Doses Of Pravastatin Research Articles

The Effects of Low Concentrations of Pravastatin on Placental Cells

Pravastatin is a promising medication to treat preeclampsia. However, the appropriate dose of pravastatin for managing preeclampsia has not been established. In this in vitro study, we examined the effects of low concentrations of pravastatin (0.01 to 10 µM) under hypoxic conditions on two types of placental cells and found that pravastatin decreased sFlt-1 levels up to 34% in cytotrophoblast cells isolated from human term placentas. Furthermore, we showed that sFlt-1 levels in HTR-8/SVneo cells, a cell line derived from first trimester trophoblast cells, decreased after exposure to very low concentrations of pravastatin (0.01, 0.1 µM). We also examined the effects of pravastatin on uterine spiral artery remodeling-related events and showed in wound healing and tube formation assays that low concentrations of pravastatin upregulated cell migration and invasion in HTR-8/SVneo cells. These results demonstrated that a low dose of pravastatin has in vitro effects that suggest a potential for anti-preeclamptic effects in vivo.

What are the effects of different doses of pravastatin for lowering lipids?

What are the effects of different doses of pravastatin for lowering lipids?

Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model.

Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg-1 day-1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg-1 day-1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg-1 day-1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg-1 day-1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg-1 day-1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg-1 day-1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg-1 day-1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.

Pravastatin reduces plasma levels of extracellular vesicles in pregnancies at high risk of term preeclampsia.

Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20mg/day dose of pravastatin for approximately 3weeks (from 35 to 37weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001). Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.

Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers.

Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4. Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity. Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC0-∞) increased 1.32-fold (90% CI 1.08-1.61). The 5mg bulevirtide twice-daily treatment resulted in a mean AUC0-12 of 1210h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated. Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide.

Effect of Pravastatin on eNOS and PECAM-1 Expression in the Placenta of Pre-Eclampsia Rat (Rattus norvegicus) Model

Introduction: Preeclampsia has two stages: improper placental and maternal circulation. Abnormal trophoblast invasion causes uteroplacental ischemia and hypoxia. Ischemia in the placenta produces endothelial cell dysfunction, which is defined by a change in endothelial cell activity to a reduced ability to vasodilate (decreased eNOS) and prothrombotic conditions (decreased PECAM-1). Reduced maternal eNOS activity and PECAM-1 can cause preeclampsia. Pravastatin is the statin class's most hydrophilic medication, and it limits placental transfer. Pravastatin can reduce endothelial dysfunction by targeting pleiotropic effects in pregnancy. The aim was to show the effects of pravastatin on the eNOS and PECAM-1 expression in the placenta of preeclampsia rat model.&#x0D; Materials and Methods: This is a true experimental study with only a post-test and a control group design. The sample was biological material in the form of placental tissue from a pravastatin-treated preeclampsia rat model (using L-NAME exposure). This research was divided into five groups, each with five samples. The parameters studied were eNOS and PECAM-1 expression.&#x0D; Results: The Shapiro-Wilk test result was significant (p&gt;0.05). Annova tests on eNOS (p=0.000) and PECAM-1 expression (p=0.000) confirmed the hypothesis. The Tukey test showed significant differences in eNOS (sig. 0.001) and PECAM-1 (sig. 0.000) expression between normal and preeclampsia rats. Positive controls and treatment groups P1, P2, and P3 all showed significant changes in eNOS and PECAM-1 expression. Pravastatin dose considerably increased eNOS (p=0.015; r=0.536) and PECAM-1 (p=0.000; r=0.734) expression..&#x0D; Conclusion: Pravastatin has been shown to increase eNOS and PECAM-1 expression in the placenta of preeclampsia rat model.

Vitamin D Deficiency Impacts Exposure and Response of Pravastatin in Male Rats by Altering Hepatic OATPs

This study aimed to determine the effect of vitamin D (VD) deficiency on the efficacy and pharmacokinetics of pravastatin and clarify whether the effects are mediated by Organic anion-transporting polypeptides (OATPs). Experiments were conducted in rats to explore the effect of VD deficiency on the pharmacodynamics and pharmacokinetics of pravastatin. In the pharmacodynamic study, rats were fed a VD-free or VD-supplement high-fat diet for 25–30 days, and plasma 25(OH)VD was dynamically monitored. The response of pravastatin (changes in blood lipids) on rats were then examined after 15 days of pravastatin treatment. In the pharmacokinetic study, rats were fed a VD-free or VD-supplement diet for 25–30 days. The pharmacokinetics of single oral dose pravastatin was then studied, and intestinal and hepatic Oatp1a1 and Oatp2b1 expression was determined using quantitative polymerase chain reaction (qPCR) and western blot. Furthermore, OATP1B1 and OATP2B1 expression in Huh7 cells with or without 1.25(OH)2D were assessed via qPCR and western blot. For the pharmacodynamic study, the decrease of total cholesterol and increase of high-density lipoprotein cholesterol in VD-deficient rats were smaller than in VD-sufficient rats, indicating that VD deficiency reduced the response of pravastatin in rats. For the pharmacokinetic study, the plasma exposure slightly increased, and liver exposure decreased in VD-deficient rats, but not significantly. VD deficiency decreased the Oatp1a1 and Oatp2b1 expression in the liver, but not in the small intestine. Similarly, OATP1B1 and OATP2B1 protein levels in Huh7 cells were reduced when 1.25(OH)2D was absent. In conclusion, VD deficiency can decrease the response of pravastatin in rats by reducing the liver pravastatin exposure and expression of hepatic OATPs, consistent with the extended hepatic clearance model theory.

Effect of pravastatin on erythrocyte membrane fatty acid contents in patients with chronic kidney disease.

BackgroundStatin treatment has decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid level is higher in patients with acute coronary syndrome. This study aimed to evaluate the effect of pravastatin on the erythrocyte membrane fatty acid (FA) contents in patients with CKD.MethodsSixty-two patients were enrolled from January 2017 to March 2019 (NCT02992548). Pravastatin was initially administered at a dose of 20 mg for 24 weeks. The pravastatin dose was increased to 40 mg after 12 weeks if it was necessary to control dyslipidemia. The primary outcome was change in erythrocyte membrane FA, including oleic acid, after pravastatin treatment for 24 weeks.ResultsForty-five patients finished this study, and there was no adverse effect related to pravastatin. Compared with baseline, total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased after pravastatin treatment. Compared with baseline, saturated FA, oleic acid, and arachidonic acid levels were significantly increased and polyunsaturated FA and linoleic acid (LA) levels were significantly decreased after pravastatin treatment. There was also a decrease in eicosapentaenoic acid after pravastatin treatment in CKD patients with estimated glomerular filtration rate < 60 mL/min/1.73 m2.ConclusionAdministration of pravastatin in patients with CKD leads to a decrease in FA known to be protective against the risk of CVD. Omega-3 FA or LA supplementation might be necessary to recover changes in erythrocyte membrane FA contents when pravastatin is used for treating dyslipidemia in patients with CKD.

A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia

Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay

Objective: To determine the direct effect of pravastatin on angiogenesis and to study the interaction between pravastatin and maternal sera from women with early- or late-onset pre-eclampsia (PE), intrauterine growth restriction, or healthy pregnancy. Methods: We collected 5 maternal serum samples from each group. The effect of pravastatin on angiogenesis was assessed with and without maternal sera by quantifying tubule formation in a human-based in vitro assay. Pravastatin was added at 20, 1,000, and 8,000 ng/mL concentrations. Concentrations of angiogenic and inflammatory biomarkers in serum and in test medium after supplementation of serum alone and with pravastatin (1,000 ng/mL) were measured. Results: Therapeutic concentration of pravastatin (20 ng/mL) did not have significant direct effect on angiogenesis, but the highest concentrations inhibited angiogenesis. Pravastatin did not change the levels of biomarkers in the test media. There were no changes in angiogenesis when therapeutic dose of pravastatin was added with maternal sera, but there was a trend to wide individual variation towards enhanced angiogenesis, particularly in the early-onset PE group. Conclusions: At therapeutic concentration, pravastatin alone or with maternal sera has no significant effect on angiogenesis, but at high concentrations the effect seems to be anti-angiogenic estimated by in vitro assay.

Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important determinants of transporter-mediated drug-drug interactions (DDIs). Current studies assessed the OATP1B1 and OATP1B3-mediated DDI potential of vemurafenib, a kinase inhibitor drug with high protein binding and low aqueous solubility, using R-value and physiologically-based pharmacokinetic (PBPK) models. The total half-maximal inhibitory concentration (IC50,total) values of vemurafenib against OATP1B1 and OATP1B3 were determined in 100% human plasma in transporter-overexpressing human embryonic kidney 293 stable cell lines. The unbound fraction of vemurafenib in human plasma before (fu,plasma) and after addition into the uptake assay plate (fu,plasma,inc) were determined by rapid equilibrium dialysis. There was no statistically significant difference between fu,plasma and fu,plasma,inc. Vemurafenib IC50,total values against OATP1B1 and OATP1B3 are 175 ± 82 and 231 ± 26 μM, respectively. The R-values [R = 1 + fu,plasma × Iin,max/(fu,plasma,inc × IC50,total)] were then simplified as R = 1+Iin,max/IC50,total, and were 1.76 and 1.57 for OATP1B1 and OATP1B3, respectively. The simulated pravastatin AUC ratio was 1.28 when a single dose of pravastatin (40 mg) was co-administered with vemurafenib (960 mg, twice daily) at steady-state, compared to pravastatin alone. Both R-value and PBPK models predict that vemurafenib has the potential to cause OATP1B1- and OATP1B3-mediated DDIs.

P0326EFFECT OF PRAVASTATIN ON ERYTHROCYTE MEMBRANE FATTY ACID CONTENTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Treatment with statin has been decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid contents are significantly higher in patients with acute coronary syndrome than control subjects. Still, there is no report about the effect of statin on erythrocyte membrane fatty acid (FA) including oleic acid. The aim of this study was to evaluate the effect of pravastatin on the erythrocyte membrane FA in patients with CKD. Method Sixty two CKD patients were enrolled in this single arm randomized clinical trial and this trial was conducted at two centers from Jan 2017 to March 2019 (NCT02992548). Pravastatin with dose of 20mg was initially treated for 24 weeks. Pravastatin dose was increased to 40mg after 12 weeks, if it is necessary to control dyslipidemia. The primary outcome of this study was the change of erythrocyte membrane FA including oleic acid after pravastatin treatment for 24 weeks. We checked total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol and adiponectin for secondary outcome at baseline and after 24 weeks. Erythrocyte membrane FA contents were measured by gas chromatography at baseline and after 24 weeks. Results Forty-five patients finished this study (age: 59.2±12.4 years, male: 42.2%, diabetes: 48.9%). There was no adverse effect related with pravastatin. Baseline serum creatinine was 1.5±0.7 mg/dL and estimated glomerular filtration rate was 54.2±27.3 ml/min/1.73 m2. Compared to baseline, total cholesterol (223.1±50.8 mg/dL vs. 168.4±32.5 mg/dL), LDL-cholesterol (149.1±35.3mg/dL vs. 100.1±25.4 mg/dL) and C-reactive protein were significantly decreased after pravastatin treatment. There were no significant changes in triglyceride, HDL-cholesterol, serum creatinine, amounts of proteinuria and adiponectin levels. Saturated FA, oleic acid and arachidonic acid contents of erythrocyte membrane were significantly increased after pravastatin treatment compared to baseline levels. Polyunsaturated FA (PUFA) and linoleic acid were significantly decreased after pravastatin treatment compared to baseline. Decreased tendency of eicosapentaenoic acid and omega-3 index were found after pravastatin treatment. Conclusion Linoleic acid or omega-3 FA supplementations may be necessary to recover erythrocyte membrane FA changes, when pravastatin is used for dyslipidemia treatment in CKD patients. Further study for reducing cardiovascular events are necessary by using combined PUFA and pravastatin treatment.

A network meta-analysis on comparative efficacy of statins focusing for prevention of contrast-induced acute kidney injury in chronic kidney disease patients undergoing percutaneus coronary intervention

Background: The use of interventional diagnostic and therapeutic procedures required intravascular iodinated contrast are performed in millions of patients worldwide and are steadily increasing the risks of contrast-induced acute kidney injury (CI-AKI). Statins are primarily used in cardiovascular medicine for their lipid-lowering effects but they possess remarkable pleiotropic effects such as improving endothelial function as well as decreasing oxidative stress and inflammation. A network meta-analysis was carried out to evaluate the effect of different statins in prevention of CI-AKI and also to investigate which type and dose of statins maybe the best choice specifically in CKD patients who have higher risk. Methods: We performed a pairwise and network meta analysis of 14 randomized studies (9847 patients) comparing a total of 6 different statins: rosuvastatin high dose, atorvastatin high dose, simvastatin high dose, rosuvastatin regular dose, atorvastatin regular dose, pravastatin regular dose versus each other and versus placebo in CKD patients undergoing PCI with iodinated contrast for prevention of CIAKI. Google Scholar, Pubmed, Science Direct databases were searched up to May 2019. The data were pooled using STATA, and R version statistics calculating odds ratios (ORs) with 95% confidence intervals. Results: Statin loading before contrast administration was associated with a significantly reduced risk of CI-AKI in patients with CKD undergoing cardiac catheterization (pooled OR= 0.51; P=0.0001). Regular dose pravastatin comprised the best effect size for a reduction in CIAKI risk (OR = 0.32, 95% CI 0.14-0.72, p=0.006). Regular dose pravastatin and high dose atorvastatin were ranked as the highest probability to be the best treatment (Pbest) with 44% and 31% respectively for effect on CIAKI prevention.Conclusion: Preloading with statins is associated with significantly reduced risk of CI-AKI in patients with CKD undergoing cardiac catheterization. Regular dose pravastatin and high dose atorvastatin have the highest probability to be the most effective prevention strategy.

Effect of OATP1B1/1B3 Inhibitor GDC-0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects.

Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study. On day 1 in period 1, a single 10-mg dose of pravastatin was administered to all subjects. Following a 4-day washout period, 600 mg of GDC-0810 was administered once daily on days 5 through 8 in period 2 to achieve steady-state concentrations. On day 7, a single dose of 10-mg pravastatin was coadministered with the 600-mg GDC-0810 dose. Concentrations of pravastatin (periods 1 and 2) and GDC-0810 (period 2 only) were quantified in blood samples and subsequently used to calculate the pharmacokinetics (PK) parameters. The pravastatin mean maximal concentration and area under the curve values were approximately 20% and 41% higher, respectively, following pravastatin coadministration with GDC-0810 compared to pravastatin alone. Based on the magnitude of change in this drug-drug interaction study, dose adjustments for pravastatin (and other OATP1B1/1B3 substrates) were not considered necessary when administered with GDC-0810. Retrospectively, the endogenous biomarkers of OATP1B1/1B3, coproporphyrin I and III, were also measured and showed changes comparable to those of pravastatin, indicating their utility in detecting weak inhibition of OATP1B1/1B3 in the clinical setting.

P-248 - Coenzyme Q10 or creatine counteract pravastatin-induced liver redox changes in hypercholesterolemic mice

Statins are the preferred therapy to treat hypercholesterolemia and decrease coronary heart disease. However, previous studies have reported mitochondrial dysfunctions of several experimental models submitted to diverse statins treatments. The aim of the present study was to investigate whether treatment with doses of pravastatin during 3 months induces hepatotoxicity in LDL receptor knockout mice (LDLr-/-), a model for human familial hypercholesterolemia. We evaluated liver mitochondrial function parameters, antioxidant enzymes activities and protein and lipid oxidation markers. We observed a higher mitochondrial H2O2 production rate, decreased activity of aconitase and increased MPT. Among several antioxidant enzymes, only G6PD activity was increased in treated mice. The presence of several oxidized lipid species was detected in pravastatin group but protein oxidation markers were not altered. Diet supplementation with the antioxidants CoQ10 or creatine fully reversed all pravastatin effects. Taken together, our results show that pravastatin chronic treatment induced liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and the co-treatment with safe antioxidants neutralize these side effects.

Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML)

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

Long-Term Effect of Pravastatin on Carotid Intima-Media Complex Thickness: The J-STARS Echo Study (Japan Statin Treatment Against Recurrent Stroke).

The effect of statins on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0-2] versus 1 [interquartile range, 0-2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010). The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530.

Effect of a single dose of pre-operative pravastatin on C-reactive protein levels and neutrophil/lymphocyte ratio in patients undergoing mastectomy for breast cancer

IntroductionIn Mexico, breast cancer is the leading cause of death from malignant tumours in women over 25 years of age. Cancer patients present pro-inflammatory status which, added to the inflammatory response to surgery, worsens their prognosis, not only from a cardiovascular perspective but also by increasing the risk of tumour relapse and the onset of metastases. The objective of this study is to determine the role of pravastatin in the modulation of the systemic inflammatory response to surgical trauma by measuring C-reactive protein (CRP) levels and the neutrophil/lymphocyte ratio (NLR) in breast cancer patients undergoing radical mastectomy. MethodsRandomised, single-blind, prospective clinical trial in breast cancer patients undergoing mastectomy, divided into two groups of 15 patients each. One of the groups was administered a pre-operative dose of pravastatin 20mg and the other was not and the pre- and post-surgical inflammatory biomarker levels were measured. The numerical variables are expressed as means and with standard deviation. The comparison between groups was performed with Student's T-test. ResultsA total of 30 patients subject to radical mastectomy were enrolled in the study and divided into 2 groups. The mean age was 56.9 years in the control group and 53.4 years in the pravastatin group. It was found that the patients who received a 20mg pre-op dose of pravastatin presented less CRP elevation, with a mean of 12.6 95% CI (8.34–16.9) vs 43.8 95% CI (34.3–53.37) in the control group, p 0.0000. Although the changes in the neutrophil/lymphocyte ratio were not statistically significant, p 0.2337, it was less elevated in the pravastatin group, with a mean of 3.57 95% CI (2.02–5.11) vs 7.17 95% CI (3–17.42) in the control group. ConclusionsThe pre-surgical administration of a single dose of pravastatin 20mg significantly reduced inflammatory biomarker elevation, especially C-reactive protein, making it the ideal drug for routine use in patients undergoing radical mastectomy.

Abstract WP421: Pravastatin Can Reduce the Progression of Carotid Intima-media Complex Thickness: The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study

Background and purpose: The preventive effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in non-stroke Western patients. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study aims to determine the effect of pravastatin on carotid IMT in Japanese patients with hyperlipidemia with noncardioembolic ischemic stroke. Methods: This is a substudy of the J-STARS, a multicenter, randomized, open-label, blinded-endpoint, parallel-group trial to examine whether pravastatin reduces stroke recurrence in patients with noncardioembolic stroke. The patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan) (pravastatin group) or not to receive any statins (control group). Carotid ultrasonography was performed by well-trained certified examiners and the recorded data was measured centrally. The primary outcome was IMT change of the distal wall in a continuous 2-cm section on the central side of the common carotid artery bifurcation over 5 years of observation. The IMT change was compared using mixed models for repeated measures. Results: Of 1578 patients who were enrolled in the J-STARS, 864 were registered in this echo substudy. After excluding 71 without baseline ultrasonography, 793 (530 men, 66.4±8.3 years old) were analyzed. Of the 793 patients, 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different except baseline NIH Stroke Scale [median 0 (IQR 0-2) vs. 1 (0-2), p=0.019] between the two groups. The baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (p=0.990). Each annual change of the IMT (mean±SD) over 5 years of observation was 0.011±0.085 mm, 0.023±0.114 mm, 0.017±0.114 mm, 0.018±0.118 mm and 0.021±0.116 mm in the pravastatin group and 0.008±0.074 mm (p=0.650), 0.020±0.087 mm (p=0.985), 0.017±0.097 mm (p=0.586), 0.030±0.113 mm (p=0.202) and 0.040±0.118 mm (p=0.018) in the control group. Conclusion: Japanese usual dose of pravastatin significantly reduced the progression of carotid mean IMT at 5 years in patients with noncardioembolic stroke.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study: Rationale and Trial Protocol

The preventive effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study aims to determine the effect of pravastatin on carotid IMT in Japanese patients with hyperlipidemia who developed noncardioembolic ischemic stroke. This is a substudy of the J-STARS, a multicenter, randomized, open-label, blinded-end point, parallel-group trial to examine whether pravastatin reduces stroke recurrence in patients with noncardioembolic stroke. The patients are randomized to receive pravastatin (10 mg daily) or not to receive any statins. Carotid ultrasonography is performed by well-trained certified examiners in each participating institute, and the recorded data are measured centrally. The primary outcome is change in the IMT of the distal wall in a consecutive 2-cm section on the central side of the common carotid artery bifurcation over 5 years of observation. The trial may help determine if the usual dose of pravastatin for daily clinical practice in Japan can affect carotid IMT in Japanese patients with noncardioembolic stroke.