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The Journal of International Medical... Jul 2020To evaluate the protective effect of pravastatin on atherosclerotic development and inflammatory monocyte subset in atherosclerotic apolipoprotein E (ApoE) mice after...
OBJECTIVE
To evaluate the protective effect of pravastatin on atherosclerotic development and inflammatory monocyte subset in atherosclerotic apolipoprotein E (ApoE) mice after myocardial infarction (MI).
METHODS
Male ApoE mice (8 weeks old) were fed a high-fat diet for 14 weeks throughout the experiment. A MI model was produced using 18-week-old ApoE mice. They were randomly divided into three groups: sham group, MI group, and MI+Pra group (40 mg/kg/day pravastatin). After 4 weeks (at the end of the study period), the mice were sacrificed and cardiac function was evaluated by echocardiography. Aortic lesion areas were evaluated using oil red O staining. Plaque macrophage in aortic sinus was analyzed by immunofluorescence staining. Flow cytometry was used to explore the proportions of monocyte subsets in the blood, spleen, and bone marrow..
RESULTS
Pravastatin improved cardiac function and reduced lesion areas. It also attenuated the supply of monocytes in spleen, especially the inflammatory Ly6C monocyte subset. Pravastatin also subsequently reduced macrophage accumulation in atherosclerotic lesions.
CONCLUSIONS
MI accelerated chronic atherosclerosis progress. Pravastatin suppressed atherosclerotic development and inhibited inflammatory monocytosis after MI in ApoE mice.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Plaque, Atherosclerotic; Pravastatin
PubMed: 32662710
DOI: 10.1177/0300060520932816 -
Journal of Pharmacological Sciences Jul 2020Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders...
Acute inflammation often contributes to the increased arrhythmogenesis in the cardiomyocytes. We investigated the protective effects of pravastatin on calcium disorders induced by acute administration of pro-inflammatory cytokines in isolated ventricular myocytes and its underlying mechanisms. Wild-type mice were intraperitoneally injected for five days with either pravastatin 20 mg/kg per day or an equal volume of normal saline. Cytosol Ca handling was studied in freshly isolated ventricular myocytes after acute exposure of interleukin-6 (IL-6) (1 ng/ml) for 120 min by Ionoptix and confocal microscopy. Acute administration of clinically relevant concentrations of IL-6 disturbed calcium handling in ventricular myocytes, which presented as decreased amplitudes, prolonged decay times of Ca transients, and reduced sarcoplasmic reticulum (SR) calcium stores. The frequency of spontaneous Ca release, including calcium sparks and spontaneous calcium waves, was dramatically enhanced in the setting of IL-6. Notably, the pretreatment of pravastatin alleviated disturbed Ca cycling, reduced spontaneous Ca leakage induced by IL-6. Mitochondrial ROS pathway may constitute the underlying mechanism of the protective effects of pravastatin. Pravastatin protected the cardiomyocytes against calcium disorders induced by IL-6 via the mitochondrial ROS pathway, which suggests that pravastatin may represent a promising auxiliary therapeutic strategy for cardiac injury under acute inflammation.
Topics: Animals; Calcium; Cardiomyopathies; Cardiotonic Agents; Cells, Cultured; Heart Ventricles; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mitochondria; Myocytes, Cardiac; Pravastatin; Reactive Oxygen Species; Sarcoplasmic Reticulum; Signal Transduction
PubMed: 32253103
DOI: 10.1016/j.jphs.2020.01.013 -
Clinical Pharmacokinetics Dec 2000Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique... (Review)
Review
Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.
Topics: Adult; Aged; Aging; Area Under Curve; Biotransformation; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Absorption; Male; Pravastatin; Sex Characteristics; Tissue Distribution
PubMed: 11192473
DOI: 10.2165/00003088-200039060-00002 -
International Journal of Radiation... Jun 2019The "PRAVACUR" phase 2 trial (NCT01268202) assessed the efficacy of pravastatin as an antifibrotic agent in patients with established cutaneous and subcutaneous...
Pravastatin Reverses Established Radiation-Induced Cutaneous and Subcutaneous Fibrosis in Patients With Head and Neck Cancer: Results of the Biology-Driven Phase 2 Clinical Trial Pravacur.
PURPOSE
The "PRAVACUR" phase 2 trial (NCT01268202) assessed the efficacy of pravastatin as an antifibrotic agent in patients with established cutaneous and subcutaneous radiation-induced fibrosis (RIF) after head and neck squamous cell carcinoma (HNSCC) radiation therapy and/or radiochemotherapy.
METHODS AND MATERIALS
The main inclusion criteria were: NSCC in remission, grade ≥2 cutaneous and subcutaneous neck RIF (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), and no current treatment with statins or fibrates. Patients received pravastatin 40 mg/d for 12 months. The primary endpoint was reduction of RIF thickness by more than 30% at 12 months, as measured by cutaneous high-frequency ultrasonography. Secondary endpoints included RIF severity reduction, pravastatin tolerance, and quality of life.
RESULTS
Sixty patients with grade 2 (n = 37), grade 3 (n = 22), or grade 4 (n = 1) RIF were enrolled from February 2011 to April 2016. The mean interval between RIF diagnosis and pravastatin initiation was 17.1 months. Pravastatin was stopped before 11 months of treatment in 18 patients (because of grade ≥2 adverse events related to pravastatin in 8 patients [13%]). In the 40 patients in whom pravastatin efficacy was assessed by high-frequency ultrasonography at baseline and at 12 months of treatment, a reduction of RIF thickness ≥30% was observed in 15 of 42 patients (35.7%; 95% confidence interval, 21.6%-52.0%). At the 12-month clinical evaluation, RIF severity was decreased in 50% of patients (n = 21; 95% confidence interval, 34.2%-65.8%), and the patients' self-perception, mood state, and social functioning were significantly improved. Pravastatin was well tolerated, with a very low occurrence of grade 3 toxicities (myalgia, n = 1) and grade 2 toxicities (myalgia/arthralgia or esophagitis, n = 3).
CONCLUSIONS
This phase 2 prospective study supports the notion of radioinduced fibrosis reversibility. It showed that pravastatin (40 mg/d for 12 months) is an efficient antifibrotic agent in patients with grade ≥2 cutaneous and subcutaneous fibrosis after HNSCC radiation therapy.
Topics: Confidence Intervals; Dermatologic Agents; Fibrosis; Head and Neck Neoplasms; Humans; Pravastatin; Prospective Studies; Quality of Life; Radiation Injuries; Skin; Squamous Cell Carcinoma of Head and Neck
PubMed: 30776452
DOI: 10.1016/j.ijrobp.2019.02.024 -
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 -
The American Journal of Geriatric... 2004The role of cholesterol in coronary heart disease (CHD) and stroke in elderly persons is controversial. Statin studies have generally included mostly middle-aged men,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
The role of cholesterol in coronary heart disease (CHD) and stroke in elderly persons is controversial. Statin studies have generally included mostly middle-aged men, been targeted at either primary or secondary prevention, and lasted 5-6 years. In contrast, the PROspective Study of Pravastatin in the Elderly at Risk was a double-blind, randomized, placebo-controlled primary and secondary prevention trial that examined the effects of pravastatin 40 mg/d on the risk of CHD, cerebral vascular events, and cognitive function over 3 years in 5804 high-risk elderly persons (mean age 75 years; 52% women). Pravastatin therapy significantly improved lipid levels: low-density lipoprotein cholesterol (-34%), high-density lipoprotein cholesterol (+5%), and triglycerides (-13%) and produced no adverse effects on liver function tests or myopathy. Moreover, pravastatin reduced the primary end point (CHD death, nonfatal myocardial infarction, and stroke) by 15% (p=0.014), including 24% reduction in CHD death (p=0.043) and 19% reduction in combined CHD death and nonfatal myocardial infarction (p=0.006). Although transient ischemic attacks fell by 25% (p=0.05) with pravastatin, there were no significant reductions in stroke or improvements in cognitive function. These results demonstrate the benefits of pravastatin in primary and, particularly, secondary prevention in elderly populations and further support the benefits of statin therapy in high-risk elderly persons.
Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Europe; Health Services for the Aged; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Prospective Studies; Randomized Controlled Trials as Topic; Treatment Outcome; United States
PubMed: 15133425
DOI: No ID Found -
La Revue de Medecine Interne Nov 2005The toxic myopathy caused by statins (HMG-CoA reductase inhibitors) is well established. Recent reports add to these effects systemic immune diseases including systemic...
INTRODUCTION
The toxic myopathy caused by statins (HMG-CoA reductase inhibitors) is well established. Recent reports add to these effects systemic immune diseases including systemic lupus erythematosus, vasculitis, polymyositis or dermatomyositis.
EXEGESIS
We report a case of dermatomyositis in a 69-year-old patient treated with pravastatin [Elisor]. She presented with typical features of dermatomyositis 2 years after she started a treatment with pravastatin. The treatment was discontinued and she slowly improved, with a transient dermocorticosteroid treatment. Eight other patients with dermatomyositis and chronic treatment with HMG-CoA reductase inhibitors are reported in the literature. All of them presented with classical features of dermatomyositis. The discontinuation of the treatment was followed by spontaneous clinical and biological improvement in 3/9 patients. The other patients received high doses of corticosteroids and improved, except one patient who died of respiratory failure (pulmonary fibrosis) despite the adjunction of oral cyclophosphamide [Endoxan]. In these patients, dermatomyositis can be considered as a severe adverse reaction to HMG-CoA reductase inhibitors although a distinct casual link cannot be definitely established.
CONCLUSION
The increasing prescription of statins has led to the parallel increment of reported side-effects, where autoimmune diseases are now described. Among them, our case of dermatomyositis in a patient receiving pravastatin adds to the eight reported cases in the literature and highlights the potential role of statins as triggers of immune systemic diseases.
Topics: Aged; Anticholesteremic Agents; Dermatomyositis; Female; Humans; Hypercholesterolemia; Pravastatin; Time Factors
PubMed: 16154665
DOI: 10.1016/j.revmed.2005.07.005 -
Kardiologiia 2002This literature review presents data on pharmacological action of pravastatin, its lipid lowering activity, and influence on main mechanisms of atherogenesis. Beneficial... (Review)
Review
This literature review presents data on pharmacological action of pravastatin, its lipid lowering activity, and influence on main mechanisms of atherogenesis. Beneficial pleiotropic (nonlipid) effects of pravastatin: normalization of endothelial function, antiinflammatory action, antiischemic- and antithrombotic effects are also described. These effects represent possible mechanisms of participation of pravastatin in stabilization of prone to rupture atheromatous plaques. Early and pronounced clinical efficacy of pravastatin demonstrated in trials with clinical endpoints is discussed and value of the drug for primary and secondary prevention of atherosclerosis stressed.
Topics: Anticholesteremic Agents; Arteriosclerosis; Hepatocytes; Humans; Pravastatin
PubMed: 12494119
DOI: No ID Found -
Ugeskrift For Laeger May 1998
Topics: Anticholesteremic Agents; Drug Information Services; Humans; Pravastatin
PubMed: 9599572
DOI: No ID Found -
Drug Design, Development and Therapy 2019Pravastatin has been suggested to increase circulating adiponectin in humans. However, results of randomized controlled trials (RCTs) are inconsistent. We aimed to... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Pravastatin has been suggested to increase circulating adiponectin in humans. However, results of randomized controlled trials (RCTs) are inconsistent. We aimed to systematically evaluate the influence of pravastatin on circulating adiponectin in humans by performing a meta-analysis of RCTs.
MATERIALS AND METHODS
Studies were identified via systematic searching of PubMed, Embase, and Cochrane's Library databases. A random effect model was used to pool the results. Meta-regression and subgroup analyses were applied to explore the source of heterogeneity.
RESULTS
Eight RCTs with nine comparisons of 595 participants were included. Pravastatin treatment was associated with a significant increased level of circulating adiponectin as compared with controls (weighted mean difference [WMD] =0.63 µg/mL; 95% CI, 0.17-1.09 µg/mL; =0.007) with moderate heterogeneity (I2=28%). These results were confirmed by meta-analysis of double-blinded placebo-controlled RCTs (WMD =0.82 µg/mL; =0.01). Meta-regression analyses indicated that proportions of males in each study were positively correlated with the effect of pravastatin on adiponectin (coefficient: 0.015, =0.03). Subgroup analyses confirmed that pravastatin significantly increased adiponectin in studies of males (WMD =1.41 µg/mL; =0.008), but not in those of females (WMD =-0.04 µg/mL; =0.94).
CONCLUSION
Pravastatin treatment is associated with increased circulating adiponectin. Gender difference may exist regarding the effect of pravastatin treatment on adiponectin.
Topics: Adiponectin; Cardiovascular Diseases; Humans; Pravastatin; Randomized Controlled Trials as Topic
PubMed: 31190742
DOI: 10.2147/DDDT.S186992