Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new lovastatin research articles will be listed here shortly after becoming available to us.
Medical research on lovastatin
Lovastatin improves neurological outcome after nucleus basalis magnocellularis lesion in rats.
Neuroscience. 2010 Feb 26;
Zhao Z, Zhao S, Xu N, Yu C, Guan S, Liu X, Huang L, Liao W, Jia W
Increasing evidence indicates that statins, specific inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, exerts neuroprotective actions rather than simply lowering cholesterol. However, the underlying mechanism has not been elucidated clearly. Here, the effect of lovastatin on the neurological outcomes of nucleus basalis magnocellularis (NBM)-lesioned rats and the pathophysiological mechanisms were investigated. Sprague-Dawley rats were divided into three groups: (i) a sham group; (ii) a model group: bilateral NBM of rats were injured by infusion of ibotenic acid; and (iii) a lovastatin-treated group: lovastatin was administrated orally for 4 weeks before treated by ibotenic acid. We show that lovastatin significantly improves the neurological outcomes as well as the choline acetyltransferase (ChAT) activity and muscarinic/NMDA receptor binding activity impaired by NBM lesion, and that lovastatin prevents neuron loss and induces Akt whereas inhibits p38 phosphorylation. Overall, the neuro-restorative and -protective effect of lovastatin may be attributed to the regulation of Akt- and p38-mediated signaling pathway together with improvement of muscarinic/NMDA receptor functions. Statins may be useful in the treatment of neurological disorders.
Hepatogastroenterology. 2009 Nov-Dec; 56(96): 1704-9
Mihăilă R, Nedelcu L, Frăţilă O, Rezi EC, Domnariu C, Ciucă R, Zaharie AV, Olteanu A, Bera L, Deac M, Mihăilă R
BACKGROUNDS/AIMS: Certain statins interfere with the mechanism of the hepatitis C virus replication. We aimed at studying the effect of statins on the level of viremia and of the pro-and anti-inflammatory cytokines in the patients with chronic hepatitis C. METHODOLOGY: We took in our study all the patients with chronic hepatitis C placed in the evidence of the clinics of internal medicine of the Emergency County Clinical Hospitals of Braşov, Oradea and Sibiu, who had been identified with viremias. The patients were treated with fluvastatin 40 mg/day or lovastatin 20 mg/day for 28 days. The level of viremia, hemoleukogram, hepatic biochemical tests and the pro and anti-inflammatory hepatic cytokines were analysed before and after the treatment. The final results were compared with the initial ones, as well as between the 2 groups. RESULTS: Regarding those 99 analysed patients, the initial average viremia was of 2376074 +/- 3427596 UI/ml, while the final one was of 1321136 +/- 1343570 UI/ml (p = 0.000987). Both, in the group treated with lovastatin, as well as in that treated with fluvastatin, the decrease of viremia was significant from the statistics point of view (p = 0.032, respectively p = 0.00092). Lovastatin administration resulted in the significant decrease of the pro-inflammatory cytokines IL-6 and TNF-alfa, while that of fluvastatin brought about the significant decrease of the serum levels of IL-6, IL-8 and TNF-alfa. There were no significant differences, statistically speaking, between the 2 determinations, regarding the levels of IL-10 (anti-inflammatory cytokine) and those of erythropoietin. Transaminases average level did not vary significantly after those 4 weeks of statins treatment. CONCLUSIONS: Lovastatin and fluvastatin, significantly decrease the level of viremia, of IL-6 and TNF-alpha in the patients with chronic hepatitis C.
Effect of niacin ER/lovastatin on claudication symptoms in patients with peripheral artery disease.
Vasc Med. 2010 Mar 8;
Hiatt WR, Hirsch AT, Creager MA, Rajagopalan S, Mohler ER, Ballantyne CM, Regensteiner JG, Treat-Jacobson D, Dale RA
In patients with peripheral artery disease (PAD), statins may improve the symptoms of claudication. The Intermittent Claudication Proof of Principle (ICPOP) study tested the hypothesis that the combination of extended release niacin plus lovastatin would improve exercise performance in patients with PAD and claudication compared with a diet intervention. A phase 3 double-blind, parallel-group, multi-center, 28-week multi-national study evaluated subjects with a history of claudication who had an ankle-brachial index (ABI)
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study.
Breast Cancer Res. 2010 Mar 5; 12(2): R16
Klawitter J, Shokati T, Moll V, Christians U, Klawitter J
ABSTRACT: INTRODUCTION: Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses. METHODS: In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques. RESULTS: Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis. CONCLUSIONS: The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells.
Tissue Eng Part A. 2010 Mar 5;
Yoshii T, Hafeman AE, Nyman JS, Esparza JM, Shinomiya K, Spengler DM, Mundy GR, Gutierrez GE, Guelcher S
Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. In this study, we combined reactive two-component PUR scaffolds with lovastatin (LV), which has been reported to have a bone anabolic effect especially when delivered locally, for effective bone tissue regeneration. To incorporate LV into PUR scaffolds, LV was combined with the hardener component prior to scaffold synthesis. The PUR scaffolds containing LV (PUR/LV) demonstrated a highly porous structure with interconnected pores, which supported in vitro cell attachment and proliferation and in vivo osteoconductive potential. The PUR/LV scaffolds showed sustained release of biologically active LV, as evidenced by the fact that LV releasates significantly enhanced osteogenic differentiation of osteoblastic cells in vitro. A study of bone formation in vivo using a rat plug defect model showed that the PUR/LV scaffolds were biocompatible. Furthermore, locally delivered LV enhanced new bone formation in the PUR scaffolds at week 4, while there were no obvious effects at week 2. These results suggest that the sustained LV delivery system from PUR scaffolds is a potentially safe and effective device for bone regeneration.
Int J Cancer. 2010 Mar 3;
Goard CA, Mather RG, Vinepal B, Clendening JW, Martirosyan A, Boutros PC, Sharom FJ, Penn LZ
Statins, prescribed for decades to control cholesterol, have more recently been shown to have promising anticancer activity. Statins induce tumor-selective apoptosis by inhibiting the mevalonate pathway. In addition, we have recently demonstrated that lovastatin modulates drug accumulation in a mevalonate-independent manner in multidrug resistant (MDR) tumor cells overexpressing the P-glycoprotein (P-gp) multidrug transporter. P-gp-mediated drug efflux can contribute to chemotherapy failure. However, direct statin-mediated inhibition of P-gp in human MDR tumor cells at clinically achievable concentrations remains unexplored. An understanding of these interactions is crucial, both to appreciate differences in the anticancer potential of different statins and to safely and effectively integrate statins into traditional chemotherapy regimens that include P-gp substrates. Here we evaluate interactions between four statins (lovastatin, atorvastatin, fluvastatin and rosuvastatin) and P-gp, at both the molecular level using purified P-gp and at the cellular level using human MDR tumor cells. Lovastatin bound directly to purified P-gp with high affinity and increased doxorubicin accumulation in MDR tumor cells, potentiating DNA damage, growth arrest and apoptosis. By contrast, while atorvastatin inhibited substrate transport by purified P-gp in proteoliposomes, it had no effect on doxorubicin transport in MDR tumor cells. Finally, fluvastatin and rosuvastatin only interacted with P-gp in vitro at high concentrations and did not inhibit doxorubicin transport in MDR cells. These differential interactions should be considered when combining statins with other traditional chemotherapeutic drugs. (c) 2010 UICC.
J Bone Miner Res. 2010 Jan 29;
Wang W, Nyman J, Moss H, Gutierrez G, Mundy G, Yang X, Elefteriou F
Post-fracture tibia non-union (pseudoarthrosis) leads to lifelong disability in patients with Neurofibromatosis type I (NF1), a disorder caused by mutations in the NF1 gene. To determine the contribution of NF1 in bone healing, we assessed bone healing in the Nf1(ob) (-/-) conditional mouse model, lacking Nf1 specifically in osteoblasts. A closed distal tibia fracture protocol and a longitudinal study design were used. During the 21 to 28 days post-fracture period, callus volume, as expected, decreased in WT, but not in Nf1(ob) (-/-) mice, suggesting delayed healing. At these two time-points, BV/TV and vBMD measured by 3D-computed microtomography were decreased in Nf1(ob) (-/-) callus bridging cortices and trabecular compartments compared to wildtype (WT) controls. Histomorphometric analyses revealed the presence of cartilaginous remnants, high amount of osteoid and increased osteoclast surfaces in Nf1(ob) (-/-) calluses 21 days post-fracture, which was accompanied by increased expression of Osteopontin, Rankl and Tgfbeta. Callus strength measured by 3-point bending 28 days post-fracture was reduced in Nf1(ob) (-/-) versus WT calluses. Importantly from a clinical point of view, this defect of callus maturation and strength could be ameliorated by local delivery of low dose lovastatin microparticles, which successfully decreased osteoid volume and cartilaginous remnant number, and increased callus BV/TV and strength in mutant mice. These results thus indicate that the dysfunctions caused by loss of Nf1 in osteoblasts impair callus maturation, weaken callus mechanical properties and suggest that local delivery of low dose lovastatin may improve bone healing in NF1 patients. (c) 2010 American Society for Bone and Mineral Research.
Metabolism. 2010 Mar 1;
Lecker JL, Matthan NR, Billheimer JT, Rader DJ, Lichtenstein AH
Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism, we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (wt/wt) coconut, olive, or safflower oil with either high cholesterol (0.1%; cholesterol supplemented) or low cholesterol coupled with cholesterol-lowering drugs 10 days before killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol depleted). Irrespective of dietary fat, cholesterol depletion, relative to supplementation, resulted in lower plasma non-high-density lipoprotein (non-HDL) and HDL cholesterol, and triglyceride concentrations (all Ps < .05). In the liver, these differences were associated with higher sterol regulatory element binding protein-2, low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 7alpha-hydroxylase messenger RNA (mRNA) levels; higher scavenger receptor B1 and apolipoprotein A-I mRNA and protein levels; lower apolipoprotein E protein levels; and in intestine, modestly lower sterol transporters adenosine triphosphate-binding cassette (ABC) A1, ABCG5, and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both Ps < .05) and modestly higher sterol regulatory element binding protein-2 mRNA levels. These data suggest that, in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest, which limits the usefulness of the experimental animal model.
J Cell Mol Med. 2009 Sep; 13(9B): 3497-516
Woods A, James CG, Wang G, Dupuis H, Beier F
Elucidating the signalling pathways that regulate chondrocyte differentiation, such as the actin cytoskeleton and Rho GTPases, during development is essential for understanding of pathological conditions of cartilage, such as chondrodysplasias and osteoarthritis. Manipulation of actin dynamics in tibia organ cultures isolated from E15.5 mice results in pronounced enhancement of endochondral bone growth and specific changes in growth plate architecture. Global changes in gene expression were examined of primary chondrocytes isolated from embryonic tibia, treated with the compounds cytochalasin D, jasplakinolide (actin modifiers) and the ROCK inhibitor Y27632. Cytochalasin D elicited the most pronounced response and induced many features of hypertrophic chondrocyte differentiation. Bioinformatics analyses of microarray data and expression validation by real-time PCR and immunohistochemistry resulted in the identification of the nuclear receptor retinoid related orphan receptor-alpha (Ror-alpha) as a novel putative regulator of chondrocyte hypertrophy. Expression of Ror-alpha target genes, (Lpl, fatty acid binding protein 4 [Fabp4], Cd36 and kruppel-like factor 5 [Klf15]) were induced during chondrocyte hypertrophy and by cytochalasin D and are cholesterol dependent. Stimulation of Ror-alpha by cholesterol results in increased bone growth and enlarged, rounded cells, a phenotype similar to chondrocyte hypertrophy and to the changes induced by cytochalasin D, while inhibition of cholesterol synthesis by lovastatin inhibits cytochalasin D induced bone growth. Additionally, we show that in a mouse model of cartilage specific (Col2-Cre) Rac1, inactivation results in increased Hif-1alpha (a regulator of Rora gene expression) and Ror-alpha(+) cells within hypertrophic growth plates. We provide evidence that cholesterol signalling through increased Ror-alpha expression stimulates chondrocyte hypertrophy and partially mediates responses of cartilage to actin dynamics.
Terje Pedersen: a pioneer trialist in preventive cardiology.
Lancet. 2010 Feb 27; 375(9716): 717
Morris K