atorvastatin Lipitor
Fertility and general reproduction studies in rats with the HMG-CoA reductase inhibitor, atorvastatin.

Dostal LA, Whitfield LR, Anderson JA.

Department of Pathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.

Fertility and reproduction studies were conducted in rats with the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin. Male rats received vehicle (0.5% methylcellulose) or atorvastatin at 20, 100, or 175 mg/kg by oral gavage for 11 weeks prior to mating with untreated females; treatment continued throughout mating and until necropsy on Day 115. An untreated control group of males was also included in the same procedures. Dose-related body weight gain suppressions of 17 and 25%, and food consumption suppressions of 7 and 16%, occurred during the 11-week premating treatment period at 100 and 175 mg/kg, respectively, compared with vehicle controls. There were no treatment-related effects on testes, epididymides, or accessory organs weights, testicular or epididymal sperm counts, sperm motility, or sperm morphology during Week 15 of treatment. Plasma drug concentrations during Week 15 increased with dose to a Cmax of 1820 +/- 1020 ng eq/ml at 175 mg/kg. There were no effects on copulation or fertility indices, number of days to mating, or female reproductive parameters (number of implants, live fetuses, or pre- and postimplantation loss). In the female fertility study, female rats received vehicle (0.5% methylcellulose) or atorvastatin at 20, 100, or 225 mg/kg by oral gavage for 2 weeks prior to mating with untreated males; treatment continued throughout mating and until Gestation Day 7. Sperm-positive females were sacrificed on presumed Gestation Day 13 to 15 for evaluation of reproductive parameters. Body weight gain in atorvastatin groups was comparable to controls during the premating period, but was suppressed by 35% at 225 mg/kg during the treatment period of gestation (Days 0-8), and was significantly increased at 225 mg/ kg during the posttreatment period of gestation (Days 8-13). Plasma drug concentrations on premating treatment Day 14 increased with dose to a Cmax of 7030 +/- 3680 ng eq/ml at 225 mg/ kg. The mean number of estrous cycles, copulation and fertility indices, number of days to mating, and number of viable litters were comparable between groups. In addition, term sacrifice parameters (number of corpora lutea, implants, live fetuses, pre- and postimplantation loss) were not significantly different between groups. Thus, these studies demonstrate no adverse effects of atorvastatin on fertility and reproduction in rats at doses up to 175 and 225 mg/kg in males and females, respectively, and 20 mg/kg was a no-effect dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8921332&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Hypocholesterolemic actions of atorvastatin are associated with alterations on hepatic cholesterol metabolism and lipoprotein composition in the guinea pig.

Conde K, Vergara-Jimenez M, Krause BR, Newton RS, Fernandez ML.

Department of Nutritional Sciences, University of Arizona, Tucson 85721, USA.

Guinea pigs were fed 15% (w/W) fat, high in lauric and myristic acids, a diet known to produce hypercholesterolemia in these animals. The diet was given alone or in combination with four doses of atorvastatin equivalent to 1, 3, 10, and 20 mg/kg per day. Atorvastatin reduced plasma LDL cholesterol concentrations by 46, 50, 53, and 70%, respectively (P < 0.001). Plasma apoB concentrations were reduced by atorvastatin (P < 0.001) and compositional changes occurred in VLDL and LDL with reductions of the relative proportion of cholesteryl ester and increases in triacylglycerol. A reduction in hepatic cholesteryl ester (66%) was observed only with the highest atorvastatin dose (20 mg/kg per day) while microsomal cholesterol was reduced by 30% with 3-20 mg/kg per day. Hepatic ACAT activity was down-regulated and apoB/E receptor number was increased by atorvastatin. In contrast, HMG-CoA reductase activity and cholesterol 7 alpha-hydroxylase were not affected by the drug. VLDL apoB secretion rates were decreased by atorvastatin treatment 59 and 76% with 3 and 20 mg/kg per day, respectively. Nascent VLDL particles were larger after drug treatment, showing an increased number in triacylglycerol molecules. These results support the hypothesis that the plasma LDL lowering induced by atorvastatin is due to a decreased secretion of apoB in combination with an increase of hepatic apoB/E receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8978489&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages.

Llaverias G, Noe V, Penuelas S, Vazquez-Carrera M, Sanchez RM, Laguna JC, Ciudad CJ, Alegret M.

Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Spain.

With the aim of identifying new target genes that could contribute to limit foam cell formation, we analyzed changes in the pattern of gene expression in human THP-1 macrophages treated with atorvastatin and oxidized-LDL (oxLDL). To this end, we used a human cDNA array containing 588 cardiovascular-related cDNAs. Exposure to oxLDL resulted in differential expression of 26 genes, while coincubation with atorvastatin modified the expression of 29 genes, compared to treatment with oxLDL alone. Changes in the expression of candidate genes, potentially connected to the atherosclerotic process, were confirmed by quantitative RT-PCR and Western blot. We show that atorvastatin prevents the increase in the expression of scavenger receptor CD68 and that of fatty acid binding protein 4 caused by oxLDL. In addition, atorvastatin reduces the expression of HDL-binding protein, apolipoprotein E, and matrix metalloproteinase 9. These findings are relevant to understand the direct antiatherogenic effects of statins on macrophages.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15110783&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.

Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI.

Department of Family Medicine, Karadeniz Technical University, School of Medicine, TR-61187 Trabzon, Turkey. fyaris meds.ktu.edu.tr

The subject is a diabetic and hypertensive woman treated early during an unplanned pregnancy with a multi-drug regimen that included three drugs with no prior history for use in pregnant women (rosiglitazone, gliclazide, atorvastatin). She was under care for chronic hypertension, which she suffered for 14 years, and diabetes mellitus, hypercholesterolemia, anxiety disorder, morbid obesity and epilepsia for 5 years. She was exposed to rosiglitazone (4mg/day), gliclazide (60mg/day), and atorvastatin (40mg/day) in addition to acarbose, spironolactone, hydrochlorothiazide, carbamazepine, thioridazine, amitryptiline, chlordiazepoxide, and pipenzolate bromide during the first 7 weeks of gestation while unaware of pregnancy. Pharmacotherapy was adjusted following clinical recognition of pregnancy during the 8th week. She gave birth to a normal healthy infant at the 36th week of gestation. This is the first reported case of human exposure to rosiglitazone, gliclazide, and atorvastatin during pregnancy. Although the normal pregnancy outcome does not address the safety of these drugs for use in pregnancy, these data contribute to a limited knowledge regarding human exposure to these antidiabetic drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15135857&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
[Clinical study of the month. REVERAL and PROVE-IT: confirmation of the concept " the lower, the better" for cholesterol therapy in patients with coronary heart disease]

[Article in French]

Scheen AJ, Kulbertus H.

Universite de Liege.

Statins, as compared to placebo, have proven their efficacy in reducing cardiovascular events in patients with or without cardiovascular disease and in a large range of cholesterol levels. Two new head-to-head randomised trials comparing intensive treatment with atorvastatin 80 mg/day with moderate treatment with pravastatin 40 mg/day were recently completed. The mechanistic "Reversing Atherosclerosis with Aggressive Lipid Lowering" (REVERSAL) trial randomised 502 patients with stable coronary disease. Atorvastatin 80 mg (leading to a mean LDL cholesterol of 79 mg/dl) was superior to pravastatin 40 mg (mean LDL of 110 mg/dl) in terms of limiting the progression of atheroma assessed with the use of intravascular ultrasonography after 18 months of follow up (p = 0.02). These differences may be related to the greater reduction in atherogenic lipoprotein (-46% versus -26%, p < 0.001) and C-reactive protein (-36% versus -5%, p < 0.001) in patients treated with atorvastatin as compared to pravastatin. In the clinical "Pravastatin or Atorvastatin Evaluation and Infection Therapy" (PROVE-IT) trial, 4162 patients with acute coronary syndromes were randomised to either atorvastatin 80 mg or pravastatin 40 mg and followed for a mean of 24 months. Again, atorvastatin (mean LDL of 62 mg/dl) was superior to pravastatin (mean LDL of 95 mg/dl), resulting in a 16% percent lower risk of the primary end point, a composite of major cardiovascular events (p = 0.005). Thus, both REVERSAL and PROVE-IT support the concept "the lower, the better". However, they do not allow to disentangle the independent and interdependent effects of statins on LDL cholesterol and the process of arterial inflammation. What so ever, the results suggest that the target LDL cholesterol level may be lower than recommended in the current guidelines in high-risk patient so that a sea change in the prevention and management of atherosclerotic vascular disease may occur very soon.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15139406&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage.

Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, Kim M, Roh JK.

Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Seoul National University, Seoul, South Korea.

BACKGROUND AND PURPOSE: Statins have neuroprotective effects on ischemic stroke. They modify the endothelial function, increase blood flow, and inhibit thrombus formation, which are independent of lipid-lowering effects. However, whether statins have a protective effect toward hemorrhagic stroke is yet unknown. To test this possibility, we attempted to determine the effect of atorvastatin on experimental intracerebral hemorrhage (ICH). METHODS: ICH was induced using stereotaxic infusion of collagenase into the left basal ganglia in adult rats. Atorvastatin (1 mg/kg or 10 mg/kg) or phosphate-buffered saline was administered for 2 weeks. To monitor the sensorimotor deficits, limb placing and Rotorod tests were performed. Hematoma volume, brain water content, and hemispheric atrophy were analyzed. Immunohistochemical staining for myeloperoxidase (MPO), microglia (OX42), inducible nitric oxide synthase (iNOS), or endothelial nitric oxide synthase (eNOS) was performed. Perihematomal cell death was determined by TUNEL staining. RESULTS: The atorvastatin-treated ICH group showed better performance on Rotorod and limb placing tests when compared with the vehicle-treated group (P<0.01). The hematoma volumes between groups were not different, but the brain water content and hemispheric atrophy were reduced in the atorvastatin-treated ICH group. Atorvastatin reduced TUNEL-positive cells, iNOS expression, and MPO-positive or OX42-positive cells in the perihematomal regions in a dose-dependent manner, whereas it increased eNOS expression. CONCLUSIONS: The present study shows that atorvastatin reduces the perihematomal cell death via antiinflammation, which is associated with sensorimotor recovery after experimental ICH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15166393&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats.

Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M.

Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan 48202, USA. nsdos neuro.hfh.edu

OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor, improves neurological functional outcome, reduces cerebral cell loss, and promotes regional cellular plasticity when administered after intracerebral hemorrhage (ICH) in rats. METHODS: Autologous blood was stereotactically injected into the right striatum in rats, and atorvastatin was administered orally beginning 24 hours after ICH and continued daily for 1 week. At a dose of 2 mg/kg, atorvastatin significantly reduced the severity of neurological deficit from 2 to 4 weeks after ICH. The area of cell loss in the ipsilateral striatum was also significantly reduced in these animals. Consistent with previous study data, higher doses of atorvastatin (8 mg/kg) did not improve functional outcome or reduce the extent of injury. Histochemical stains for markers of synaptogenesis, immature neurons, and neuronal migration revealed increased labeling in the region of hemorrhage in the atorvastatin-treated rats. CONCLUSIONS: Analysis of the data in this study indicates that atorvastatin improves neurological recovery after experimental ICH and may do so in part by increasing neuronal plasticity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15255259&dopt=Abstract atorvastatin Lipitor