: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. Methods: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. Results: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. Conclusions: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein— high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease. (Arch Intern Med. 1994;154:73-82)
TL;DR: Since HIV infection has been shown to induce alterations in membrane cholesterol content, suggesting that the virus cycle may be partially dependent upon cellular cholesterol, inhibitors of cholesterol synthesis could be an interesting way of research to slower HIV propagation.
TL;DR: It was found that while dietary cholesterol had little effect on HMG-CoA reductase mRNA levels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity; any possible effect on catalytic efficiency is thus ruled out.
Journal Article•
TL;DR: The analysis showed that the cost-effectiveness of cholesterol-lowering therapy is sensitive to pretreatment risk of CHD, as expressed by pretreatment cholesterol levels and the presence of additional risk factors such as hypertension, diabetes, and smoking.
TL;DR: To establish whether lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, exhibits a specific effect on apolipoprotein (apo) A- and apoB-containing lipoproteins, 63 subjects, a subset of the 270 Monitored Atherosclerosis Regression Study (MARS) patients with hypercholesterolemia, were randomized into either lovASTatin 40 mg twice daily
Abstract: To establish whether lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, exhibits a specific effect on apolipoprotein (apo) A- and apoB-containing lipoproteins, 63 subjects, a subset of the 270 Monitored Atherosclerosis Regression Study (MARS) patients with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease, were randomized into either lovastatin 40 mg twice daily or matching placebo tablets twice daily. Both groups consumed a diet containing 27% calories as fat (polyunsaturated fat/saturated fat ratio, 2.85) and a daily cholesterol intake of less than 250 mg. The plasma lipid and apolipoprotein profiles were determined at the time of randomization and after 2 years of treatment, and the levels of apoA- and apoB-containing lipoprotein families were measured after 2 years of treatment. After this treatment period, the drug group was characterized in comparison with the placebo group by significantly reduced levels of total cholesterol (33%), triglycerides (30%), very-low-density lipoprotein cholesterol (36%), low-density lipoprotein cholesterol (43%), apoB (36%), apoC-III (18%), and apoE (17%) and slightly but insignificantly increased levels of high-density lipoprotein cholesterol (6%) and apoA-I (1%). The 2-year levels of lipoprotein containing apoA-I but no apoA-II (LpA-I) and lipoprotein containing both apoA-I and apoA-II (LpA-I/A-II) particles separated by immunoaffinity chromatography on an anti-apoA-II immunosorber did not differ between the two treatment groups. However, the apoB-containing lipoprotein (Lp) families defined by apolipoprotein composition and separated by immunoaffinity chromatography on anti-apoA-II and anti-apoC-III immunosorbers were affected in a selective manner.(ABSTRACT TRUNCATED AT 250 WORDS)