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Lifibrol is a potent lipid-lowering drug with an unknown mechanism of action. We investigated its effects on lipoprotein and sterol metabolism in normocholesterolemic male participants. Seven participants were treated for 4 weeks with 600 mg/d lifibrol and 9 with 40 mg/d pravastatin in a double-blind randomized parallel-group trial. Kinetic studies were performed at baseline and under acute and chronic treatment. Turnover of apolipoprotein B-100 was investigated with endogenous stable-isotope labeling, and kinetic parameters were derived by multicompartmental modeling. Lathosterol and cholesterol metabolism were investigated using mass isotopomer distribution analysis (MIDA) after [1-(13)C]acetate labeling. Carbon metabolism was investigated by calculating the total isotope incorporation into newly formed sterols and measuring the disposal of acetate by (13)CO(2) breath analysis. Total- and low-density lipoprotein (LDL) cholesterol decreased by 18% and 27% under lifibrol and by 17% and 28% under pravastatin, respectively, whereas very-low-density lipoprotein (VLDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol did not change. Very-low-density lipoprotein apoB fractional synthesis and production increased under lifibrol but remained unchanged under pravastatin. Low-density lipoprotein apoB fractional synthesis and production increased under pravastatin but remained unchanged under lifibrol. Mass isotopomer distribution analysis indicated that both drugs decrease endogenous sterol synthesis after acute administration, but pravastatin had more powerful effects. Carbon-13 appearance in breath was higher during pravastatin than during lifibrol treatment. Mass isotopomer distribution analysis and carbon metabolism analysis indicated compartmentalization at the site of sterol synthesis, thus suggesting differential effects of the 2 drugs. Although having comparable lipid-lowering properties, lifibrol seems to have a mechanism of action distinct from that of statins. Lifibrol could serve as a model compound for the development of new lipid-lowering agents.

Statins decrease apoB-100-containing lipoproteins by increasing their fractional catabolic rates through LDL receptor-mediated uptake. Their influence on hepatic secretion of these lipoproteins is controversial. The objective of the study was to examine the influence of simvastatin on the secretion of apoB-100-containing lipoproteins in fasting non-obese subjects. Turnover of apoB-100-containing lipoproteins was investigated using stable isotope-labeled tracers. Multicompartmental modeling was used to derive kinetic parameters. Eight male subjects (BMI 25 +/- 3 kg/m(2)) with mild hypercholesterolemia (LDL cholesterol 135 +/- 30 mg/dL) and normal triglycerides (111 +/- 44 mg/dL) were examined under no treatment (A), under chronic treatment with simvastatin 40 mg/day (B) and after an acute-on-chronic dosage of 80 mg simvastatin under chronic simvastatin treatment (C). Lipoprotein concentrations changed as expected under 40 mg/day simvastatin. Fractional catabolic rates increased in IDL and LDL but not in VLDL fractions versus control [VLDL +35% in B (n.s.) and +21% in C (n.s.); IDL +169% in B (P = 0.08) and +187% in C (P = 0.032); LDL +87% in B (P = 0.025) and +133% in C (P = 0.025)]. Chronic (B) and acute-on-chronic simvastatin treatment (C) did not affect lipoprotein production rates [VLDL -8 and -13%, IDL +47 and +38%, and LDL +19 and +30% in B and C, respectively (all comparisons n.s.)]. The data indicate that simvastatin does not influence the secretion of apoB-100-containing lipoproteins in non-obese subjects with near-normal LDL cholesterol concentrations.

Objective: To assess the long-term efficacy and safety profile of ezetimibe 10 mg/day in patients with homozygous sitosterolemia., Methods: This was an extension of a multi-centre, randomised, double-blind, placebo-controlled base study in which patients with homozygous sitosterolemia and plasma sitosterol concentrations > 5 mg/dl were randomised 4 : 1 to ezetimibe 10 mg/day (n = 30) or placebo (n = 7) for 8 weeks. Patients who successfully completed the base study with > 80% compliance to study medication were eligible to enter two, successive, 1-year extension studies in which ezetimibe 10 mg/day was administered in an open-label manner. Patients remained on their current treatment regimen (e.g. bile salt-binding resins, statins and low-sterol diet) during the base and extension studies. Patients had to be off ezetimibe therapy for > or = 4 weeks prior to entering the first extension. Efficacy and safety/tolerability parameters were evaluated every 12 and 26 weeks in the first and second years respectively. The primary efficacy end-point was mean percentage change in plasma sitosterol from baseline to study end for the cohort of patients (n = 21) who successfully completed the second extension study., Results: Treatment with ezetimibe 10 mg/day led to significant mean percentage reductions from baseline in plasma concentrations of sitosterol (-43.9%; p < 0.001), campesterol (-50.8%; p < 0.001), low-density lipoprotein (LDL) sterols (-13.1%; p < 0.050), total sterols (-10.3%; p < 0.050) and apolipoprotein (apo) B (-10.1%; p < 0.050). No significant changes from baseline were observed for lathosterol, high-density lipoprotein sterol, triglycerides or apo A-1. Maximal reductions in sitosterol and campesterol occurred within the first 52 weeks of treatment and were sustained for the duration of the study. For LDL sterol, total sterols and apo B, maximal reductions were achieved early (by weeks 4 or 16) and waned slightly through the remainder of the study. Overall ezetimibe 10 mg was well tolerated., Conclusion: In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.

Objective: To assess the effect of ezetimibe (EZE) 40 mg/day on non-cholesterol sterol plasma concentrations in patients with homozygous sitosterolaemia (HoS)., Methods: This was a multi-centre, randomised, double-blind, placebo-controlled parallel group study. Twenty-seven patients (> or = 18 years) with HoS and plasma sitosterol levels > 5 mg/dl who had been taking EZE 10 mg/day for > or = 6 months prior to enrolment received open-label EZE 10 mg/day for the duration of the study and were randomised 1 : 1 to blinded EZE 30 mg/day (4 x EZE 10 mg tablets; n = 13) or placebo (1 x EZE 10 mg tablet and 3 x matching placebo tablets; n = 14) for 26 weeks. Patients were permitted to remain on other ongoing treatments (e.g. bile salt-binding resin, statin and/or low sterol diet). End-points included median per cent between-group changes from baseline in plasma sitosterol, campesterol, lathosterol, low-density lipoprotein (LDL) sterols, LDL cholesterol (LDL-C) measured by gas-liquid chromatography, and Achilles tendon thickness size measured radiographically., Results: Ezetimibe 40 mg/day resulted in median per cent changes from baseline in plasma sitosterol levels of 3.3% vs. -10% in the EZE 10 mg/day group, in plasma campesterol of -0.5% vs. -9.7% in the EZE 10 mg/day group, and in plasma lathosterol of 0.8% vs. 1.1% in the EZE 10 mg/day group (p = ns for all between-group differences). Median per cent changes in the EZE 40 mg/day and EZE 10 mg/day groups, respectively, were 1.3% and 0% for LDL sterols and 2.5% and 4.4% for LDL-C (p = ns for both between-group differences). At study end-point, Achilles tendon thickness remained unchanged in the EZE 40 mg/day group and increased slightly in the EZE 10 mg/day group (2.2%), yielding a non-significant between-group difference of -2.2%. EZE 40 mg/day was generally well tolerated., Conclusions: In patients with HoS, treatment with EZE 40 mg/day for 26 weeks was no more effective at reducing plasma plant sterol concentrations vs. EZE 10 mg/day. EZE 40 mg/day had a safety and tolerability profile similar to EZE 10 mg/day.

Results of previous studies have shown that ezetimibe (10 mg/day) reduces LDL cholesterol in patients with mild hypercholesterolemia on a normal-cholesterol diet (dietary intake of 200-500 mg/day) by 16-22%. However, the LDL cholesterol-lowering effect of ezetimibe in subjects with an extremely low dietary cholesterol intake (vegetarians) has not been studied. We conducted a randomized, double-blind, placebo-controlled, two-phase crossover study in 18 healthy pure vegetarians to assess the effect of ezetimibe (10 mg/day) on plasma lipids, cholesterol absorption, and its synthesis. Treatment periods lasted 2 weeks each, with an intervening 2 week washout period. Fractional cholesterol absorption was determined using the continuous dual stable isotope feeding method. Mean dietary cholesterol intake in the pure vegetarians was extremely low and averaged 29.4 +/- 16.8 and 31.4 +/- 14.4 mg/day during the placebo and ezetimibe administration phases, respectively. Fractional cholesterol absorption during the placebo phase was 48.2 +/- 8.2% and was decreased by 58% during ezetimibe treatment to 20.2 +/- 6.2% (P < 0.001). This change in intestinal cholesterol absorption was followed by a significant reduction in LDL cholesterol of 17.3%. In individuals with extremely low dietary cholesterol intake, treatment with ezetimibe (10 mg/day) leads to a significant reduction of cholesterol absorption and a clinically relevant decrease of plasma LDL cholesterol, comparable to that of subjects with a normal dietary cholesterol intake. Thus, the lipid-lowering effect of ezetimibe is mediated mainly through a reduction of the absorption of endogenous (biliary) cholesterol.

We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415-421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis. We analyzed the serum levels of cholesterol, lathosterol, and campesterol in healthy white males which had been grouped on the basis of their SLCO1B1 haplotype: *1a (n=10), *1b (n=10), and *5 (n=8). The subjects received a single oral dose of 40 mg pravastatin. Cholesterol and lathosterol levels were lower in all subjects following pravastatin intake for up to 24. Median levels 6 h post-dosing of lathosterol decreased in each SLCO1B1 haplotype group in the rank order of *1b (-0.11 mg dl(-1); min-max: -0.20 to -0.04; p=0.005) > *1a (-0.09 mg dl(-1); min-max: -0.22 to -0.05; p=0.005) > *5 (-0.07 mg dl(-1); min-max: -0.17 to -0.05; p=0.012). Lathosterol median-change values were significantly greater in haplotype *1b than in haplotype *5 individuals (p=0.041, non-adjusted), which was congruent with the extent of mean changes in lathosterol-to-cholesterol ratios, although the latter did not reach statistical significance. Post-treatment serum levels of campesterol were not affected by SLCO1B1 haplotype. Interestingly, sterol basal serum levels tended to be highest in *1b carriers, followed by those in *1a and *5 individuals, with significant differences in lathosterol concentrations between the *1b and *5 (p=0.041, non-adjusted) haplotype group. Our findings suggest an association of SLCO1B1*1b and *5 haplotypes to pravastatin's inhibition of the hepatocellular HMG-CoA reductase. Furthermore, SLCO1B1 haplotypes seem to play a role in basal cholesterol homeostasis.

Background and Aims: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin)., Methods: Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles., Results: Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 +/- 78.1 ng.h/mL versus 49.9 +/- 31.0 ng.h/mL and 635 +/- 302 ng.h/mL versus 225 +/- 86.4 ng.h/mL, respectively; both P = .002) and increased intestinal clearances (2400 +/- 1560 mL/min versus 5500 +/- 4610 mL/min [P = .003] and 76.6 +/- 113 mL/min versus 316 +/- 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2., Conclusions: The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.

Objective: The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake transporter OATP1B1, influence the short-term effects of pravastatin on cholesterol synthesis., Methods: We determined plasma concentrations of lathosterol and cholesterol up to 12 h after intake of a single dose of 40 mg pravastatin in 41 healthy Caucasian subjects, in whom SLCO1B1 single nucleotide polymorphisms (SNP; 521T>C and -11187G>A) and haplotypes (*15B and *17) had been previously shown to be associated with considerably elevated plasma pravastatin levels., Results: The effects of pravastatin on plasma lathosterol concentration and lathosterol to cholesterol concentration ratio, which are established markers of the rate of cholesterol synthesis in vivo, were significantly smaller among the three heterozygous carriers of the SLCO1B1 *17 haplotype (containing the -11187G>A, 388A>G and 521T>C SNPs) as compared with non-carriers. Significant inverse relationships were found between pravastatin area under the concentration-time curve (AUC) values and effects of pravastatin on lathosterol and lathosterol to cholesterol ratio among the whole study population., Conclusion: These results suggest that uptake of pravastatin into hepatocytes is impaired in carriers of the SLCO1B1 haplotype *17, resulting in higher plasma pravastatin concentrations but lower concentrations of pravastatin in hepatocytes and thereby in a smaller inhibitory effect on cholesterol synthesis. The cholesterol-lowering response to pravastatin may be impaired in carriers of the *17 haplotype.

Recent insights in the role of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8, the discovery of ezetimibe, the first approved direct cholesterol absorption inhibitor, as well as the identification of Niemann-Pick C1 Like 1 (NPC1L1) protein as sterol transporter in the gut, focused attention on sterol transport processes in the small intestine and the liver. The identification of defective structures in the ABCG5 or ABCG8 transporters in patients with the rare disease of sitosterolemia elucidated their role as sterol efflux pumps regulating at least in parts the intestinal sterol absorption and the hepatic sterol output. ABCG5 and ABCG8 themselves are regulated by cholesterol via liver X receptors (LXRs), which are also activated by oxysterols and some derivatives of plant sterols. NPC1L1 could recently be identified as a major sterol transporter for the intestinal uptake of cholesterol as well as plant sterols. Studies in NPC1L1 knockout mice indicate that this transporter is essential for the intestinal uptake of sterols and that NPC1L1 might also be involved in the mechanism of action of ezetimibe. However, studies with photoreactive cholesterol as well as with photoreactive ezetimibe analogues suggest that other processes might also be involved in the mechanism of action of ezetimibe.

During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.

Background: Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops., Methods and Results: In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% (P<0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P<0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P<0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported., Conclusions: Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.

Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXRalpha, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8(-/-) mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8(-/-) mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo.

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.

Background: Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far., Methods and Results: The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8+/-13.8% on placebo and 22.7+/-25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; P< 0.001). Cholesterol synthesis increased by 89% from 931+/-1027 mg/d on placebo to 1763+/-1098 mg/d on ezetimibe (P<0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P<0.001). Bile acid synthesis was insignificantly increased (placebo: 264+/-209 mg/d, ezetimibe: 308+/-184 mg/d; P=0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were -20.4% and -15.1%, respectively (P<0.001 for both), whereas campesterol and sitosterol were decreased by -48% and - 41%, respectively., Conclusion: In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.

In a randomized, placebo-controlled, double-blind study, we investigated whether statins alter cholesterol metabolites and reduce Abeta levels in the cerebrospinal fluid of 44 patients with Alzheimer's disease. Individuals were given up to 80mg simvastatin daily or placebo for 26 weeks. Overall, simvastatin did not significantly alter cerebrospinal fluid levels of Abeta40 and Abeta42. In post hoc analysis, simvastatin significantly decreased Abeta40 levels in the cerebrospinal fluid of patients with mild Alzheimer's disease. The reduction of Abeta40 correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected patients.

There is mounting evidence that specific sterol precursors of cholesterol are associated with reproductive functions. Testicular meiosis-activating sterol (T-MAS) and follicular fluid meiosis-activating-sterol (FF-MAS) are 2 cholesterol precursors found in reproductive organs of mammals, which are able to overcome meiotic arrest in vitro. This study investigates the influence of simvastatin and pravastatin, 2 inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, and BM 15.766, an inhibitor of 7-dehydrocholesterol reductase, on concentrations of neutral sterols in liver and testis of guinea pigs. Concentrations of T-MAS, lathosterol, and desmosterol were markedly higher in testis compared with liver. Simvastatin (150 mg/d) and pravastatin (150 mg/d and 350 mg/d) markedly reduced cholesterol precursors in liver. In contrast, T-MAS and desmosterol in testis remained unchanged, albeit other cholesterol precursors were reduced. BM 15.766 led to the accumulation of 7- and 8-dehydrocholesterol, both in liver and testis. However, concentrations of T-MAS in testis were not changed by BM 15.766. We conclude that treatment of guinea pigs with simvastatin, pravastatin, or BM 15.766, which simulates the biochemical defect of the Smith-Lemli-Opitz (SLO) syndrome, does not affect T-MAS concentrations in testis., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol). Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease., Objective: To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol., Design: Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24., Setting: An academic outpatient clinical study., Patients: Eighteen patients who met the criteria for hypercholesterolemia., Intervention: Treatment with 80 mg/d of simvastatin at night., Main Outcome Measures: Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry., Results: Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P=.01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P=.02 for both)., Conclusions: The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.

The benefits of lipid lowering therapy on coronary heart disease have been clearly established in many clinical trials on primary and secondary prevention. Despite the availability of potent lipid lowering drugs, many patients do not reach the current treatment goals. This paper reviews new therapeutic approaches in lipid lowering drugs focusing on compounds which lower cholesterol absorption. The role of plant sterols and stanols, new acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, and ezetimibe are summarised. Although the lipid lowering effect of plant sterols and plant stanols is only moderate, their use as functional foods is beneficial for patients with mild hypercholesterolaemia and is able to enhance the lipid lowering effect of HMG-CoA reductase inhibitors (statins). The role of ACAT inhibitors that might also inhibit cholesterol absorption remains unclear. Avasimibe, the first oral bioavailable ACAT inhibitor, has entered phase III trials. However, the presently available data in humans do not indicate a clear clinical benefit. The role of MTP inhibitors, which exhibit remarkable effects on all plasma lipids, also remains unclear, as safety concerns must first be addressed. Ezetimibe, the first available 2-azetidinone, succeeded in phase III trials showing remarkable effects in inhibition of cholesterol absorption as well as cholesterol lowering. The synergistic effect of co-administration of ezetimibe with statins seemingly offers a new approach in reaching the therapeutic goals.

Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Abeta42 levels and the varepsilon4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Abeta42 and Abeta40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Abeta42 and Abeta40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Abeta42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.

Objective: To determine the efficacy of stanol esters in lowering cholesterol in a US population., Subjects and Methods: After a run-in phase, 318 subjects were randomized to receive one of the following margarine-like spreads containing stanol ester or placebo for 8 weeks: EU 3 G: 1 g of stanol (ester form) per 8-g serving of a European formula 3 times a day; US 3 G: 1 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; US 2 G: 0.67 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; or placebo spread., Results: Mean +/- SD baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were 233+/-20 and 153+21 mg+/-dL, respectively. In the US 3 G group, 3 g daily of stanol esters lowered TC and LDL-C levels by 6.4% and 10.1%, respectively. There was a dose-dependent response compared with 2 g daily (US 2 G). Triglyceride and high-density lipoprotein cholesterol levels were unchanged. The incidence of adverse effects was not different from placebo. Serum vitamin A and 25-hydroxyvitamin D levels were not affected., Conclusions: Stanol esters lowered TC and LDL-C levels in a mildly hypercholesterolemic US population without evidence of adverse effects. It may be a useful dietary adjunct to lower cholesterol.

Absorption of dietary cholesterol, campesterol, and sitosterol, cholesterol balance, and fecal excretion of plant sterols were determined in three unrelated patients with phytosterolemia and three healthy volunteers during constant intake of cholesterol and plant sterols using accurate gas-liquid chromatography-mass spectrometry techniques. Each subject received a mixture of [26,26,26,27,27,27-2H6]cholesterol, [6,7,7-2H3]sitostanol, and [6,7,7-2H3]campesterol together with two non-absorbable markers, [5,6,22,23-2H4]sitostanol and chromic oxide. Feces were collected from days 5 to 7 and absorption of different sterols was calculated from the intestinal disappearance of the different sterols relative to [5,6,22,23-2H4]sitostanol and chromic oxide. The results obtained by the two markers were not different and the absorption of cholesterol averaged 53 +/- 4% for the patients (mean +/- SD) and 43 +/- 3% for the volunteers. Campesterol absorption averaged 24 +/- 4% in patients and 16 +/- 3% in healthy volunteers, whereas sitosterol absorption averaged 16 +/- 1% and 5 +/- 1%, respectively. Cholesterol synthesis expressed by body weight varied considerably in the two groups but appeared to be about 5 times lower in patients than in controls. Administration of a high dose of sitostanol (0.5 g t.i.d.) to two patients was followed by a reduction in cholesterol absorption by 24% and 44%, an increase in fecal output of cholesterol and steroids derived from cholesterol and plant steroids, and a marked reduction of serum cholesterol, campesterol, and sitosterol. Under the conditions used, inhibition of cholesterol absorption by sitostanol was not followed by a significant rise in cholesterol synthesis. The time of observation was, however, too short to allow final conclusion on this. The results show that the absolute difference in absorption rate of different sterols between the patients and healthy volunteers was about the same. As a consequence, increasing hydrophobicity causes a relative decrease of absorption rates. Thus, patients with phytosterolemia seem to have a generally increased absorption of sterols rather than a loss of a specific discriminatory mechanism, and oral administration of sitostanol seems to be an interesting new approach for treatment of phytosterolemia.

The cholesterol requirements of the lens for the formation of plasma membranes are met by self-synthesis only until early postnatal life. This ability subsequently decreases with increasing age and probably ceases altogether. The cholesterol supply then has to come from exogenous sources. These findings are of great importance for the qualitative assessment of extrahepatic side effects of HMG-CoA-reductase inhibitors given for disturbances of lens transparency. The observation of cataracts in chronic toxicity tests with high doses in beagle dogs suggested that the lens enzyme was also affected by the inhibitor, thus causing cataracts. In contrast to other workers' results, we did not find any activity of HMG-CoA-reductase in our experiments with calf, bovine, dog and rat lenses. Preliminary studies with bovine eyes demonstrate a direct correlation between the cholesterol serum level and the content of the aqueous humor. This shows the importance of the exogenous supply for the lens requirements. A further strong argument is that the use of HMG-CoA-reductase inhibitors in patients with pathologically increased cholesterol level is safe as far as the lens transparency is concerned, as demonstrated in clinical trials.

A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082, N-(2,4-difluorophenyl)-N-(4-neopentylbenzyl)-N-(n-heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single-blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study.

Reports that simvastatin reduces levels of Alzheimer's disease Beta-amyloid peptides ABeta42 and ABeta40 in vitro and in vivo. Effect of cholesterol depletion on ABeta secretion; Familial AD mutation; Reduction of Abeta production in the absence of CDX by statins; Simvastatin's reduction of ABeta levels in vivo.

Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined. [ABSTRACT FROM AUTHOR]