atorvastatin Lipitor
Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo.

O'Meara SJ, Kinsella BT.

Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

Prostacyclin plays a central role within the vasculature. We have previously established that the prostacyclin receptor (IP) undergoes isoprenylation, a lipid modification obligate for its function. The aim of the current study was to investigate the effect of the hydroxy methyl glutaryl co-enzyme A reductase inhibitor atorvastatin on signalling and function of the IP expressed in mammalian whole cells and in platelets isolated from patients undergoing therapeutic intervention with atorvastatin. Initially, the effect of atorvastatin on signalling by the human (h) and mouse (m) IP overexpressed in human embryonic kidney 293 cells and the hIP endogenously expressed in human erythroleukaemic 92.1.7 cells was investigated. Atorvastatin significantly reduced IP-mediated cAMP generation (IC(50) 6.6-11.1 microm) and [Ca(2+)](i) mobilization (IC(50) 7.2-16.4 microm) in a concentration-dependent manner, but had no effect on signalling by the nonisoprenylated beta(2) adrenergic receptor or the alpha or beta isoforms of the human thromboxane A(2) receptor (TP). Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TP alpha (IC(50) 10.4 microm), but not by TP beta. In contrast to the whole-cell data, atorvastatin therapy did not interfere with IP-mediated cAMP generation or IP-induced inhibition of TP-mediated aggregation of platelets isolated from human volunteers undergoing therapeutic intervention with atorvastatin (10-80 mg per daily dose). In conclusion, while data generated in whole cells indicated that atorvastatin significantly impairs signalling by both the hIP and mP, the in vivo clinical data indicated that, at the administered therapeutic dose, atorvastatin does not significantly compromise IP signalling and function in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15326037&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study.

Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, Daida H.

Department of Cardiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku Tokyo 113-8421 Japan. shinya med.juntendo.ac.jp

BACKGROUND: Recent clinical trials have demonstrated that aggressive lipid lowering by statins could prevent recurrent events after acute coronary syndrome (ACS). We hypothesized that this efficacy was caused by a significant reduction in plaque volume by aggressive LDL cholesterol (LCL-C) lowering. The present study investigated the effect of early statin treatment on plaque volume of a nonculprit lesion by serial volumetric intravascular ultrasound in patients with ACS. METHODS AND RESULTS: Seventy patients with ACS were enrolled. All patients underwent emergency coronary angiography and percutaneous coronary intervention (PCI). They were randomized to intensive lipid-lowering therapy (n=35; atorvastatin 20 mg/d) or control (n=35) groups after PCI. Volumetric intravascular ultrasound analyses were performed at baseline and 6-month follow-up for a non-PCI site in 48 patients (atorvastatin, n=24; control, n=24). LDL-C level was significantly decreased by 41.7% in the atorvastatin group compared with the control group, in which LDL-C was increased by 0.7% (P<0.0001). Plaque volume was significantly reduced in the atorvastatin group (13.1+/-12.8% decrease) compared with the control group (8.7+/-14.9% increase; P<0.0001). Percent change in plaque volume showed a significant positive correlation with follow-up LDL-C level (R=0.456, P=0.0011) and percent LDL-C reduction (R=0.612, P<0.0001), even in patients with baseline LDL-C <125 mg/dL. CONCLUSIONS: Early aggressive lipid-lowering therapy by atorvastatin for 6 months significantly reduced the plaque volume in patients with ACS. Percent change in plaque volume showed a significant positive correlation with percent LDL-C reduction, even in patients with low baseline LDL-C.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15326073&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin versus pravastatin: intensive versus moderate lipid lowering.

Doggrell SA.

The University of Queensland, School of Biomedical Sciences, QLD 4072, Australia. s_doggrell yahoo.com

With so many statins available for clinical use in coronary artery syndromes, there has been much discussion about which is the best. Two recent trials have compared the clinical outcomes of intensive lipid lowering with atorvastatin 80 mg/day and standard lowering with pravastatin 40 mg/day. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial, patients with acute coronary artery syndromes were enrolled, and pravastatin lowered the low-density lipoprotein (LDL)-cholesterol to 2.46 mmol/l, whereas atorvastatin lowered it to 1.60 mmol/l. Associated with this, there was a lower rate of clinical events (myocardial infarction, revascularisation) over 2 years with atorvastatin than pravastatin (22.4 versus 26.3%, respectively). The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial also enrolled patients requiring angiography, and pravastatin lowered the LDL-cholesterol to 2.84 mmol/l, whereas atorvastatin lowered the LDL-cholesterol to 2.04 mmol/l. In the REVERSAL trial, atheroma volume progressed with pravastatin by 2.7% whilst remaining stable in the atorvastatin group (-0.4%) over 18 months. Thus, atorvastatin 80 mg/day causes a greater reduction in LDL-cholesterol than pravastatin 40 mg/day, and this is associated with a reduced progression of atheroma and reduced clinical events. As a consequence of these findings, the National Cholesterol Education Programme and European guidelines for LDL-cholesterol levels should be lowered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15330739&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effects of atorvastatin on triglyceride-rich lipoproteins, low-density lipoprotein subclass, and C-reactive protein in hemodialysis patients.

Ikejiri A, Hirano T, Murayama S, Yoshino G, Gushiken N, Hyodo T, Taira T, Adachi M.

First Department of Internal Medicine, Showa University School of Medicine, Tokkyo, Japan.

Dyslipidemia is an important risk factor for cardiovascular disease in patients with chronic renal failure (CRF). We evaluated the safety and efficacy of atorvastatin in patients with dyslipidemia associated with CRF who were undergoing hemodialysis (HD). Thirty-five patients who were receiving HD were given atorvastatin (10 mg/d) for 3 months. Chylomicron (CM), light and dense very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and light and dense low-density lipoprotein (LDL) were separated by ultracentrifugation. Apolipoprotein (apo) B was measured by electroimmunoassay. Mean LDL particle diameter was measured by gradient gel electrophoresis. Atorvastatin therapy reduced LDL-cholesterol (C) by 36% and remnant-like particle (RLP)-C by 58%. Atorvastatin significantly reduced apo B, apo CIII, and apo E in VLDL by 40% to 46% and IDL-apo B by 66%. Atorvastatin also significantly reduced cholesterol in CM, light VLDL, and dense VLDL without consistently affecting triglyceride (TG) in these lipoproteins. Atorvastatin similarly reduced both light and dense LDL-apo B by 38%. LDL particle size in the HD patients significantly increased during atorvastatin treatment from 25.7 +/- 0.4 to 26.2 +/- 0.6 nm. High sensitive C-reactive protein (HS-CRP) was halved by atorvastatin decreasing from 0.08 +/- 0.05 to 0.04 +/- 0.03 mg/dL. Atorvastatin treatment did not affect the creatinine kinase level, and no classical adverse effects were observed during the study. These results suggest that atorvastatin is safe and effective for the management of dyslipidemia in patients with CFR who are receiving HD, which may help to suppress the development of atherosclerosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15334369&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
The effect of atorvastatin on markers of bone turnover in patients with type 2 diabetes.

Braatvedt GD, Bagg W, Gamble G, Davidson J, Reid IR.

University Department of Medicine, Auckland Hospital, University of Auckland, Auckland, New Zealand. g.braatvedt auckland.ac.nz

Retrospective and uncontrolled studies suggest that the lipid-lowering statin class of drugs has either no or beneficial effects on bone density and may reduce fracture risk. We have examined the effects of atorvastatin on serum and plasma markers of bone turnover in 25 patients (age 56 +/- 8 years) with type 2 diabetes (duration: 4.7 +/- 5.0 years, 16 female, 2 insulin-treated, 4 diet alone, and 19 on oral hypoglycemic agents) and baseline hypercholesterolemia (cholesterol 6.6 +/- 0.8 mmol/l) in a double-blind, placebo-controlled, crossover study of 12 weeks of placebo/40 mg of atorvastatin with an 8-week wash-out period. Atorvastatin resulted in a fall in total cholesterol of 2.3 +/- 0.9 mmol/l. There were no effects of active or placebo therapy on total alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, or beta C-telopeptide of type 1 collagen (beta-CTX). We conclude that atorvastatin (40 mg/day) has no significant effect on bone turnover in man.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15336614&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin.

Kanda M, Satoh K, Ichihara K.

Department of Pharmacology, Hokkaido College of Pharmacy, Katsuraoka, Otaru, Japan.

Effects of atorvastatin and pravastatin on glucose tolerance in mildly induced diabetic rats by streptozotocin at 24 mg/kg, i.v. were studied. Non-diabetic and diabetic rats were given orally 0.5% carboxymethylcellulose (control), 8 mg/kg atorvastatin or 8 mg/kg pravastatin once a day for 6 weeks. An oral glucose tolerance test (OGTT) was carried out 1, 2, 3, and 6 weeks after the administration. The blood glucose and plasma insulin levels measured before OGTT in the diabetic rats were not different from those in the non-diabetic rats. However, the hyperglycemic response to OGTT in the diabetic rats significantly exceeded that in the non-diabetic rats. The plasma insulin increased by OGTT in the diabetic rats appeared to be lower than that in the non-diabetic rats. Statin treatments for 1 week did not modify the OGTT-induced hyperglycemia appreciably, although there were some significant differences. More than 2 weeks after administration, the blood glucose levels at several time points after a glucose intake in the atorvastatin-treated diabetic rats were significantly higher than the respective levels in the control diabetic rats. Neither atorvastatin nor pravastatin modified the OGTT-induced insulin secretion. Statins, especially atorvastatin, may influence the glucose tolerance in mildly induced diabetic rats without alterations of insulin secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14646170&dopt=Abstract atorvastatin Lipitor