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.
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Medical research on lovastatin
Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death.
Neurosci Lett. 2008 Jun 6;
Lee JK, Won JS, Singh AK, Singh I
Statins are inhibitors of HMG-CoA reductase that have been recently recognized as anti-inflammatory and neuroprotective drugs. Herein, we investigated anti-excitotoxic and anti-seizure effects of statins by using kainic acid (KA)-rat seizure model, an animal model for temporal lobe epilepsy and excitotoxic neurodegeneration. We observed that pre-treatment with Lipitor (atorvastatin) efficiently reduced KA-induced seizure activities, hippocampal neuron death, monocyte infiltration and proinflammatory gene expression. In addition, we also observed that lovastatin treatment attenuated KA- or glutamate-induced excitotoxicity of cultured hippocampal neurons. These observations suggest a potential for use of statin treatment in modulation of seizures and other neurological diseases associated with excitotoxicity.
FEBS Lett. 2008 Jun 23;
Herrero-Martin G, López-Rivas A
Statins are inhibitors of the mevalonate synthesis pathway that induce apoptosis in tumor cells although the apoptotic mechanism activated by statins remains to be elucidated. We have examined the role of the mitochondria-operated pathway of apoptosis in the cell death induced by statins in breast tumor cells and its regulation by protein prenylation and ErbB2 overexpression. Lovastatin treatment down-regulates the expression of Bcl-2 and activates apoptosis through a mitochondria-operated, ErbB2- regulated mechanism. Apoptosis induced by statins is independent of their effects on cholesterol synthesis and involves protein prenylation. Our results indicate that prenylation of apoptosis-regulating proteins is a key event in the survival of breast tumor cells and this requirement could be circumvented in cells overexpressing the oncogene ErbB2.
RENAL NA-K-CL COTRANSPORTER ACTIVITY AND VASOPRESSIN-INDUCED TRAFFICKING ARE LIPID RAFT-DEPENDENT.
Am J Physiol Renal Physiol. 2008 Jun 25;
Welker P, Boehlick A, Mutig K, Salanova M, Kahl T, Schlueter H, Blottner D, Ponce-Coria J, Gamba G, Bachmann S
Apical bumetanide-sensitive Na(+)-K(-)-2Cl(-)-cotransporter (NKCC2), the kidney-specific member of a cation-chloride cotransporter superfamily, is an integral membrane protein responsible for the transepithelial reabsorption of NaCl. The role of NKCC2 is essential for renal volume regulation. Vasopressin (AVP) controls NKCC2 surface expression in cells of the thick ascending limb of the loop of Henle (TAL). We found that 40-70% of Triton X-100-insoluble NKCC2 was present in cholesterol-enriched lipid rafts (LR) in rat kidney and cultured TAL cells. The related Na(+)Cl(-)-cotransporter, NCC, from rat kidney was distributed in LR as well. NKCC2-containing LR were detected both intracellularly and in the plasma membrane. Bumetanide-sensitive transport of NKCC2 as analyzed by 86Rb+ influx in Xenopus laevis oocytes was markedly reduced by methyl-beta-cyclodextrin (MbetaCD)-induced cholesterol depletion. In TAL, short term AVP application induced apical vesicular trafficking along with a shift of NKCC2 from non-raft to LR fractions. In parallel, increased colocalization of NKCC2 with the LR ganglioside GM1 and their polar translocation were assessed by confocal analysis. Apical biotinylation showed twofold increases in NKCC2 surface expression. These effects were blunted by mevalonate-lovastatin/MbetaCD-induced cholesterol deprivation. Collectively, these findings demonstrate that a pool of NKCC2 distributes in rafts. Results are consistent with a model in which LR mediate polar insertion, activity, and AVP-induced trafficking of NKCC2 in the control of transepithelial NaCl transport. Key words: thick ascending limb, lipid raft, Xenopus oocyte, cholesterol depletion.
Cloning and Characterization of Monacolin K Biosynthetic Gene Cluster from Monascus pilosus.
J Agric Food Chem. 2008 Jun 26;
Chen YP, Tseng CP, Liaw LL, Wang CL, Chen IC, Wu WJ, Wu MD, Yuan GF
Monacolin K is a secondary metabolite synthesized by polyketide synthases (PKS) from Monascus, and it has the same structure as lovastatin, which is mainly produced by Aspergillus terreus. In the present study, a bacterial artificial chromosome (BAC) clone, mps01, was screened from the BAC library constructed from Monascus pilosus BCRC38072 genomic DNA. The putative monacolin K biosynthetic gene cluster was found within a 42 kb region in the mps01 clone. The deduced amino acid sequences encoded by the nine genes designated as mokA- mokI, which share over 54% similarity with the lovastatin biosynthetic gene cluster in A. terreus, were assumed to be involved in monacolin K biosynthesis. A gene disruption construct designed to replace the central part of mokA, a polyketide synthase gene, in wild-type M. pilosus BCRC38072 with a hygromycin B resistance gene through homologous recombination, resulted in a mokA-disrupted strain. The disruptant did not produce monacolin K, indicating that mokA encoded the PKS responsible for monacolin K biosynthesis in M. pilosus BCRC38072.
J Neurooncol. 2008 Jun 20;
Cemeus C, Zhao TT, Barrett GM, Lorimer IA, Dimitroulakos J
The epidermal growth factor receptor (EGFR) is commonly amplified and mutated in glioblastoma, making it a compelling therapeutic target. Recent reports have demonstrated clinical activity of the EGFR inhibitors gefitinib and erlotinib in a subset of glioblastoma patients. Co-expression of EGFRvIII, a constitutively active mutant receptor expressed in 50% of tumours, and PTEN, an inhibitor of PI3K activity, by glioblastoma cells is associated with clinical response to these EGFR kinase inhibitors. PTEN loss and resulting increased PI3K pathway activity appears to act as a resistance factor. A critical therapeutic challenge is to identify agents that enhance the anti-cancer effects of these agents and promote responsiveness to EGFR kinase inhibitors in a broader spectrum of glioblastoma patients. For example, combining gefitinib with inhibitors of the PI3K/AKT pathway show enhanced cytotoxicity in glioblastoma derived cell lines. Here, we show that targeting HMG-CoA reductase with lovastatin, that can affect the activity of multiple cell signaling pathways, significantly enhanced the sensitivity of glioblastoma cells to the EGFR kinase inhibitor gefitinib in the five cell lines tested. In an isogenic model system, U87MG glioblastoma cells expressing EGFRvIII and PTEN in relevant combinations, we show that combined gefitinib and lovastatin treatments induce potent synergistic cytotoxicity irrespective of EGFRvIII and PTEN status. These studies demonstrate the potential of lovastatin to augment the cytotoxic effects of gefitinib and provide a rationale for combined statin/EGFR targeted therapies in glioblastoma patients.
Arterioscler Thromb Vasc Biol. 2008 Jun 19;
Lamon-Fava S, Diffenderfer MR, Barrett PH, Buchsbaum A, Nyaku M, Horvath KV, Asztalos BF, Otokozawa S, Ai M, Matthan NR, Lichtenstein AH, Dolnikowski GG, Schaefer EJ
OBJECTIVE: Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoproteins (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. METHODS AND RESULTS: We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. CONCLUSIONS: Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.
Clin Pharmacokinet. 2008; 47(7): 463-74
Neuvonen PJ, Backman JT, Niemi M
HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.
Evaluation of coenzyme q as an antioxidant strategy for Alzheimer's disease.
J Alzheimers Dis. 2008 Jun; 14(2): 225-34
Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF
Increasing evidence suggests that Alzheimer's disease (AD) is associated with oxidative damage that is caused in part by mitochondrial dysfunction. Here we investigated the feasibility of modifying Alzheimer pathology with the mitochondrial antioxidant coenzyme Q (CoQ). Exogenous CoQ protected MC65 neuroblastoma cells from amyloid-beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity in a concentration dependent manner, with concentrations of 6.25 muM and higher providing near complete protection. Dietary supplementation with CoQ at a dose of 10 g/kg diet to C65/Bl6 mice for one month significantly suppressed brain protein carbonyl levels, which are markers of oxidative damage. Treatment for one month with 2 g lovastatin/kg diet, which interferes with CoQ synthesis, resulted in a significant lowering of brain CoQ10 levels. Mitochondrial energetics (brain ATP levels and mitochondrial membrane potential) were unaffected by either CoQ or lovastatin treatment. Our results suggest that oral CoQ may be a viable antioxidant strategy for neurodegenerative disease. Our data supports a trial of CoQ in an animal model of AD in order to determine whether a clinical trial is warranted.
J Clin Endocrinol Metab. 2008 Jun 17;
Blesa S, Vernia S, Garcia-Garcia AB, Martinez-Hervas S, Ivorra C, Gonzalez-Albert V, Ascaso JF, Martín-Escudero JC, Real JT, Carmena R, Casado M, Chaves FJ
Context: Autosomal Dominant Hypercholesterolemia is a genetic disorder characterized by increased LDL-cholesterol levels leading to high risk of premature cardiovascular disease. More than 900 mutations in LDLR, 6 in APOB and 10 in PCSK9 have been identified as a cause of the disease in different populations. All known mutations in PCSK9 causing hypercholesterolemia produce an increase in the enzymatic activity of this protease. Up to now, there are data about the implication of PCSK9 in ADH in a low number of populations, not including Spanish population. Objective: To study the prevalence of PCSK9 mutations in ADH Spanish population. Participants: We have screened PCSK9 gene in 42 independent ADH patients in whom mutations in LDLR and APOB genes had been excluded. Results: None of the known mutations causing ADH was detected in our sample, but we have found two variations in the promoter region that could cause ADH, c.-288G>A and c.-332C>A, (each one of them in one proband). The analysis of the effect of these two variations on the transcription activity of the PCSK9 promoter showed that c.-288G>A did not modify the transcription while c.-332C>A variant caused a 2.5 fold increase when compared to the wild type sequence, either with or without Lovastatin. Conclusions: PCSK9 is a rare cause of ADH in Spanish population and, up to what we know; none of the previously described mutations has been detected. We have identified a new mutation that could cause ADH by increasing the transcription of PCSK9.
Drug Metab Dispos. 2008 Jun 12;
Chen C, Stock JL, Liu X, Shi J, Van Deusen JW, Dimattia DA, Dullea RG, Morais SM
We generated the organic anion transporting polypepetide (Oatp) 1b2 knockout (KO) mouse model and assessed its utility to study hepatic uptake using model compounds (cerivastatin, lovastatin acid, pravastatin, simvastatin acid, rifampicin, and rifamycin SV) that are known to interact with OATP1B1. A selective panel of liver P450s (Cyp3a11, 13, 16; 2c29 and 39) and transporters (Oatp 1b2, 1a1, 1a4, 1a5; Oat1, Oat2, Oat3; Mdr1a, 1b; Bsep, Mrp2, Mrp3; Bcrp) were measured by RT-PCR in both KO and wild-type (WT) male mice. Male KO and WT mice received each model compound subcutaneously at 3 mg/kg. Blood and liver samples were obtained at 0, 0.5, and 2 h post dose and analyzed using LC/MS/MS. Liver/plasma concentration ratio (Kp,liver) was calculated. Student's t-test was used to compare the mRNA and Kp,liver between the KO and WT mice. A similar mRNA expression was observed between the KO and WT for the selected P450s and transporters, except for Oatp1b2 for which the level was negligible in the KO but prominent in the WT mice with P