Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia is a major risk factor for the development of coronary heart disease. HMG-CoA reductase inhibitors have been used as first-line drugs because of both their superior cholesterol lowering effect and reliable safety profile. Since there are many patients whose plasma cholesterol level does not reach the therapeutic target even if reductase inhibitors are available, more effective drugs have been strongly required for a long time. Atorvastatin, one of the most recently introduced statins, produces greater plasma LDL-cholesterol reductions than other statins. This pronounced effect of atorvastatin seems to be due to its long-lasting action, presumably a reflection of longer residence time of atorvastatin and its active metabolites in the liver. Clinical trials of atorvastatin have also demonstrated marked plasma triglyceride reductions. The triglyceride reduction with atorvastatin seems to stem from the following two indirect mechanisms, limiting VLDL secretion from the liver and increase in clearance of triglyceride-rich lipoprotein via induced LDL receptors from plasma. Eleven clinical trials of atorvastatin, which have been developed in Japan, clearly demonstrated its ability to reduce LDL-C levels more strongly and in significantly more patients to LDL-C treatment goals than other reductase inhibitors with similar safety profiles. Therefore, atorvastatin adds a new dimension to the effective management of hypercholesterolemia and combined hyperlipidemia.
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PMID:[Atorvastatin (Lipitor): a review of its pharmacological and clinical profile]. 1123 99

We conducted an open-label study to test the effects of atorvastatin on serum lipids, lipoprotein(a) [Lp(a)] and plasma fibrinogen levels. A total of 90 dyslipidaemic, non-smoking patients (45 patients with primary hypercholesterolaemia and 45 patients with primary mixed hyperlipidaemia) aged 48 +/- 11 years were studied. The patients were treated with 20 mg of atorvastatin for 24 weeks, in a single nocturnal dose. At baseline and every eight weeks, the fasting lipid profile, together with serum Lp(a) and plasma fibrinogen levels (Clauss method), were measured. Atorvastatin was highly effective in normalising the serum lipid profile. No significant change in median serum Lp(a) levels was observed in the whole group of patients (0.14 g/l before, vs. 0.16 g/l after, treatment) as well as in patients with raised (> 0.30 g/l) baseline levels (n = 32). A small non-significant increase of plasma fibrinogen was found (3.04 g/l vs. 3.14 g/l) after 24 weeks of atorvastatin administration. The effects of atorvastatin on both these variables did not differ in patients with hypercholesterolaemia or mixed hyperlipidaemia. In conclusion, our findings suggest that the effect of atorvastatin on plasma fibrinogen levels in dyslipidaemic patients without evident vascular disease is not clinically relevant. Furthermore, any rise in fibrinogen levels that may occur is likely to be transient in nature. Further studies are necessary to clarify this issue. There was no evidence that atorvastatin influences serum Lp(a) levels.
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PMID:The effect of atorvastatin on serum lipids, lipoprotein(a) and plasma fibrinogen levels in primary dyslipidaemia--a pilot study involving serial sampling. 1126 11

Enhanced and prolonged postprandial lipaemia is implicated in coronary and carotid artery disease. This study assessed the effects of atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on postprandial plasma concentrations of triglyceride-rich lipoproteins (TRLs). Sixteen middle-aged men with combined hyperlipidaemia (baseline low density lipoprotein (LDL) cholesterol and plasma triglyceride concentrations (median (interquartile range) of 4.54 (4.17-5.26)) and 2.66 (2.04-3.20) mmol/l, respectively) and previous myocardial infarction were randomised to atorvastatin 40 mg or placebo once daily for 8 weeks in a double-blind, cross-over design. The apolipoprotein (apo) B-48 and B-100 contents were determined in subfractions of TRLs as a measure of chylomicron remnant and very low density lipoprotein (VLDL) particle concentrations (expressed as mg apo B-48 or apo B-100 per litre of plasma), in the fasting state and after intake of a mixed meal. Atorvastatin treatment reduced significantly the fasting plasma concentrations of VLDL cholesterol, LDL cholesterol and VLDL triglycerides (median% change) by 29, 44 and 27%, respectively, and increased high density lipoprotein (HDL) cholesterol by 19%, compared with baseline. The postprandial plasma concentrations of large (Svedberg flotation rate (Sf) 60-400) and small (Sf 20-60) VLDLs and chylomicron remnants were almost halved compared with baseline (mean 0-6 h plasma concentrations were reduced by 48% for Sf 60-400 apo B-100, by 46% for Sf 60-400 apo B-48, by 46% for Sf 20-60 apo B-100 and by 27% for Sf 20-60 apo B-48), and the postprandial triglyceridaemia was reduced by 23% during active treatment. In conclusion, atorvastatin 40 mg once daily causes profound reductions of postprandial plasma concentrations of all TRLs in combined hyperlipidaemic patients with premature coronary artery disease.
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PMID:Effects of atorvastatin on postprandial plasma lipoproteins in postinfarction patients with combined hyperlipidaemia. 1194 10

Type IIB hyperlipidemia is associated with premature vascular disease, an atherogenic lipoprotein phenotype characterised by elevated levels of triglyceride-rich VLDL and small dense LDL, together with subnormal levels of HDL. The dose-dependent and independent effects of a potent HMGCoA reductase inhibitor, Atorvastatin, at daily doses of 10 and 40 mg, were evaluated on triglyceride-rich lipoprotein subclasses (VLDL-1, VLDL-2 and IDL), on the major LDL subclasses (light LDL, LDL-1+LDL-2, D: 1.019-1.029 g/ml; intermediate LDL, LDL-3, D: 1.029-1.039 g/ml and small dense LDL, LDL-4+LDL+5, D: 1.039-1.063 g/ml), on CETP-mediated cholesteryl ester transfer from HDL to apoB-containing lipoproteins, on phospholipid transfer protein activity and on plasma-mediated cellular cholesterol efflux in patients (n=10) displaying type IIB hyperlipidemia. Plasma concentrations of triglyceride-rich lipoprotein subclasses (TRL: VLDL-1, Sf 60-400; VLDL-2, Sf 20-60 and IDL, Sf 12-20) and of LDL (D: 1.019-1.063 g/ml) were markedly diminished after 6 weeks of statin treatment at 10 mg per day (-31 and -36%, respectively; P<0.002) and by 42 and 51%, respectively at the 40 mg per day dose. Increasing doses of atorvastatin progressively normalised both the quantitative and qualitative features of the LDL subclass profile, in which dense LDL predominated at baseline. Indeed, dense LDL levels were reduced by up to 57% at the 40-mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles typical of normolipidemic subjects. In addition, marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease (P<0.02) in CETP-mediated CE transfer from HDL. Finally, a significant dose-dependent statin-mediated elevation (+15% at 10 mg; P=0.0003 and +35% at 40 mg; P<0.0001 compared to baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Moreover, atorvastatin (40 mg per day) significantly increased plasma apoAI levels (+24%; P<0.05), thereby suggesting that this statin enhances production of apoAI and with it, formation of nascent pre-beta HDL particles. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing the dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in type IIB dyslipidemia, thereby diminishing the atherosclerotic burden in subjects characterised by high cardiovascular risk.
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PMID:Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. 1205 75

Subjects with moderate combined hyperlipidemia (n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL(1)) apoB (4.52+/-3.06 pools per day on atorvastatin; 5.48+/-4.76 pools per day on simvastatin versus 2.26+/-1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL(1) concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL(1) to VLDL(2) and of VLDL(2) to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54+/-0.30 pools per day at baseline to 1.17+/-0.87 pools per day on atorvastatin and to 0.95+/-0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58-84% by statin treatment (P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22+/-0.04 pools per day) increased to 0.44+/-0.11 pools per day on atorvastatin and 0.38+/-0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.
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PMID:Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates. 1211 2

The aim of the present short-term study was to evaluate the use of a new HMG-CoA reductase inhibitor, atorvastatin, in the treatment of hyperlipidemia and the effect on blood pressure in a group of hypertensive stable renal transplant recipients with hypercholesterolemia who received kidney grafts before 18 years of age. Eight patients (aged 10.8-30.1 years) with inadequately controlled total cholesterol (TC) levels by a lipid-lowering diet (8 weeks) were treated daily for 12 weeks with atorvastatin at an initial dose of 2.5 mg. The dose was increased monthly by 2.5 mg in order to lower TC levels to less than 200 mg/dl. Serum lipoprotein profile, cyclosporin A (CsA), serum creatinine (SCr), and liver and muscle enzyme levels were measured before starting the lipid-lowering diet, at the start of treatment (baseline), and during treatment. Ambulatory blood pressure monitoring (ABPM) (24-h) was carried out in each patient at both baseline and the end of the follow-up. During the lipid-lowering diet, no significant changes in lipoprotein parameters were observed. Atorvastatin was tolerated well and no clinical side effects were noted during the follow-up. The final dose of atorvastatin ranged from 2.5 to 7.5 mg/day. At the end of the study, TC was reduced by 32.2% ( P<0.05), low-density lipoprotein cholesterol (LDL-C) by 41.8% ( P<0.05), and apo B by 29.5% ( P<0.05). No significant changes in HDL-C, VLDL-C, apolipoprotein AI, and lipoprotein(a) were observed. SCr and CsA levels were unaffected. Overall, no significant changes in mean 24-h, daytime, and nighttime ABPM values between the first and the second recordings were observed. However, both daytime and nighttime systolic and diastolic ABPM values dropped in four patients. In conclusion, low-dose atorvastatin appears to be safe, well tolerated, and effective in the treatment of post-transplant hyperlipidemia. In addition, the capacity of atorvastatin to reduce blood pressure, whether or not related to its lipid-lowering action, deserves further investigation.
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PMID:Use of atorvastatin in hyperlipidemic hypertensive renal transplant recipients. 1217 71

The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0-12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.
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PMID:Triglyceride-lowering effect of pitavastatin [corrected] in a rat model of postprandial lipemia. 1219 89

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.
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PMID:Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia. 1223 78

Treatment of HIV infection with potent combination antiretroviral therapy has resulted in major improvement in overall survival, immune function and the incidence of opportunistic infections. However, HIV infection and treatment has been associated with the development of metabolic complications, including hyperlipidaemia, diabetes mellitus, hypertension, lipodystrophy and osteopenia. Safe pharmacological treatment of these complications requires an understanding of the drug-drug interactions between antiretroviral drugs and the drugs used in the treatment of metabolic complications. Since formal studies of most of these interactions have not been performed, predictions must be based on our understanding of the metabolism of these agents. All HIV protease inhibitors are metabolised by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir is the most potent inhibitor of CYP3A4. Ritonavir and nelfinavir also induce a host of CYP isoforms as well as some conjugating enzymes. The non-nucleoside reverse transcriptase inhibitor delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Drug interaction studies have been performed with HIV protease inhibitors and HMG-CoA reductase inhibitors. Coadministration of ritonavir plus saquinavir to HIV-seronegative volunteers resulted in increased exposure to simvastatin acid by 3059%. Atorvastatin exposure increased by 347%, but exposure to active atorvastatin increased by only 79%. Conversely, pravastatin exposure decreased by 50%. Similar results have been obtained with combinations of simvastatin and atorvastatin with other HIV protease inhibitors. Thus, the lactone prodrugs simvastatin and lovastatin should not be used with HIV protease inhibitors. Atorvastatin may be used with caution. Although there are no formal studies available, calcium channel antagonists and repaglinide may have significant interactions and toxicity when used with HIV protease inhibitors because of their metabolism by CYP3A4. Sulfonylurea drugs utilise mainly CYP2C9 for metabolism, and this isoenzyme may be induced by ritonavir and nelfinavir with a resulting decrease in efficacy of the sulfonylurea. Losartan may have increased effect when coadministered with ritonavir and nelfinavir because of the induction of CYP2C9 and the expected increase in formation of the active metabolite, E-3174. Overall, well-designed drug-drug interaction studies at steady state are needed to determine whether antiretroviral drugs may be safely coadministered with many of the drugs used in the treatment of the metabolic complications of HIV infection.
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PMID:Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. 1240 66

The objective of this prospective study was to determine the prevalence of hyperlipidemia in our pediatric renal transplant patients and to treat those with persistently elevated cholesterol and/or low-density lipoprotein (LDL) levels. All patients with a functioning renal allograft for greater than 6 months were studied (n = 18). Patients with cholesterol and/or LDL levels greater than the 95th percentile (n = 9) were commenced on an HMG-CoA reductase inhibitor, Atorvastatin and monitoring was performed for efficacy and adverse effects. Total serum cholesterol was elevated in 11 of 18 (61%) and triglyceride (TG) was elevated in 12 of 18 (67%) patients. Atorvastatin treatment was effective with a mean percentage reduction of total cholesterol of 41 +/- 10% (p < 0.01 vs. before treatment), LDL 57 +/- 7% (p < 0.01 vs. before treatment) and TG 44 +/-25% (p = 0.05 vs. before treatment). No adverse effects on allograft function or cyclosporin levels were experienced. Hyperlipidemia is a common problem and Atorvastatin is a safe and effective treatment in pediatric renal transplant recipients.
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PMID:Atorvastatin treatment for hyperlipidemia in pediatric renal transplant recipients. 1258 21


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