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The New England Journal of Medicine Apr 2004Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear.
METHODS
We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).
RESULTS
The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen.
CONCLUSIONS
Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.
Topics: Angina, Unstable; Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardial Infarction; Pravastatin; Proportional Hazards Models; Pyrroles
PubMed: 15007110
DOI: 10.1056/NEJMoa040583 -
Circulation Research Oct 2021[Figure: see text].
[Figure: see text].
Topics: Animals; Antineoplastic Agents; Autophagy; Autophagy-Related Protein 7; Cardiotoxicity; Doxorubicin; Myocarditis; Pravastatin; Spironolactone; Zebrafish; Zebrafish Proteins
PubMed: 34384247
DOI: 10.1161/CIRCRESAHA.121.319104 -
The Cochrane Database of Systematic... Jan 2016This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of dementia due to Alzheimer's disease and of vascular dementia. Some observational studies have suggested an association between statin use and lowered incidence of dementia.
OBJECTIVES
To evaluate the efficacy and safety of statins for the prevention of dementia in people at risk of dementia due to their age and to determine whether the efficacy and safety of statins for this purpose depends on cholesterol level, apolipoprotein E (ApoE) genotype or cognitive level.
SEARCH METHODS
We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 11 November 2015.
SELECTION CRITERIA
We included double-blind, randomised, placebo-controlled trials in which statins were administered for at least 12 months to people at risk of dementia.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05).
AUTHORS' CONCLUSIONS
There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.
Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Anticholesteremic Agents; Cognition; Dementia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Pravastatin; Randomized Controlled Trials as Topic; Simvastatin
PubMed: 26727124
DOI: 10.1002/14651858.CD003160.pub3 -
International Journal of Nanomedicine 2023Pravastatin sodium (PVS) is a hypolipidemic drug which suffers from extensive first-pass metabolism and short half-life. Poly(d,l-lactide--glycolide) (PLGA) is...
PURPOSE
Pravastatin sodium (PVS) is a hypolipidemic drug which suffers from extensive first-pass metabolism and short half-life. Poly(d,l-lactide--glycolide) (PLGA) is considered a promising carrier to improve its hypolipidemic and hepatoprotective activities.
METHODS
PVS-loaded PLGA nanoparticles (PVS-PLGA-NPs) were prepared by double emulsion method using a full 3 factorial design. The in vitro release and the physical stability studies of the optimized PVS-PLGA-NPs (F5) were performed. Finally, both hypolipidemic and hepatoprotective activities of the optimized F5 NPs were studied and compared to PVS solution.
RESULTS
All the studied physical parameters of the prepared NPs were found in the accepted range. The particle size (PS) ranged from 90 ± 0.125 nm to 179.33 ± 4.509 nm, the poly dispersity index (PDI) ranged from 0.121 ± 0.018 to 0.158 ± 0.014. The optimized NPs (F5) have the highest entrapment efficiency (EE%) (51.7 ± 5%), reasonable PS (168.4 ± 2.506 nm) as well as reasonable zeta potential (ZP) (-28.3 ± 1.18mv). Solid-state characterization indicated that PVS is well entrapped into NPs. All NPs have distinct spherical shape with smooth surface. The prepared NPs showed a controlled release profile. F5 showed good stability at 4 ± 2°C during the whole storage period of 3 months. In vivo study and histopathological examination indicated that F5 NPs showed significant increase in PVS hypolipidemic as well as hepatoprotective activity compared to PVS solution.
CONCLUSION
The PVS-PLGA-NPs could be considered a promising model to evade the first-pass effect and showed improvement in the hypolipidemic and hepatoprotective activities compared to PVS solution.
Topics: Polylactic Acid-Polyglycolic Acid Copolymer; Lactic Acid; Polyglycolic Acid; Drug Carriers; Pravastatin; Nanoparticles; Particle Size
PubMed: 36816332
DOI: 10.2147/IJN.S394701 -
American Journal of Obstetrics and... Dec 2021Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
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.
OBJECTIVE
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.
STUDY DESIGN
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.
RESULTS
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.
CONCLUSION
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.
Topics: Adult; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pilot Projects; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Prenatal Care; Treatment Outcome; Young Adult
PubMed: 34033812
DOI: 10.1016/j.ajog.2021.05.018 -
Obstetrics and Gynecology Feb 2013Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with...
Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Attempts at prevention of preeclampsia using various supplements and classes of medications have failed or had limited success, and they were not convincing enough to lead to widespread adoption of any particular strategy. Contrary to the experience with preeclampsia, prevention of cardiovascular mortality and other cardiovascular events in nonpregnant patients using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted. Pravastatin and other statins have been shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress. These beneficial effects are likely to contribute substantially to preventing preeclampsia and provide biological plausibility for the use of pravastatin in this setting. Pravastatin has favorable safety and pharmacokinetic profiles. In addition, animal studies and human pregnancy exposure data do not support teratogenicity claims for pravastatin. Therefore, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network started a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women (identifier NCT01717586, clinicaltrials.gov).
Topics: Clinical Trials as Topic; Female; Humans; Pravastatin; Pre-Eclampsia; Pregnancy; Risk Factors
PubMed: 23344286
DOI: 10.1097/AOG.0b013e31827d8ad5 -
Journal of Controlled Release :... Aug 2022Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design...
Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified.
Topics: Animals; Contact Lenses; Cornea; Drug Delivery Systems; Hydrogels; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ophthalmic Solutions; Pravastatin; Rabbits
PubMed: 35688348
DOI: 10.1016/j.jconrel.2022.06.001 -
Cells Aug 2019Statins and fibrates are widely used for the management of hypertriglyceridemia but they also have limitations, mostly due to pharmacokinetic interactions or side...
Statins and fibrates are widely used for the management of hypertriglyceridemia but they also have limitations, mostly due to pharmacokinetic interactions or side effects. It is conceivable that some adverse events like liver dysfunction or gastrointestinal discomfort are caused by mitochondrial dysfunction. Data about the effects of statins and fibrates on mitochondrial function in different organs are inconsistent and partially contradictory. The aim of this study was to investigate the effect of pravastatin (statin) and gemfibrozil (fibrate) on hepatic and colonic mitochondrial respiration in tissue homogenates. Mitochondrial oxygen consumption was determined in colon and liver homogenates from 48 healthy rats after incubation with pravastatin or gemfibrozil (100, 300, 1000 μM). State 2 (substrate dependent respiration) and state 3 (adenosine diphosphate: ADP-dependent respiration) were assessed. RCI (respiratory control index)-an indicator for coupling between electron transport chain system (ETS) and oxidative phosphorylation (OXPHOS) and ADP/O ratio-a parameter for the efficacy of OXPHOS, was calculated. Data were presented as a percentage of control (Kruskal-Wallis + Dunn's correction). In the liver both drugs reduced state 3 and RCI, gemfibrozil-reduced ADP/O (complex I). In the colon both drugs reduced state 3 but enhanced ADP/O. Pravastatin at high concentration (1000 µM) decreased RCI (complex II). Pravastatin and gemfibrozil decrease hepatic but increase colonic mitochondrial respiration in tissue homogenates from healthy rats.
Topics: Animals; Cell Respiration; Colon; Dose-Response Relationship, Drug; Gemfibrozil; Liver; Male; Mitochondria; Oxygen; Pravastatin; Rats; Rats, Wistar
PubMed: 31461874
DOI: 10.3390/cells8090983 -
AIDS (London, England) Mar 2017Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population.
DESIGN
Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites.
METHODS
Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066).
RESULTS
One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ± 0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/μl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin).
CONCLUSION
Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.
Topics: Anticholesteremic Agents; Arteritis; Biomarkers; Double-Blind Method; HIV Infections; Humans; Immunologic Factors; Pravastatin; Quinolines; Treatment Outcome
PubMed: 28252528
DOI: 10.1097/QAD.0000000000001427 -
International Journal of Molecular... Mar 2023Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response,...
Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response, microcirculation, and mitochondrial function, possibly through their action on peroxisome proliferator-activated receptor alpha (PPAR-α). The aim of this study was to examine the effects of pravastatin on microcirculation and mitochondrial function in the liver and colon and the role of PPAR-α under septic conditions. This study was performed with the approval of the local animal care and use committee. Forty Wistar rats were randomly divided into 4 groups: sepsis (colon ascendens stent peritonitis, CASP) without treatment as control, sepsis + pravastatin, sepsis + PPAR-α-blocker GW6471, and sepsis + pravastatin + GW6471. Pravastatin (200 µg/kg s.c.) and GW6471 (1 mg/kg) were applied 18 h before CASP-operation. 24 h after initial surgery, a relaparotomy was performed, followed by a 90 min observation period for assessment of microcirculatory oxygenation (μHbO) of the liver and colon. At the end of the experiments, animals were euthanized, and the colon and liver were harvested. Mitochondrial function was measured in tissue homogenates using oximetry. The ADP/O ratio and respiratory control index (RCI) for complexes I and II were calculated. Reactive oxygen species (ROS) production was assessed using the malondialdehyde (MDA)-Assay. Statistics: two-way analysis of variance (ANOVA) + Tukey's/Dunnett's post hoc test for microcirculatory data, Kruskal-Wallis test + Dunn's post hoc test for all other data. In control septic animals µHbO in liver and colon deteriorated over time (µHbO: -9.8 ± 7.5%* and -7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment μHbO remained constant (liver: µHbO pravastatin: -4.21 ± 11.7%, pravastatin + GW6471: -0.08 ± 10.3%; colon: µHbO pravastatin: -0.13 ± 7.6%, pravastatin + GW6471: -3.00 ± 11.24%). In both organs, RCI and ADP/O were similar across all groups. The MDA concentration remained unchanged in all groups. Therefore, we conclude that under septic conditions pravastatin improves microcirculation in the colon and liver, and this seems independent of PPAR-α and without affecting mitochondrial function.
Topics: Rats; Animals; Rats, Wistar; Pravastatin; Microcirculation; Reactive Oxygen Species; Peroxisome Proliferator-Activated Receptors; Sepsis; Colon; Mitochondria; Liver
PubMed: 36982530
DOI: 10.3390/ijms24065455