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Clinical Pharmacy Aug 1992The chemistry, pharmacology, pharmacokinetics, clinical trials, adverse effects, role in lipid-lowering therapy, and dosage and administration of pravastatin are... (Comparative Study)
Comparative Study Review
The chemistry, pharmacology, pharmacokinetics, clinical trials, adverse effects, role in lipid-lowering therapy, and dosage and administration of pravastatin are reviewed. Pravastatin sodium is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for the treatment of hypercholesterolemia. Its structural formula is similar to those of lovastatin and simvastatin, but it is active in the parent form. It competitively inhibits HMG-CoA reductase, reduces hepatic cellular cholesterol synthesis, increases the expression of hepatic low-density lipoprotein (LDL) receptors, and reduces hepatic very low-density lipoprotein (VLDL) synthesis. Pravastatin has been demonstrated to reduce cholesterol in patients with familial and nonfamilial polygenic hypercholesterolemia and patients with diabetes mellitus. In doses of 10-40 mg/day, pravastatin has been shown to reduce total cholesterol by 15-30% and LDL cholesterol by 15-40%. It also increases high-density lipoprotein cholesterol by 2-20% and reduces triglycerides. It is generally well tolerated, with few adverse effects reported in clinical trials. Pravastatin reduces LDL cholesterol and increases HDL cholesterol comparably to lovastatin but possibly with fewer adverse effects. Further studies and clinical use will be needed to confirm potential differences in adverse effect profiles between the two drugs.
Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipoproteinemia Type II; Pravastatin
PubMed: 1511541
DOI: No ID Found -
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 -
American Journal of Obstetrics and... Mar 2022
Topics: Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Pre-Eclampsia; Pregnancy
PubMed: 34666054
DOI: 10.1016/j.ajog.2021.10.011 -
Yakugaku Zasshi : Journal of the... Sep 1991The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis... (Review)
Review
The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
Topics: Animals; Arteriosclerosis; Chemical Phenomena; Chemistry, Physical; Drug Stability; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Liver; Molecular Structure; Penicillium; Pravastatin; Streptomyces
PubMed: 1762049
DOI: 10.1248/yakushi1947.111.9_469 -
International Journal of Molecular... Mar 2020Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is...
Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.
Topics: Animals; Disease Models, Animal; Endothelial Cells; Female; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes; Mice; Pravastatin; Proctitis; THP-1 Cells; Thrombomodulin
PubMed: 32164317
DOI: 10.3390/ijms21051897 -
American Journal of Obstetrics and... Aug 2023
Topics: Pregnancy; Female; Animals; Humans; Pravastatin; Pre-Eclampsia; Vascular Endothelial Growth Factor Receptor-1; Disease Models, Animal; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 36972893
DOI: 10.1016/j.ajog.2023.03.036 -
Drug Metabolism and Disposition: the... Nov 2020Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3'-iso-pravastatin acid (3PVA) under acidic pH conditions. Previous studies reported interindividual...
Pravastatin acid (PVA) can be isomerized to its inactive metabolite 3'-iso-pravastatin acid (3PVA) under acidic pH conditions. Previous studies reported interindividual differences in circulating concentrations of PVA and 3PVA. This study investigated the functional consequences of PVA isomerization on OATP1B1-mediated transport. We characterized 3PVA inhibition of OATP1B1-mediated PVA uptake into human embryonic kidney 293 cells expressing the four different OATP1B1 proteins (*1a, *1b, *5, and *15). 3PVA inhibited OATP1B1-mediated PVA uptake in all four OATP1B1 gene products but with lower IC/K values for OATP1B1*5 and *15 than for the reference proteins (*1a and *1b). PVA and 3PVA were transported by all four OATP1B1 proteins. Kinetic experiments revealed that maximal transport rates (V values) for OATP1B1 variants *5 and *15 were lower than for *1a and *1b for both substrates. Apparent affinities for 3PVA transport were similar for all four variants. However, the apparent affinity of OATP1B1*5 for 3PVA was higher (lower K value) than for PVA. These data confirm that PVA conversion to 3PVA can have functional consequences on PVA uptake and impacts OATP1B1 variants more than the reference protein, thus highlighting another source variation that must be taken into consideration when optimizing the PVA dose-exposure relationship for patients. SIGNIFICANCE STATEMENT: 3'α-iso-pravastatin acid inhibits pravastatin uptake for all OATP1B1 protein types; however, the IC values were significantly lower in OATP1B1*5 and *15 transfected cells. This suggests that a lower concentration of 3'α-iso-pravastatin is needed to disrupt OATP1B1-mediated pravastatin uptake, secondary to decreased cell surface expression of functional OATP1B1 in variant-expressing cells. These data will refine previous pharmacokinetic models that are utilized to characterize pravastatin interindividual variability with an ultimate goal of maximizing efficacy at the lowest possible risk for toxicity.
Topics: Biological Variation, Population; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inhibitory Concentration 50; Liver-Specific Organic Anion Transporter 1; Mutagenesis, Site-Directed; Pharmacogenomic Variants; Pravastatin; Stereoisomerism
PubMed: 32892153
DOI: 10.1124/dmd.120.000122 -
European Heart Journal Jun 2020Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels. (Meta-Analysis)
Meta-Analysis
AIMS
Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels.
METHODS AND RESULTS
This subject-level meta-analysis includes 5256 patients (1371 on placebo and 3885 on statin) from six randomized trials, three statin-vs.-placebo trials, and three statin-vs.-statin trials, with pre- and on-treatment (4-104 weeks) Lp(a) levels. Statins included atorvastatin 10 mg/day and 80 mg/day, pravastatin 40 mg/day, rosuvastatin 40 mg/day, and pitavastatin 2 mg/day. Lipoprotein(a) levels were measured with the same validated assay. The primary analysis of Lp(a) is based on the log-transformed data. In the statin-vs.-placebo pooled analysis, the ratio of geometric means [95% confidence interval (CI)] for statin to placebo is 1.11 (1.07-1.14) (P < 0.0001), with ratio >1 indicating a higher increase in Lp(a) from baseline in statin vs. placebo. The mean percent change from baseline ranged from 8.5% to 19.6% in the statin groups and -0.4% to -2.3% in the placebo groups. In the statin-vs.-statin pooled analysis, the ratio of geometric means (95% CI) for atorvastatin to pravastatin is 1.09 (1.05-1.14) (P < 0.0001). The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein.
CONCLUSION
This meta-analysis reveals that statins significantly increase plasma Lp(a) levels. Elevations of Lp(a) post-statin therapy should be studied for effects on residual cardiovascular risk.
Topics: Atorvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoprotein(a); Pravastatin; Randomized Controlled Trials as Topic; Rosuvastatin Calcium
PubMed: 31111151
DOI: 10.1093/eurheartj/ehz310 -
Acta Diabetologica Dec 1997Patients with diabetes mellitus (DM), type 1 and type 2, have an increased risk of coronary heart disease as a result of accelerated atherosclerosis. Dyslipidemia, often... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Patients with diabetes mellitus (DM), type 1 and type 2, have an increased risk of coronary heart disease as a result of accelerated atherosclerosis. Dyslipidemia, often found in these patients, plays an important role in this process. This study investigates the efficacy and safety of lipid-lowering therapy with pravastatin, a 3-HMG-Coenzym A reductase inhibitor in hypercholesterolemic type-1 and type-2 diabetic patients. Of 49 patients (22 type-1 DM and 27 type-2 DM), 24 patients were treated with pravastatin, 20 mg/day, and 25 patients with placebo. After 24 weeks, total cholesterol (TC) was decreased by 22.2%, low-density lipoprotein (LDL) cholesterol by 25.8% and triglycerides (TG) by 13.6%. Pravastatin treatment did not induce a significant change in high-density (HDL) cholesterol levels. No differences in effects of pravastatin treatment on serum lipids and lipoproteins were found with respect to the diabetes type. No serious side effects occurred and pravastatin treatment did not cause any deterioration in glycemia control. The data suggest that pravastatin is effective and safe in the treatment of dyslipidemia in both type-1 and type-2 diabetic patients.
Topics: Adult; Aged; Anticholesteremic Agents; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypercholesterolemia; Lipid Metabolism; Lipids; Male; Middle Aged; Pravastatin; Time Factors
PubMed: 9451475
DOI: 10.1007/s005920050091 -
Placenta Jan 2019Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent...
INTRODUCTION
Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent miscarriages. Here, we investigated the effects of pravastatin on HO-1 expression, placental development, and fetal survival in mice with a partial HO-1 deficiency.
METHODS
At E14.5, untreated pregnant wild-type (WT, n=13-18), untreated HO-1 (Het, n=6-9), and Het mice treated with pravastatin (Het+Pravastatin, n=12-14) were sacrificed. Numbers of viable fetuses/resorbed concepti were recorded. Maternal livers and placentas were harvested for HO activity. Hematoxylin and eosin (H&E) and CD31 immunohistochemical staining were performed on whole placentas.
RESULTS
Compared with WT, HO activity in Het livers (65±18%, P<0.001) and placentas (74±7%, P<0.001) were significantly decreased. Number of viable fetuses per dam was significantly lower in Untreated Het dams (6.0±2.2) compared with WT (9.1±1.4, P<0.01), accompanied by a higher relative risk (RR) for concepti resorption (17.1, 95% CI 4.0-73.2). In Hets treated with pravastatin, maternal liver and placental HO activity increased, approaching levels of WT controls (to 83±7% and 87±14%, respectively). The number of viable fetuses per dam increased to 7.7±2.5 with a decreased RR for concepti resorption (2.7, 95% CI 1.2-5.9). In some surviving Untreated Het placentas, there were focal losses of cellular architecture and changes suggestive of reduced blood flow in the labyrinth. These findings were absent in Het+Pravastatin placentas.
DISCUSSION
Pravastatin induces maternal liver and placental HO activity, may affect placental function and improve fetal survival in the context of a partial deficiency of HO-1.
Topics: Animals; Drug Evaluation, Preclinical; Female; Heme Oxygenase-1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Membrane Proteins; Mice; Placentation; Pravastatin; Pre-Eclampsia; Pregnancy; Random Allocation
PubMed: 30712660
DOI: 10.1016/j.placenta.2018.11.001