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Orvosi Hetilap Mar 2020The treatment of preeclampsia, which occurs in 3-8% of pregnancies, is not yet resolved. In preeclampsia, NO synthesis is insufficient, which can contribute to...
The treatment of preeclampsia, which occurs in 3-8% of pregnancies, is not yet resolved. In preeclampsia, NO synthesis is insufficient, which can contribute to hypertension, proteinuria and abnormal vascularization of the placenta. Decreased NO synthesis in the preeclamptic placenta may also be due to a decrease in the affinity of NO synthase for tetrahydrobiopterin (BH4), resulting in BH4 resistance. In recent years, pravastatin has been shown to prevent preeclampsia in animal models and in human studies. One of the known pleiotropic effects of pravastatin is that it increases NO synthase activity. Description of the effect of pravastatin on BH4-resistant NO synthase activity in the preeclamptic placenta. NO synthase activity in the placental microsome was measured with C14 arginine substrate using healthy (n = 9) and preeclamptic (n = 9) samples. NO synthase activity was measured at 0.02 µM, physiological at 0.20 µM and pharmacological at 50 µM BH4. One of the 9 preeclamptic patients was BH4-resistant; physiologic BH4 concentration did not significantly increase NO synthase activity, whereas healthy placental microsomes showed a mean increase of 60% (p<0.01), and BH4-sensitive preeclamptic specimen showed a 67% (p<0.01) increase. 10 µM pravastatin increased NO synthase activity by 32-38% at each BH4 concentration in healthy, BH4-sensitive and BH4-resistant preeclampsia samples. 10 µM pravastatin increased BH4-resistant placental NO synthase activity to a similar extent as placental physiological BH4 concentration (0.06-0.20 µM) to BH4-sensitive NO synthase activity. The NO synthase activity of BH4-resistant preeclamptic placenta can be increased by pravastatin to physiological level. Orv Hetil. 2020; 161(10): 389-395.
Topics: Biopterins; Female; Humans; Nitric Oxide Synthase; Placenta; Pravastatin; Pre-Eclampsia; Pregnancy
PubMed: 32115993
DOI: 10.1556/650.2020.31670 -
BJOG : An International Journal of... May 2020
Topics: Female; Humans; Pravastatin; Pre-Eclampsia; Pregnancy
PubMed: 32096602
DOI: 10.1111/1471-0528.16160 -
Journal of Controlled Release :... Dec 2010The chronic inflammatory environment of tumors is a target for novel antitumor therapeutic strategies. Besides cholesterol lowering effects, statins have been studied...
The chronic inflammatory environment of tumors is a target for novel antitumor therapeutic strategies. Besides cholesterol lowering effects, statins have been studied for their anti-inflammatory and immunomodulatory properties. These pleiotropic effects result mainly from the altered post-translational modification of GTP-binding proteins which regulate many intracellular pathways involved in cell growth and survival. Although pre-clinical studies suggest that statins may be effective anticancer agents required doses that are 100 to 500 fold higher than those needed to lower cholesterol levels. Furthermore, in view of their wide-ranging effects on cellular metabolism, target site-specific delivery is preferred. In this study, we investigated tumor-specific delivery of pravastatin using small long-circulating liposomes. In vitro studies on the effects of (liposomal) pravastatin on viability and proliferation of tumor cells, endothelial cells and macrophages revealed that the latter were the most sensitive cell type towards (liposomal) pravastatin treatment. In vivo, liposome-encapsulated pravastatin (5mg/kg) inhibited murine B16F10-melanoma growth over 70% as compared to free pravastatin, which was ineffective. As expected, treatments did not influence serum cholesterol levels within the time frame of the study. At 48 h post-injection, 3 μg of pravastatin could still be recovered from the tumors of liposomal pravastatin treated mice, whereas pravastatin could not be detected in tumors of the free drug treated mice (i.e. < 20 ng). In contrast to the free drug, liposomal pravastatin treatment effectively inhibited the production of several pro-inflammatory/pro-angiogenic mediators involved in inflammation and angiogenesis, out of a range of a panel of 24 proteins studied. Furthermore, liposomal pravastatin treatment increased MHC class I protein expression in the tumor tissue whereas free drug showed no effect. Taken together, targeted delivery of statins can improve their tumor growth inhibiting activity by increasing local drug concentration and direct modulation of macrophage function. The antitumor activity seems to result primarily from a local inhibition of tumor inflammation and stimulation of antitumor immune response.
Topics: Angiogenic Proteins; Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Genes, MHC Class I; Humans; Inflammation; Lipid Metabolism; Liposomes; Male; Mice; Mice, Inbred C57BL; Neoplasms; Pravastatin
PubMed: 20869410
DOI: 10.1016/j.jconrel.2010.09.011 -
Acta Tropica Mar 2017The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs....
The conventional treatment for toxoplasmosis with pyrimethamine and sulfadiazine shows toxic effects to the host, and it is therefore necessary to search for new drugs. Some studies suggest the use of statins, which inhibit cholesterol synthesis in humans and also the initial processes of isoprenoid biosynthesis in the parasite. Thus, the objective of this study was to evaluate the activity of the statins pravastatin and simvastatin in HeLa cells infected in vitro with the RH strain of T. gondii. HeLa cells (1×10) were infected with T. gondii tachyzoites (5×10) following two different treatment protocols. In the first protocol, T. gondii tachyzoites were pretreated with pravastatin (50 and 100μg/mL) and simvastatin (1.56 and 3.125μg/mL) for 30min prior to infection. In the second, HeLa cells were first infected (5×10) with tachyzoites and subsequently treated with pravastatin and simvastatin for 24h at the concentrations noted above. Initially, we evaluated the cytotoxicity of drugs by the MTT assay, number of tachyzoites adhered to cells, number of infected cells, and viability of tachyzoites by trypan blue exclusion. The supernatant of the cell cultures was collected post-treatment for determination of the pattern of Th1/Th2/Th17 cytokines by cytometric bead array. There was no cytotoxicity to HeLa cells with 50 and 100μg/mL pravastatin and 1.56 and 3.125μg/mL simvastatin. There was no change in the viability of tachyzoites that received pretreatment. Regarding the pre- and post-treatment of the cells with pravastatin and simvastatin alone, there was a reduction in adhesion, invasion and proliferation of cells to T. gondii. As for the production of cytokines, we found that IL-6 and IL-17 were significantly reduced in cells infected with T. gondii and treated with pravastatin and simvastatin, when compared to control. Based on these results, we can infer that pravastatin and simvastatin alone possess antiproliferative effects on tachyzoites forms of T. gondii, giving these drugs new therapeutic uses.
Topics: Cell Adhesion; Cell Survival; Dose-Response Relationship, Drug; HeLa Cells; Humans; Pravastatin; Simvastatin; Toxoplasma
PubMed: 28012901
DOI: 10.1016/j.actatropica.2016.12.006 -
Biochemical and Biophysical Research... Apr 2019HMG-CoA reductase inhibitor statins are used to treat patients with hypercholesterolemia. The pleiotropic effects of statins have been recently extended to the...
HMG-CoA reductase inhibitor statins are used to treat patients with hypercholesterolemia. The pleiotropic effects of statins have been recently extended to the regulation of angiogenesis. However, the observations on the effects of statins on endothelial cells seem to be contradictory. In this work, we systematically analysed the effects of pravastatin at concentrations covering 10,000-fold range on the functions of human cardiac microvascular endothelial cells (HMVEC-C) under HO-induced oxidative stress and normal physiological conditions. We observed the biphasic effects of pravastatin in protecting HMVEC-C dysfunctions induced by HO: pravastatin at low concentrations significantly enhanced vascular network formation, growth, migration and survival under HO-induced oxidative stress condition whereas this effect disappeared at higher concentrations. Interestingly, pravastatin at low concentrations did not affect HMVEC-C functions but at high concentrations significantly inhibited HMVEC-C vascular network formation, growth, migration and survival in a dose-dependent manner. We further demonstrated the different molecular mechanisms of the action of pravastatin at low and high concentrations on HMVEC-C: pravastatin at low concentrations alleviates HO-induced oxidative stress and damage and at high concentrations inhibits prenylation. Our work provides better understanding on the multiple differential effects and the underlying mechanisms of pravastatin on HMVEC-C, which may be of relevance to the influence of statins in cardiovascular system.
Topics: Anticholesteremic Agents; Cell Line; Cell Movement; Cell Survival; Dose-Response Relationship, Drug; Endothelial Cells; Heart; Humans; Myocardium; Neovascularization, Physiologic; Oxidative Stress; Pravastatin; Prenylation
PubMed: 30803760
DOI: 10.1016/j.bbrc.2019.02.090 -
Xenobiotica; the Fate of Foreign... Jan 20171. Diabetes is often accompanied with depression and hypercholesterolemia. It is possible that paroxetine and pravastatin are co-administered to diabetic patients. The...
1. Diabetes is often accompanied with depression and hypercholesterolemia. It is possible that paroxetine and pravastatin are co-administered to diabetic patients. The aim of this study was to research the differential effect of pravastatin on plasma exposure of paroxetine in normal and diabetic rats. 2. Pharmacokinetics of paroxetine was investigated following oral administration of paroxetine with and without pravastatin in normal and diabetic rats. Effects of pravastatin on metabolism, intestinal absorption and hepatic uptake of paroxetine were investigated. Activity and expression of hepatic Oatp1 and Oatp2 were also assessed. 3. Pravastatin decreased plasma exposure of paroxetine in normal rats, but increased exposure of paroxetine in diabetic rats. Pravastatin neither affected metabolism nor intestinal absorption of paroxetine. Data from hepatocytes demonstrated that hepatic uptake of paroxetine were involved in Oatp1 and Oatp2. Diabetes suppressed Oatp1 activity and expression, but enhanced Oatp2 activity and expression. Pravastatin stimulated Oatp1 but inhibited Oatp2 activity. 4. We concluded that differential effects of pravastatin on plasma exposure of paroxetine in normal and diabetic rats was partly due to the fact that diabetes suppressed Oatp1 activity and expression but enhanced Oatp2 activity and expression as well as that pravastatin stimulated Oatp1 activity but inhibited Oatp2 activity.
Topics: Animals; Anticholesteremic Agents; Biological Transport; Diabetes Mellitus, Experimental; Hepatocytes; Liver; Paroxetine; Pravastatin; Rats; Selective Serotonin Reuptake Inhibitors
PubMed: 27145862
DOI: 10.3109/00498254.2016.1154999 -
American Journal of Obstetrics and... Oct 2013The objective of the study was to determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between...
OBJECTIVE
The objective of the study was to determine the bidirectional transfer of pravastatin across the dually perfused term human placental lobule and its distribution between the tissue and maternal and fetal circuits.
STUDY DESIGN
The transfer of pravastatin was determined in the maternal-to-fetal (n = 11) and fetal-to-maternal (n = 10) directions. Pravastatin was coperfused with its [(3)H]-isotope and the marker compound antipyrine (20 μg/mL) and its [(14)C]-isotope. The concentration of pravastatin in the perfused tissue and the maternal and fetal circuits was determined using liquid scintillation spectrometry. Inside-out vesicles prepared from placental brush border membranes were utilized to investigate the role of efflux transporters in the transplacental transfer of pravastatin.
RESULTS
Pravastatin was transferred from the maternal to the fetal circuit and vice versa. In the maternal-to-fetal direction, the distribution of pravastatin at the end of experiment was as follows: 14 ± 5% of the drug was retained by the tissue, 68 ± 5% remained in the maternal circuit, and 18 ± 4% was transferred to the fetal circuit. The normalized transfer of pravastatin (clearance index) to antipyrine in the fetal-to-maternal direction (0.48 ± 0.07) was higher than its transfer in the maternal-to-fetal direction (0.36 ± 0.07, P < .01). Furthermore, pravastatin inhibited the adenosine triphosphate (ATP)-dependent uptake of the paclitaxel and estrone sulfate.
CONCLUSION
The transfer of pravastatin across the dually perfused placental lobule suggests that fetal exposure to pravastatin is plausible. The higher transfer of pravastatin in the fetal-to-maternal direction than the reverse as well as its inhibition of the ATP-dependent uptake of [(3)H]-paclitaxel and [(3)H]-estrone sulfate strongly suggest the involvement of efflux transporters in decreasing its transfer across the placenta and support pravastatin's favorable pharmacokinetic profile in pregnancy.
Topics: Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Maternal-Fetal Exchange; Placenta; Pravastatin; Pregnancy
PubMed: 24070396
DOI: 10.1016/j.ajog.2013.05.038 -
Zeitschrift Fur Geburtshilfe Und... Feb 2018Statins seem to positively influence the inflammatory, anti-angiogenic milieu of pregnancies with underlying placental ischemia by their pleiotropic effects. This might...
Statins seem to positively influence the inflammatory, anti-angiogenic milieu of pregnancies with underlying placental ischemia by their pleiotropic effects. This might prevent, ameliorate and delay preeclampsia. To confirm the benefits of pravastatin on gestational age at birth as well as clinic and angiogenic markers in pregnancies at high-risk for preeclampsia, the Department of Obstetrics at the University Hospital Leipzig plans a randomized, double-blinded, placebo-controlled feasibility study.
Topics: Anticholesteremic Agents; Double-Blind Method; Feasibility Studies; Female; Fetal Development; Gestational Age; Humans; Infant, Newborn; Neovascularization, Physiologic; Pravastatin; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy, High-Risk; Regional Blood Flow; Ultrasonography, Prenatal; Uterus
PubMed: 29499584
DOI: 10.1055/s-0044-100789 -
Hepatobiliary & Pancreatic Diseases... Apr 2011Our earlier study with cultured gallbladder epithelial cells demonstrated that statins (HMG-CoA reductase inhibitors) activate the expression of PPARalpha and PPARgamma,...
BACKGROUND
Our earlier study with cultured gallbladder epithelial cells demonstrated that statins (HMG-CoA reductase inhibitors) activate the expression of PPARalpha and PPARgamma, consequently blocking the production of pro-inflmmatory cytokines. The present study used hamsters to investigate the effects of pavastatin on PPARalpha/PPARgamma expression in the liver and gallbladder epithelium, and to determine whether pravastatin suppresses cholesterol crystal formation in the gallbladder.
METHODS
A total of 40 Golden Syrian male hamsters (4 weeks old) were randomly assigned to four groups (basal diet control; basal diet+pavastatin; high cholesterol diet; high cholesterol diet+pravastatin). All hamsters were 11 weeks old at the end of the experiment. The liver, gallbladder and bile were harvested. Immunohistochemical staining and Western blotting for PPARalpha and PPARgamma were performed in the liver and gallbladder. A drop of fresh bile was examined for cholesterol crystals under a microscope.
RESULTS
In the gallbladder and liver of the hamsters, pravastatin activated the PPARalpha and PPARgamma expression of gallbladder epithelial cells and hepatocytes, and particularly the response of PPARgamma was much stronger than that of PPARalpha. Pravastatin suppressed the formation of cholesterol gallstones or crystals in the gallbladder.
CONCLUSION
Pravastatin is an effective medication to activate PPARs (especially PPARgamma) in the liver and the gallbladder epithelium of hamsters, and contributes to the prevention of gallstone formation.
Topics: Animals; Cholesterol; Cricetinae; Gallbladder; Gallstones; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Liver; Male; Mesocricetus; PPAR alpha; PPAR gamma; Pravastatin
PubMed: 21459726
DOI: 10.1016/s1499-3872(11)60029-5 -
Pregnancy Hypertension Mar 2024Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative...
Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative stress. There is evidence that statins show antioxidant effects that can improve endothelial function without adverse perinatal effects. We aimed to compare early vs. late pravastatin treatment on the oxidative stress and cardiovascular features of an experimental model of preeclampsia. Female Wistar rats were randomly divided into preeclampsia phenotype rats (PEP) developed by sub renal aortic coarctation (SRAC) and healthy pregnant rats (C). Each group received pravastatin (5 mg/Kg) p.o. either for one week before and during the first week or during the last two weeks of gestation. Blood pressure was determined using the plethysmographic method. Phenylephrine (Phe)-induced contractility was evaluated in isolated thoracic and abdominal aortic rings with or without endothelium. Blood samples were obtained to determine anion superoxide concentration as indicator of NADPH activity. Two-way ANOVA and Bonferroni post hoc tests were used to define statistical significance. Early or late pravastatin treatment decreased hypertension of PEP animals but did not change BP of the healthy pregnant group. Thoracic and abdominal aorta from PEP rats showed increased contractility that was reverted by pravastatin early treatment in endothelium intact rings. Pravastatin did not significantly change contractility neither in the thoracic nor in the abdominal aorta segments from healthy pregnant control rats (C), and decrease anion superoxide concentration by NADPH activity. We conclude pravastatin can improve both blood pressure and endothelium-dependent Phe-induced contractility in an experimental model of preeclampsia by reducing oxidative stress.
Topics: Pregnancy; Humans; Rats; Female; Animals; Pravastatin; Pre-Eclampsia; Superoxides; NADP; Rats, Wistar; Oxidative Stress; Phenylephrine; Endothelium, Vascular
PubMed: 38306739
DOI: 10.1016/j.preghy.2024.01.131