atorvastatin Lipitor
Cost effectiveness of HMG-CoA reductase inhibition in Canada.

Russell MW, Huse DM, Miller JD, Kraemer DF, Hartz SC.

ICSL Healthcare Research, Waltham, Massachusetts 02451-7341, USA. mason.russell icsltd.net

OBJECTIVE: To assess the cost effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy, particularly atorvastatin, in primary and secondary prevention of coronary artery disease (CAD) in Canada. METHODS: A Markov model was developed in which costs and effectiveness of atorvastatin were compared with those of other statins and with no drug therapy in primary and secondary prevention of CAD. PATIENTS: Cost effectiveness was assessed for cohorts of patients with risk profiles defined by CAD status, age, sex, pretreatment low density lipoprotein cholesterol level and presence of sentinel coronary risk factors. Coronary risk was estimated by using initial and subsequent event coronary risk equations from the Framingham Heart Study, and risk factors were estimated by using Canadian population survey data. Recent estimates of the costs of CAD-related medical care in Canada were used to assign costs to health states and acute coronary events. INTERVENTIONS: Interventions included atorvastatin 10 mg, simvastatin 10 mg, pravastatin 20 mg, fluvastatin 20 mg, lovastatin 20 mg and no pharmacological therapy. RESULTS: Incremental cost effectiveness ratios (CDN$/year of life gained) relative to no therapy were lowest for atorvastatin and highest for pravastatin across all risk profiles. Atorvastatin was less costly and more effective than lovastatin, pravastatin and simvastatin in primary and secondary prevention, and conferred additional health benefits at a reduced cost per year of life gained compared with fluvastatin. CONCLUSIONS: Atorvastatin was found to be the most cost effective statin in primary and secondary prevention of CAD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11283756&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Cholesterol-lowering effect of NK-104, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in guinea pig model of hyperlipidemia.

Aoki T, Yamazaki H, Suzuki H, Tamaki T, Sato F, Kitahara M, Saito Y.

Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., Higashimurayama, Tokyo, Japan. t-aoki kowa.co.jp

Although benefits of statins have been demonstrated even in normolipidemic patients at high risk, the main target of statin therapy is the hypercholesterolemic patient. The aim of this study was to examine the hypocholesterolemic effect of NK-104 ((+)-monocalcium bis((3R,5S,6S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]- 3,5-dihydroxy-6-heptenoate), CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and its mechanism of action in hypercholesterolemic animals. In guinea pigs fed a diet containing 15% (w/w) fat rich in laurate for 6 weeks, the liver cholesterol content was markedly increased and plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and LDL-apoB were elevated 4.8, 5.2 and 1.7 times, respectively, compared with normal diet fed animals. These changes were maintained by reduced LDL clearance in the presence of markedly cholesterol-enriched LDL in the plasma. In this model, the LDL-C reduction rates by 0.1, 0.3 and 1 mg/kg of NK-104 orally administered for 2 weeks (from week 4 to week 6), were 11, 27 and 32%, respectively, from controls, being similar in normal guinea pigs previously examined. Those for 3 and 10 mg/kg of atorvastatin (CAS 134523-00-5) were 25 and 39%, respectively. Thus about 10 times higher doses of atorvastatin were required than of NK-104 to cause a similar cholesterol-lowering effect. This reduction of plasma cholesterol was accompanied by an improvement of LDL clearance (24 and 47% increase in fractional catabolic rate by 1 mg/kg of NK-104 and 10 mg/kg of atorvastatin, respectively) and LDL composition. In conclusion, in guinea pig hypercholesterolemia caused by high-laurate diet, NK-104 and atorvastatin lowered plasma cholesterol levels with an improvement of LDL composition and with an increase in LDL clearance, presumably through reduction of the liver cholesterol content, although hepatic cholesterol synthesis might have been markedly suppressed in this model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11304935&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Limitation of heart growth in neonatal piglets by simvastatin and atorvastatin: comparison with pravastatin.

Satoh K, Shirota F, Tsunajima T, Beinlich CJ, Morgan HE, Ichihara K.

Department of Pharmacology, Hokkaido College of Pharmacy, Otaru 047-0264, Japan.

The pig heart grows rapidly in the first few days after birth. We examined the effects of simvastatin, atorvastatin, and pravastatin on heart growth in piglets. After vehicle, 2 mg x kg(-1) x day(-1) simvastatin, 2 mg x kg(-1) x day(-1) atorvastatin, or 4 mg x kg(-1) x day(-1) pravastatin were administered orally for 6 days, the thoracic cavity was opened, and the heart was removed under pentobarbital sodium (30 mg/kg ip) anesthesia. The heart was perfused to remove residual blood. After the heart was blotted dry, the right and left ventricular free walls were dissected. Each free wall was weighed and used for determination of DNA, RNA, and protein concentrations and mitogen-activated protein (MAP) kinase activity. Simvastatin and atorvastatin resulted in smaller increases with age in the weight, concentrations of RNA and protein, and activity of MAP kinase in the left ventricular free wall, whereas pravastatin did not. The parameters of heart growth in the right ventricular free wall were not appreciably affected by either drug. The blood pressure and heart rate were not changed by the treatments. These results suggest that simvastatin and atorvastatin interfere with heart growth in neonatal piglets after birth, especially in the left ventricular free wall.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11356632&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin prevents glomerulosclerosis and renal endothelial dysfunction in hypercholesterolaemic rabbits.

Vazquez-Perez S, Aragoncillo P, de Las Heras N, Navarro-Cid J, Cediel E, Sanz-Rosa D, Ruilope LM, Diaz C, Hernandez G, Lahera V, Cachofeiro V.

Physiology Department, School of Medicine, Universidad Complutense, Barcelona, Spain.

BACKGROUND: Numerous studies have shown that elevated plasma cholesterol can exacerbate renal disease. However, the effect of lipids on renal structure and vascular function in normal kidneys is less well established. Therefore, the aim of this study was to evaluate the impact of hypercholesterolaemia on glomerular structure and vascular reactivity of segmental arteries in rabbits. In addition, we also studied whether or not atorvastatin can prevent these structural and vascular alterations in hypercholesterolaemic rabbits. METHODS: Male New Zealand rabbits were fed either a normal rabbit chow or a diet containing 1% cholesterol and treated or not with atorvastatin (1 mg/kg/day) for 12 weeks. Dose-response curves to acetylcholine (10(-9)-10(-4) mol/l) and sodium nitroprusside (10(-9)-10(-4) mol/l) were studied in segmental arteries in the presence or absence of the thromboxane A2/PGH2 receptor antagonist ifetroban (10(-5) mol/l). Glomerular size and structure were also evaluated. RESULTS: Compared with control animals, hypercholesterolaemic rabbits presented glomerular hypertrophy and several types of injuries (capillary collapse, hyalinosis and alterations of Bowman's capsule), suggesting diffuse glomerulosclerosis. Segmental arteries also showed relaxing responses to acetylcholine and sodium nitroprusside which were lower than and similar to, respectively, those of control animals. The presence of ifetroban improved the acetylcholine response only in hypercholesterolaemic rabbits. Atorvastatin treatment prevented vascular and most glomerular changes associated with hypercholesterolaemia even in the presence of very high cholesterol levels. CONCLUSIONS: Atorvastatin exerts a protective effect on renal damage associated with hypercholesterolaemia even in the presence of deleterious levels of plasma cholesterol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11369819&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages.

Lopez S, Peiretti F, Bonardo B, Deprez-Beauclair P, Laouenan H, Juhan-Vague I, Nalbone G.

Hematology Laboratory, Faculty of Medicine, Marseille, France.

The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherothrombosis and is produced by macrophages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate the synthesis of PAI-1 in human monocytes/macrophages. To this end, we studied the effect of atorvastatin in different models of monocyte/macrophage differentiation, such as differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages. HL-60 cells were differentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (D3). In these conditions, PAI-1 synthesis was strongly induced and atorvastatin upregulated this synthesis, especially during TGF-beta1/D3-induced differentiation. Recombinant human tumor necrosis factor-alpha (TNF-alpha) strongly upregulated PAI-1 synthesis in PMA- or TGF-beta1/D3-differentiated cells, and the potentiating effect of atorvastatin was of the same order as in the absence of TNF-alpha. Mevalonate reversed the enhancing effect of atorvastatin. In mature human monocyte-derived macrophages, atorvastatin, alone or in combination with TNF-alpha, TGF-beta1, or PMA, did not exert any significant effect on PAI-1 synthesis. Basal production of urokinase (uPA), which was below detection limits in HL-60 cells and very low in human monocyte-derived macrophages, was not altered by atorvastatin. These results show that atorvastatin upregulates PAI-1 synthesis during the early stages of monocyte/macrophage differentiation, but has no effect on PAI-1 and uPA synthesis in mature human monocyte-derived macrophages. Atorvastatin did not significantly interact with the upregulating action of TNF-alpha on PAI-1 synthesis during differentiation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11392473&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
A cost-effectiveness model of alternative statins to achieve target LDL-cholesterol levels.

Maclaine GD, Patel H.

Medical Department, Pfizer Ltd, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

An economic model was developed to estimate the relative cost-effectiveness of alternative HMG-CoA reductase inhibitors (statins)--atorvastatin, cerivastatin, fluvastatin, pravastatin and simvastatin--to achieve target low-density lipoprotein cholesterol (LDL-C) levels in a population of secondary CHD prevention patients. By using a cholesterol target as the endpoint of interest and a dose titration approach, the model assumes that the statins demonstrate a class effect through cholesterol lowering. The model was used to estimate the proportion of patients achieving target LDL-C levels (< 3 mmol/l) under each scenario tested. Total costs and incremental cost-effectiveness relative to no treatment and to the lowest cost option were estimated for each scenario. Total costs were highest for pravastatin and lowest for cerivastatin. Compared with no treatment, the incremental cost per patient treated to target LDL-C varied between 383 Pounds (atorvastatin) and 1213 Pounds (pravastatin). Incremental cost-effectiveness ratios in comparison with the lowest cost treatment (cerivastatin) were 141 Pounds per additional patient achieving target LDL-C with atorvastatin, and 275 Pounds with simvastatin. Fluvastatin and pravastatin were both less effective and more expensive than the lowest cost therapy. Although cerivastatin was associated with lowest expected costs, therapy with atorvastatin achieved the lowest cost-effectiveness ratios. Hence atorvastatin would allow the largest number of patients to be treated to target LDL-C within a fixed drug budget. Choosing between drug therapies on the basis of price alone may be misleading if the effectiveness of therapies varies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11406909&dopt=Abstract atorvastatin Lipitor