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Medical research on pravastatin
Am J Pathol. 2008 Jul 3;
Favaro E, Miceli I, Bussolati B, Schimitt-Ney M, Cavallo Perin P, Camussi G, Zanone MM
Pancreatic islet microendothelium and beta cells exhibit an interdependent physical and functional relationship. In this study, we analyzed the effect of chronic hyperglycemia on human pancreatic islet microendothelial cells as well as the involvement of the phosphatidylinositol 3-kinase/Akt and nephrin pathways, interleukin-1beta, and nitric oxide production. In addition, whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reverse the response to high-glucose conditions was investigated. Proliferation of purified islet microendothelial cells cultured under hyperglycemic conditions (28 mmol/L glucose) decreased compared to that of normoglycemic cells (from 12.7% after 2 days to 47.7% after 30 days, P < 0.05). In parallel, apoptosis progressively increased from 7% after 2 days to 79% after 30 days in high glucose (P < 0.05) concomitant with an early increase of caspase-3 activity. Intermittent hyperglycemia induced greater apoptosis than sustained hyperglycemia. Apoptosis was accompanied by a reduced p-Akt/Akt ratio and inhibition of nephrin tyrosine phosphorylation. Pravastatin (1 micromol/L) decreased apoptosis induced by high glucose or oxidized LDL and increased Akt phosphorylation. Hyperglycemia significantly increased the production of the proinflammatory cytokine interleukin-1beta and stimulated the expression of inducible nitric oxide synthase and the production of nitric oxide, possibly relevant to beta cell mass and function. Thus, chronic hyperglycemia reduces islet microendothelial cell survival by inhibiting the serine-threonine kinase Akt pathway, and the effect of pravastatin on this pathway represents a potential tool to improve islet vascularization and, indirectly, islet function.
J Cardiovasc Pharmacol. 2008 Jun 26;
Tani S, Nagao K, Anazawa T, Kawamata H, Furuya S, Takahashi H, Iida K, Fuji T, Matsumoto M, Kumabe T, Sato Y, Hirayama A
Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (-20.7 +/- 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 +/- 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 +/- 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.
Lovastatin, but not pravastatin, limits in vitro infection due to Coxiella burnetii.
J Antimicrob Chemother. 2008 Jun 30;
Botelho-Nevers E, Espinosa L, Raoult D, Rolain JM
[Metabolic side effects of antiretroviral therapy]
Ned Tijdschr Geneeskd. 2008 May 31; 152(22): 1260-4
van der Valk M, Reiss P
Antiretroviral therapy for HIV-I-infections is accompanied with the occurrence of several metabolic side effects. An often encountered complication of antiretroviral therapy is the adipose redistribution syndrome characterised by an altered distribution of body fat, and linked with protease inhibitor (PI) and nucleoside-reverse-transcriptase inhibitors (NRTIs). Some NRTIs have lactate acidosis as a side effect in rare cases (0.1%), which is accompanied by a high mortality. The far less serious side effect hyperlactaemia is more frequently observed; this is a symptomatic elevation of the lactate level without acidosis. Insulin resistance is not only ascribed to therapy-induced lipoatrophy and visceral fat accumulation, it is also directly related to the use of some PIs and NRTIs. PIs and abacavir and to a lesser extend didanosine result in a high risk of cardiovascular disease. Moreover, the prevalence of traditional cardiovascular risk factors in HIV-infected subjects is higher than that in HIV-seronegative subjects. Clinically relevant interactions exist between PIs and statins. Pravastatin seems to be accompanied with the lowest chance of interaction and is therefore recommended as cholesterol-lowering therapy. The metabolic side effects are outweighed by the favourable effect of the antiretroviral agents. Counteraction of these side effects may therefore not be at the expense of the antiretroviral therapy.
Enferm Infecc Microbiol Clin. 2008 Jun; 26(6): 325-9
Bottaro EG, Caravello O, Scapellato PG, Stambulian M, Vidal GI, Loggia V, Scapellato JL, Thompson F, Cassetti I
INTRODUCTION: Highly active antiviral therapy (HAART) results in a sharp decrease in HIV-related morbidity and mortality, but also induces adverse effects such as dyslipidemia, which is difficult treat because of drug interactions. Guidelines recommend lipid-lowering therapy with pravastatin or atorvastatin to reduce LDL cholesterol in these patients, and gemfibrozil or fenofibrate for treating hypertriglyceridemia. The use of statins in the management of dyslipidemia is complicated by drug interactions with some of the components of HAART. Rosuvastatin, a statin with minimal cytochrome P-450-mediated metabolism, could be an alternative option for this population. METHODS: Retrospective study to evaluate the efficacy and safety of rosuvastatin (10 mg/day) for 16 weeks in HAART-treated HIV-infected patients with dyslipidemia, and moderate to high cardiovascular risk. Results were analyzed with the Shapiro-Wilks, K-S Lilliefors, and sign tests. Percentages were analyzed with the chi-square test. RESULTS: Seventy-eight patients were started on rosuvastatin for dyslipidemia, 60 as single therapy. After 16 weeks of treatment, a significant median decrease was seen in both LDL-cholesterol and non-HDL cholesterol (31.3% reduction in LDL and 29.9% in non-HDL). The therapeutic goal for non-HDL was achieved in 65.8% of patients. The decrease in triglyceride levels was also significant (34.1%); 35% of subjects achieved the therapeutic goal. The drug was withdrawn in 2 patients because of myositis, and in 1 because of gastrointestinal intolerance. There were no differences in efficacy or toxicity between patients receiving protease inhibitors, non-nucleoside reverse transcriptase inhibitors, or fibrates. CONCLUSION: Rosuvastatin was safe and effective for treating dyslipidemia in HAART-treated HIV-infected patients. Results were similar to those observed in the HIV-uninfected population.
J Am Coll Cardiol. 2008 Jul 1; 52(1): 24-32
Choi SH, Chae A, Miller E, Messig M, Ntanios F, DeMaria AN, Nissen SE, Witztum JL, Tsimikas S
OBJECTIVES: This study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume. BACKGROUND: Oxidative stress is thought to play an important role in atherogenesis but the relationship between OxLDL, statin therapy, and atheroma volume in humans is not known. METHODS: In a subgroup of 214 patients from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes per apolipoprotein B-100 (apoB), immunoglobin (Ig) G and IgM apoB immune complexes, and OxLDL autoantibodies were measured at baseline and after 18 months of treatment with atorvastatin or pravastatin. Relationships between changes of OxLDL biomarkers and quantitative coronary angiography (QCA), total atheroma volume, and percentage atheroma volume were analyzed. RESULTS: There were no differences in QCA parameters or atheroma volume in the 2 groups at baseline. Compared with baseline values, OxPL/apoB and MDA/apoB, and lipoprotein (a) levels increased 21% to 48% (p < 0.001 for all) in response to atorvastatin and 17% to 39% (p < 0.001 for all) in response to pravastatin. In contrast, IgG apoB immune complexes, IgM apoB immune complexes, and IgM OxLDL autoantibodies were significantly reduced by both atorvastatin and pravastatin (p value range 0.003 to
LDL-C reductions and goal attainment among naive statin users in the Netherlands: real life results.
Curr Med Res Opin. 2008 Jun 24;
Heintjes EM, Hirsch MW, van der Linden MW, O'Donnell JC, Stalenhoef AF, Herings RM
OBJECTIVE: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD).RESEARCH DESIGN AND METHODS: Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses. RESULTS: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05).CONCLUSIONS: In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.
J Pharmacol Exp Ther. 2008 Jun 23;
Abe K, Bridges A, Yue W, Brouwer KL
Previous reports have indicated that in vitro biliary clearance (Clbiliary) determined in sandwich-cultured hepatocytes correlates well with in vivo Clbiliary for limited sets of compounds. This study was designed to estimate the in vitro Clbiliary in sandwich-cultured rat hepatocytes (SCRH) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Clbiliary values with published in vivo Clbiliary data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. Average biliary excretion index (BEI) and in vitro Clbiliary of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15%, 19%, 43%, 45%, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Clbiliary predicted from SCRH, accounting for plasma unbound fraction, correlated with reported in vivo Clbiliary for these drugs. The rank order of Clbiliary values predicted from SCRH was consistent with in vivo Clbiliary values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Clbiliary values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp)2 substrates, were reduced in SCRH from Mrp2-deficient (TR(-)) compared to wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Clbiliary were reduced in TR(-) compared to WT SCRH; Bcrp expression in SCRH from TR(-) rats was decreased. In conclusion, in vitro Clbiliary determined in SCRH can be used to estimate and compare in vivo Clbiliary of compounds in rats, and to characterize transport proteins responsible for their hepatic uptake and excretion.
J Mol Cell Cardiol. 2008 Jun 4;
Allen CL, Bayraktutan U
Angiotensin II (Ang II) and platelet-derived growth factor-BB (PDGF-BB) are associated with excessive cell migration, proliferation and many growth-related diseases. However, whether these agents utilise similar mechanisms to trigger vascular pathologies remains to be explored. The effects of Ang II and PDGF-BB on coronary artery smooth muscle cell (CASMC) migration and proliferation were investigated via Dunn chemotaxis assay and the measurement of [(3)H]thymidine incorporation rates, respectively. Both atherogens produced similar degrees of cell migration which were dramatically inhibited by mevastatin (10 nM). However, the inhibitory effects of losartan (10 nM) and MnTBAP (a free radical scavenger; 50 muM) were found to be unique to Ang II-mediated chemotaxis. In contrast, MnTBAP, apocynin (an antioxidant and phagocytic NADPH oxidase inhibitor; 500 muM), mevastatin and pravastatin (100 nM) equally suppressed both Ang II and PDGF-BB-induced cellular growth. Although atherogens produced similar changes in NADPH oxidase, NOS and superoxide dismutase activities, they differentially regulated antioxidant glutathione peroxidase activity which was diminished by Ang II and unaffected by PDGF-BB. Studies with signal transduction pathway inhibitors revealed the involvement of multiple pathways i.e. protein kinase C, tyrosine kinase and MAPK in Ang II- and/or PDGF-BB-induced aforementioned enzyme activity changes. In conclusion, Ang II and PDGF-BB may induce coronary atherosclerotic disease formation by stimulating CASMC migration and proliferation through agent-specific regulation of oxidative status and utilisation of different signal transduction pathways.
Eur Heart J. 2008 Jun 18;
Divchev D, Grothusen C, Luchtefeld M, Thoenes M, Onono F, Koch R, Drexler H, Schieffer B
Aims To evaluate the impact of a combined treatment of angiotensin II type 1 (AT(1))-receptor blockade and 3-hydroxy-3-methyl-glutaryl-CoA-reductase inhibition (statin) on the secretory phospholipase A(2) type IIA (sPLA(2)-IIA) and oxidized low density lipoprotein (oxLDL) in patients with coronary artery disease (CAD). Methods and results Sixty patients with angiographically documented CAD and a history of arterial hypertension were randomized in a double-blinded fashion to pravastatin (PRAV, 40 mg/day, n = 30) or PRAV plus irbesartan (PRAV+IRB, 40 mg/day+300 mg/day, n = 30) and were treated for 3 months. Blood pressure (BP) and cholesterol fractions were determined at baseline and after 3 months. SPLA(2) activity as primary endpoint, sPLA(2)-IIA protein, oxLDL levels, and high-sensitivity (hs)-C-reactive protein were measured by an enzyme-linked immunabsorbent assay. In both treatment groups, systolic BP levels and circulating HDL and LDL levels were reduced to the same extent. The combined treatment of PRAV+IRB significantly decreased sPLA(2)-IIA activity and sPLA(2)-IIA-protein concentration compared with PRAV treatment alone (P < 0.05). In addition, PRAV+IRB significantly reduced oxLDL levels compared with PRAV treatment alone (P < 0.05). This effect was independent of changes in LDL cholesterol levels. Conclusion These findings are consistent with the notion that the combined treatment of pravastatin with irbesartan reduced sPLA(2)-IIA-activity, sPLA(2)-IIA-protein concentration, and oxLDL in patients with CAD suggesting a novel anti-atherogenic effect by combining AT(1)-receptor blockade with statin treatment.