| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| pH, cholesterol sulfate, and fatty acids affect the stratum corneum lipid organization Bouwstra, J. A., G. S. Gooris, et al. (1998), J Investig Dermatol Symp Proc 3(2): 69-74. Abstract: Lipid mixtures prepared from cholesterol (CHOL), isolated ceramides (CER), and free fatty acids can serve as attractive tools to study the role various stratum corneum (SC) lipids or microenvironmental conditions play in the SC lipid organization, as the phase behavior in these mixtures and in SC are similar: two lamellar phases with periodicities of approximately 6 and 13 nm are present. Because pH and cholesterol sulfate (CSO4) gradients exist in SC and may affect the local SC lipid organization, the effects of pH and CSO4 on lipid phase behavior was examined. X-ray diffraction studies with CHOL:CER mixtures revealed that the lamellar ordering at pH 5 and 7.4 were similar: both the short and the long periodicity phases were present. Upon addition of free fatty acids the phase behavior became pH dependent; the long periodicity phase being more dominant at pH 7.4 than at pH 5. Similar observations have been made upon addition of CSO4. Furthermore, only in the presence of CSO4 did phase-separated CHOL disappear, indicating that CHOL completely dissolves in the lamellar phases. A major phase change from an hexagonal to an orthorhombic lateral packing has been observed in the presence of free fatty acids. Furthermore, in the presence of CSO4 next to orthorhombic also liquid lateral packing could be detected. In contrast to lamellar ordering, changes in pH did not affect the lateral packing in any of the lipid mixtures studied. |
| Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin Kosoglou, T., I. Meyer, et al. (2002), Br J Clin Pharmacol 54(3): 309-19. Abstract: AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted. |
| Pharmacoeconomic evaluation of pravastatin in the secondary prevention of coronary heart disease in patients with average cholesterol levels. An analysis for Germany based on the CARE study Szucs, T. D., G. Guggenberger, et al. (1998), Herz 23(5): 319-29. Abstract: Those people who are to decide about health care systems are increasingly forced to identify unnecessary costs and achieve savings in health care. Especially for diseases with high prevalence like illnesses of the heart and the circulatory system preventive measures are very important. This economic analysis tries to clarify whether the secondary-preventive application of the HMG-CoA reductase-inhibitor pravastatin is, apart from the clinical benefit, economically justified in patients suffering from coronary heart disease with average cholesterol levels. In the case of this study, the underlying type of economic evaluation was an incremental cost-effectiveness analysis. The outcome was defined as costs per life-year saved. This retrospective study is based on the results of the CARE (Cholesterol And Recurrent Events) study which has been published elsewhere 21. When calculating costs we took into account the perspective of 3rd party payers (public health insurance) in Germany. The calculation of cost-effectiveness was carried out for the whole study population in CARE as well as for all patients aged 60 or more years in the CARE study. This was done because the different groups vary by the numbers of avoided myocardial infarctions, strokes and loss of life years. Netcosts for pravastatin therapy, i.e. drug costs for pravastatin minus costs for avoided events, were about 9.54 Mio DM (referring to 1,000 patients treated for a period of 5 years). Net-costs for patients aged 60 or more years were 8.18 Mio DM. The effectiveness was defined as the number of life years saved and amounted to 216 years of life saved (YOLS) in the overall study group. For patients aged 60 or more years we found that 358 years were saved. The costs per life years saved (i.e. the net-costs of pravastatin therapy divided through the number of life years saved) turned out to be 44,000 DM per person in the study group. For patients over 60 the costs were 23,000 DM. Lipid-lowering with pravastatin in the secondary prevention of coronary heart disease in Germany is cost-effective. In those patients aged 60 or more yeas the use of pravastatin is even more cost-effective than in all patients included in the CARE study. |
| Pharmacogenetic study of statin therapy and cholesterol reduction Chasman, D. I., D. Posada, et al. (2004), Jama 291(23): 2821-7. Abstract: CONTEXT: Polymorphisms in genes involved in cholesterol synthesis, absorption, and transport may affect statin efficacy. OBJECTIVE: To evaluate systematically whether genetic variation influences response to pravastatin therapy. DESIGN, SETTING, AND POPULATION: The DNA of 1536 individuals treated with pravastatin, 40 mg/d, was analyzed for 148 single-nucleotide polymorphisms (SNPs) within 10 candidate genes related to lipid metabolism. Variation within these genes was then examined for associations with changes in lipid levels observed with pravastatin therapy during a 24-week period. MAIN OUTCOME MEASURE: Changes in lipid levels in response to pravastatin therapy. RESULTS: Two common and tightly linked SNPs (linkage disequilibrium r2 = 0.90; heterozygote prevalence = 6.7% for both) were significantly associated with reduced efficacy of pravastatin therapy. Both of these SNPs were in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the target enzyme that is inhibited by pravastatin. For example, compared with individuals homozygous for the major allele of one of the SNPs, individuals with a single copy of the minor allele had a 22% smaller reduction in total cholesterol (-32.8 vs -42.0 mg/dL -0.85 vs -1.09 mmol/L; P =.001; absolute difference, 9.2 mg/dL 95% confidence interval CI, 3.8-14.6 mg/dL) and a 19% smaller reduction in low-density lipoprotein (LDL) cholesterol (-27.7 vs -34.1 mg/dL -0.72 vs -0.88 mmol/L; P =.005; absolute difference, 6.4 mg/dL 95% CI, 2.2-10.6 mg/dL). The association for total cholesterol reduction persisted even after adjusting for multiple tests on all 33 SNPs evaluated in the HMG-CoA reductase gene as well as for all 148 SNPs evaluated was similar in magnitude and direction among men and women and was present in the ethnically diverse total cohort as well as in the majority subgroup of white participants. No association for either SNP was observed for the change in high-density lipoprotein (HDL) cholesterol (P>.80) and neither was associated with baseline lipid levels among those actively treated or among those who did not receive the drug. Among the remaining genes, less robust associations were found for squalene synthase and change in total cholesterol, apolipoprotein E and change in LDL cholesterol, and cholesteryl ester transfer protein and change in HDL cholesterol, although none of these met our conservative criteria for purely pharmacogenetic effects. CONCLUSION: Individuals heterozygous for a genetic variant in the HMG-CoA reductase gene may experience significantly smaller reductions in cholesterol when treated with pravastatin. |
| Pharmacogenetic study of statin therapy and cholesterol reduction Marian, A. J. (2005), Curr Atheroscler Rep 7(3): 177-8. |
| Pharmacogenetic study of statin therapy in cholesterol reduction Kotchen, T. A. (2004), Curr Hypertens Rep 6(6): 449-50. |
| Pharmacogenomics and pharmacogenetics of cholesterol-lowering therapy Schmitz, G. and W. Drobnik (2003), Clin Chem Lab Med 41(4): 581-9. Abstract: Cholesterol-lowering therapy is the central approach in the primary and secondary prevention of cardiovascular disease, the leading cause of death in industrialized countries. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are currently the most potent and widely used cholesterol-lowering drugs. Large-scale clinical trials unequivocally demonstrated the efficacy of statin treatment in reducing the risk of cardiovascular events. In general, HMG-CoA reductase inhibitors are well tolerated, although in a minority of patients severe adverse effects like myopathy or rhabdomyolysis may develop. The incidence of this potentially life-threatening side effects increases with co-adminstration of drugs that are metabolized via the same pharmacokinetic pathways or at high-dose statin therapy. The recent focus on the pleiotropic effects of statins that are more frequently observed at higher doses and the conclusion drawn from the large statin trials that low-density lipoprotein (LDL)-cholesterol is "the lower the better", may need careful consideration in individuals at risk of adverse drug reactions. On the other hand, not all patients respond to statin therapy with a reduction in coronary heart disease (CHD) risk. It is therefore of interest to develop diagnostic test systems, which would allow to identify patients at increased risk of adverse drug reactions or patients with a lack of therapeutic effect. Beside exogenous factors, genetic variability determines the response of an individual to drug therapy and the analysis of genetic variants affecting pharmacokinetic or pharmacodynamic aspects of drug therapy is the subject of pharmacogenomics. This review summarizes current knowledge of the pharmacology and the pharmacogenomics of statin therapy. |
| Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin Hatanaka, T., S. Honda, et al. (1998), J Pharmacokinet Biopharm 26(3): 329-47. Abstract: The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after i.v. bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions. |
| Pharmacokinetic properties of YM17E, an inhibitor of acyl coenzyme A: cholesterol acyl transferase, and serum cholesterol levels in healthy volunteers Uchida, T., T. Usui, et al. (1997), Eur J Clin Pharmacol 51(5): 399-406. Abstract: We conducted a single and repeat oral dose study of YM17E, a novel inhibitor of acyl coenzyme A (CoA): cholesterol acyltransferase, in healthy male volunteers to evaluate the pharmacokinetic profile, tolerability and effect of the drug on serum cholesterol. In the single administration study, YM17E was administered after a meal to two groups of subjects (each containing six subjects taking the drug and three taking placebo) receiving 3, 60 and 300 mg or 15, 60 and 450 mg YM17E, respectively. Plasma concentrations of unchanged drug following single oral administration at 3-300 mg after a meal increased with increasing dose. In contrast, plasma concentrations after administration of 450 mg were almost the same as after 300 mg. Unchanged YM17E was not detected in urine after single administration, suggesting that it was excreted via the bile or urine after metabolism. Five active metabolites (M1, M2-a, M2-b, M3 and M4) were observed in plasma at concentrations comparable to those of unchanged YM17E. Their plasma concentrations increased in a slightly greater than dose-dependent manner from 3 to 300 mg. The effect of food was studied in an open crossover design with a 1-week washout period. Twelve subjects received 150 mg YM17E in both the fasted and post-prandial states. The AUC and Cmax after fasting were closely similar to those after a meal, showing that bioavailability was not affected by food intake. In the repeated oral dose study, the subjects received test drug at 150 mg or 300 mg (n = 6 each) or placebo (n = 3) twice a day (after breakfast and after dinner) for 7 days. On days 1 and 7, the subjects received YM17E once a day (after breakfast) for evaluation of pharmacokinetic properties. After repeated oral administration of 150 mg b.d., plasma concentrations reached steady state by day 5 (mean Cmin 48.6 ng.ml-1). After repeated administration of 300 mg b.d., plasma concentrations prior to each daily morning dose increased up to the 5th day (mean Cmin 166.6 ng.ml-1) and then tended to decrease until the 7th day. No significant signs, symptoms or changes in serum cholesterol levels were observed during the single and repeated oral dose studies at 150 mg b.d. Although statistical analysis was not conducted because of the small number of subjects, all subjects receiving repeated oral administration of 300 mg twice daily showed a 25% decrease in serum cholesterol level on day 7, but also the simultaneous occurrence of diarrhoea. |
| Pharmacokinetics and antitumor effects of vincristine carried by microemulsions composed of PEG-lipid, oleic acid, vitamin E and cholesterol Junping, W., K. Takayama, et al. (2003), Int J Pharm 251(1-2): 13-21. Abstract: In this study, injectable microemulsions of vincristine (M-VCR) were prepared and its pharmacokinetics, acute toxicity and antitumor effects were evaluated. In M-VCR, the surfactants were PEG-lipid and cholesterol, the oil phase was a vitamin E solution of oleic acid and VCR. The particle size distribution and zeta potential of M-VCR were measured by the laser light dynamic scattering method. The VCR-loading efficiency was measured by Sephadex G50 column chromatography. The stability of M-VCR was monitored by particle size, VCR-loading efficiency and VCR content changes of M-VCR stored at 7 degrees C. The pharmacokinetics, acute toxicity and antitumor effects of M-VCR were studied in C57BL/6 mice bearing mouse murine histocytoma M5076 tumors. When stored at 7 degrees C in the dark for 1 year, the average diameter and VCR-loading efficiency of M-VCR changed from 138.1+/-1.2 nm and 94.6+/-4.7% to 127.1+/-2.4 nm and 91.3+/-4.8% (n=3), respectively, while 7.4+/-0.3% VCR decomposition was observed (n=3). The plasma AUC of M-VCR was significantly greater than that of free VCR (F-VCR). The heart, spleen and liver AUC(0.08-12 h) of M-VCR were significantly smaller than those of F-VCR while the kidney AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. The tumor AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. M-VCR had lower acute toxicity and greater potential antitumor effects than F-VCR in M5076 tumor-bearing C57BL/6 mice. M-VCR is a useful tumor-targeting microemulsion drug delivery system. |
| Pharmacokinetics of zidovudine following intravenous bolus administration of a novel niosome preparation devoid of cholesterol Gopinath, D., D. Ravi, et al. (2001), Arzneimittelforschung 51(11): 924-30. Abstract: A novel niosome preparation composed of nonionic surfactants, polyglyceryl-3-diisostearate and polysorbate-80, bilayers stabilized by myristyl alcohol instead of cholesterol was developed. Polyglyceryl-3-diisostearate, myristyl alcohol and polysorbate-80 were in 1:2:1 molar ratio in which 85% zidovudine (3'-azido-3'-deoxythymidine, azidothymidine, AZT, CAS 30516-87-1) was found to be encapsulated in aqueous core. Pharmacokinetic and tissue distribution studies were conducted on this niosome preparation using rabbits and albino rats, respectively, as animal models. AZT levels in rabbit serum were higher following application of niosomal AZT than with AZT solution. Such levels were maintained for prolonged time. T1/2 increased, clearance became slow and as a result AUC and AUMC increased and consequently MRT increased following niosomal AZT treatment. Tissue distribution studies on albino rats also confirmed higher concentration and slower decline of serum levels of AZT due to niosomal AZT. In addition niosomal AZT escaped uptake by reticuloendothelial tissues (liver, spleen, and kidney). Invitro release of AZT from niosomes was slow, about 20% releasing in 18 h. The prolonged AZT levels in rabbit serum following the treatment with niosomal AZT appear to be due to the combined effect of slow invivo release and avoidance of extravascular distribution. Though this preparation seems to maintain AZT levels in serum for a prolonged time, its therapeutic efficacy cannot be claimed as the present method estimates total AZT in the preparation and not free AZT. Further no specific experiments were conducted to substantiate its therapeutic effect. |
| Pharmacokinetics, excretion, and mass balance of 14C after administration of 14C-cholesterol-labeled AmBisome to healthy volunteers Bekersky, I., R. M. Fielding, et al. (2001), J Clin Pharmacol 41(9): 963-71. Abstract: Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides higher plasma concentrations and greater safety than the conventional deoxycholate formulation. The authors compared the disposition of the liposome's drug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and feces for 1 week after a single 2-hour infusion of 14C-cholesterol-labeled AmBisome (2 mg/kg, 1 microgCi/kg) in healthy adults (4 males, 1 female). The plasma profile of 14C-cholesterol differed from that of AmB, lacking an initial rapid disappearance phase, having a lower total clearance, and having a volume of distribution (0.13 L/kg) close to that of the plasma compartment. The biphasic disappearance and long plasma half-life (147 h) of 14C-cholesterol were similar to those of other low-clearance liposomes. This and the low clearance of 14C-cholesterol from the plasma compartment suggest that it served as a liposome marker. The plasma drug-lipid ratio fell during the study, showing that AmB was cleared from plasma more rapidly than cholesterol or liposomes and suggesting that the composition of the liposomes changed over time. 14C-radioactivity was recovered mainly in the feces (9.5% of dose), consistent with the catabolism of cholesterol to bile salts. Combined fecal and renal clearances were < 18% of total clearance, suggesting that most of the liposomal drug and lipid remained in the body 1 week after dosing. Thus, AmBisome remains in the circulation for an extended period of time while releasing AmB, resulting in its markedly altered pharmacokinetic and safety profiles. |
| Pharmacologic advantages of individual cholesterol synthesis inhibitors? Prof. Dr. Dr. med. W. Schunack, Free University Berlin, elaborates on differential therapeutic considerations Schunack, W. (1991), Fortschr Med 109(19): 71-2. |
| Pharmacologic consequences of cholesterol absorption inhibition: alteration in cholesterol metabolism and reduction in plasma cholesterol concentration induced by the synthetic saponin beta-tigogenin cellobioside (CP-88818; tiqueside) Harwood, H. J., Jr., C. E. Chandler, et al. (1993), J Lipid Res 34(3): 377-95. Abstract: Natural and synthetic saponins inhibit cholesterol absorption and reduce plasma cholesterol levels in experimental animals and are therefore of potential pharmacologic utility in the treatment of hypercholesterolemia. To determine the effects of this class of compounds on cholesterol absorption and metabolism, we evaluated the effects of the synthetic saponin, beta-tigogenin cellobioside (tiqueside; CP-88818), on male golden Syrian hamsters. When administered as either a single oral bolus or as a dietary supplement for up to 2 weeks, tiqueside inhibited cholesterol absorption in a dose-dependent manner in both the presence and absence of dietary cholesterol. Administration of tiqueside to chow-fed hamsters as a 0.2% dietary supplement (150 mg/kg per day) for 4 days resulted in a 68% decrease in intestinal cholesterol absorption with no change in either bile absorption or cholesterol 7 alpha-hydroxylase activity, suggesting that tiqueside inhibits cholesterol absorption without interfering with enterohepatic bile acid recirculation. Under these conditions, hepatic cholesterol levels were also reduced in a dose-dependent manner. Hepatic cholesterol reduction was highly correlated with cholesterol absorption inhibition, and induced compensatory increases in both hepatic HMG-CoA reductase activity and hepatic low density lipoprotein (LDL) receptor levels. Compensatory increases in intestinal HMG-CoA reductase activity were also noted after tiqueside administration, and are consistent with a luminal mechanism for tiqueside action. As a consequence of these changes to cholesterol metabolism, tiqueside administration induced plasma cholesterol reductions that were highly correlated with both hepatic cholesterol reduction and cholesterol absorption inhibition. Tiqueside also produced comparable plasma cholesterol lowering in a variety of other species fed either cholesterol-free diets (hamster, rat, mouse, dog) or cholesterol-containing diets (hamster, rat, rabbit, mouse, cynomolgus monkey, rhesus monkey, SEA quail) indicating the ubiquity of tiqueside action. For all species evaluated except the dog, the reduction in plasma cholesterol was due primarily to a reduction in circulating non-HDL cholesterol levels with little or no change in HDL cholesterol levels. Taken together, these results indicate that inhibition of cholesterol absorption by tiqueside produces profound effects on cholesterol metabolism without affecting bile acid metabolism, and that these changes lead to reductions primarily in plasma non-HDL cholesterol concentrations. The synthetic saponin, tiqueside, may thus represent a prototypical form of therapy for the treatment of hypercholesterolemia. |
| Pharmacologic options for aggressive low-density lipoprotein cholesterol lowering: benefits versus risks McKenney, J. M. (2005), Am J Cardiol 96(4A): 60E-66E. Abstract: Lessons from recent end point trials of lipid-lowering drugs indicate that patients at very high risk for coronary artery disease (CAD) benefit from treatment that lowers low-density lipoprotein (LDL) cholesterol plasma levels to < or = 1.81 mmol/L (< or = 70 mg/dL), that patients with > or = 2 risk factors benefit from treatment that lowers plasma LDL cholesterol to <2.59 mmol/L (<100 mg/dL), and that a significant reduction in CAD event rates is most often associated with a minimum plasma LDL cholesterol reduction of 30%. Recently, the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) recommendations were amended to incorporate these lessons. To reach these more aggressive goals and plasma LDL cholesterol reductions, more aggressive therapies will be required. The best way to implement more aggressive therapy is to start with one of the more potent statins, especially atorvastatin or rosuvastatin, or higher doses of other statins. This approach alone is likely to achieve treatment goals in 50% to 80% of patients. For patients needing additional plasma LDL cholesterol lowering, combination therapies will be required. Adding colesevelam, ezetimibe, or niacin to a stable statin regimen will generally provide an additional 10% to 15% lowering of plasma LDL cholesterol. These more potent statins, even when used in higher doses, appear to be safe. The incidence of myopathy and rhabdomyolysis, as documented in long-term clinical trials, is <0.1% and <0.01%, respectively, except for simvastatin, which has a higher incidence of these problems. Less information is available about the safety of lowering levels of plasma LDL cholesterol to < or = 1.81 mmol/L (< or = 70 mg/dL), but an analysis of a recent 2-year-long clinical trial, in which patients had on-treatment plasma LDL cholesterol levels as low as 0.67 mmol/L (26 mg/dL), reported no signals of untoward effects in patients with progressively lower levels. |
| Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann-Pick C mice Erickson, R. P., W. S. Garver, et al. (2000), J Inherit Metab Dis 23(1): 54-62. Abstract: Niemann-Pick type C (NPC) is a neurodegenerative disorder with somatically altered cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequences shared with known sterol-sensing proteins. We have used a mouse model with a disrupted Npc1 gene to study two cholesterol-lowering drugs (nifedipine and probucol) and the effects of introducing a null mutation in the low-density lipoprotein receptor (LDLR). Although these treatments significantly ameliorated liver cholesterol storage, little effect on the onset of neurological symptoms was found. |
| Pharmacological control of phagocyte function: inhibition of cholesterol accumulation Paoletti, R., S. Bellosta, et al. (1997), Ann N Y Acad Sci 832: 322-9. Abstract: Phagocytes play a major role in several diseases. In particular mononuclear phagocyte-derived foam cells have a prominent role in the development of the atherosclerotic lesions. Macrophages are present in all stages of atherogenesis; they internalize lipoproteins and accumulate cholesterol. Moreover, lipid-filled macrophages, by secreting extracellular matrix-degrading enzymes, may weaken rupture-prone atherosclerotic plaques, thus increasing the probability of precipitating atherosclerotic acute symptoms (i.e., myocardial infarction, angina, etc.). Therefore, control of cellular functions and cholesterol accumulation in macrophages represent pharmacological targets against atherosclerosis. In our laboratory we studied the effect of calcium antagonists on cellular cholesterol esterification in cultured macrophages. We also demonstrated that the HMG-CoA reductase inhibitors (vastatins) fluvastatin and simvastatin prevented cholesterol deposition in cultured human and murine macrophage by inhibiting modified LDL endocytosis. Interestingly, vastatin activity was more pronounced in cholesterol-loaded macrophages (i.e., foam cells) than in normal cells. In conclusion, in vitro pharmacological control of cholesterol accumulation in macrophages may be achieved with some calcium antagonists and vastatins independently of their effects on blood pressure or cholesterolemia. |
| Pharmacological inhibition of the intracellular transport of low-density lipoprotein-derived cholesterol in Chinese hamster ovary cells Liscum, L. (1990), Biochim Biophys Acta 1045(1): 40-8. Abstract: Mammalian cells, cultured in the presence of serum lipoproteins, acquire cholesterol necessary for growth from the uptake and lysosomal hydrolysis of low-density lipoproteins (LDL). The mechanism(s) of intracellular transport of LDL-derived cholesterol from lysosomes to other cellular sites is unknown. In this study, various pharmacological agents were assessed for their ability to inhibit the movement of LDL-cholesterol from lysosomes to the plasma membrane. The only pharmacological agent tested in these experiments that specifically inhibited LDL-cholesterol movement was U18666A. Ketoconazole impaired the intracellular transport of LDL-cholesterol; however, ketoconazole also had a general effect on cholesterol movement, since it impeded the desorption of endogenously synthesized cholesterol into the medium. Other drugs that affected cholesterol movement appeared to be nonspecific. Cholesterol transport from lysosomes to plasma membranes was not significantly altered by agents that affect lysosomal function or cytoskeletal organization, as well as energy poisons and cycloheximide. |
| Pharmacological interference with intestinal bile acid transport reduces plasma cholesterol in LDL receptor/apoE deficiency Galman, C., A. M. Ostlund-Lindqvist, et al. (2003), Faseb J 17(2): 265-7. Abstract: Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often sub-optimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of PR835, a drug belonging to a new class of lipid-lowering agents that inhibit the Slc10a2 protein, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several-fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed to induction of other known hepatic lipoprotein receptors and indicate the presence of new points of targeting in lipid-lowering therapy. |
| Pharmacological management of high triglycerides and low high-density lipoprotein cholesterol Szapary, P. O. and D. J. Rader (2001), Curr Opin Pharmacol 1(2): 113-20. Abstract: Elevated serum triglycerides and low high-density lipoprotein (HDL) cholesterol are part of a metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular disease. Several classes of pharmacological agents including fibrates, niacin and statins, can modify the triglyceride-HDL axis. Fibrates in particular have recently been shown in clinical trials not only to increase HDL, but also to reduce cardiovascular mortality in secondary prevention. More research is needed to further define the role of fibrates when used alone and in combination with statins in high-risk individuals. |