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Vascular Pharmacology Nov 2018The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and... (Observational Study)
Observational Study
Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect.
The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and intrauterine growth restriction (IUGR). Although the pathogenesis of IUGR is unclear and thus management remains a major challenge, feto-placental blood vessels are compromised, and altered umbilical blood flow is observed. In this pilot observational study we investigated the effects of pravastatin plus l-arginine on umbilical artery (umb art) blood flow. Between 2013 and 2016, five women received daily doses l-arginine and pravastatin when an umb art pulsatility index above limits for gestational age was observed and concerns about selective growth restrictions arose. All patients showed selective absent or reversed end-diastolic umbilical artery Doppler flow (AREDV) associated with increased perinatal mortality. Pravastatin (PRAV) plus l-arginine (l-Arg) treatment diminished umb art resistance significantly and allowed pregnancy to continue. No signs of acidosis or hypoxia, normal cardiotocography tracing, normal fetal movement and fetal weight gain were observed in the twins that showed abnormal umb art Dopplers. All neonates were born around 33 weeks (median 33 weeks, IQR [31.4-33.0]), thus diminishing substantially the chances for any prematurity-associated adverse neonatal outcomes. The infants now show normal growth and development. In in vitro studies, pravastatin induced relaxation of aortic rings. Murine studies identified were performed to investigate the mechanism behind PRAV+L-Arg beneficial effects. A nitric oxide (NO)-dependent synergistic vasorelaxant effect of PRAV+L-Arg was demonstrated using aortic rings. Increased levels of placental NO and increased synthesis of eNOS in placental endothelial cells were observed in mice treated with PRAV+L-Arg compared to untreated mice and mice treated with PRAV- or L-Arg alone. This study suggests that PRAV plus L-Arg might be a good therapeutic option to improve blood flow in umbilical arteries prolonging pregnancy and improving pregnancy outcomes in twins. A RCT should be organized to confirm these results.
Topics: Adult; Animals; Arginine; Blood Flow Velocity; Drug Combinations; Female; Fetal Growth Retardation; Gestational Age; Humans; In Vitro Techniques; Infant, Newborn; Infant, Premature; Live Birth; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Pilot Projects; Pravastatin; Pregnancy; Pregnancy, Twin; Premature Birth; Treatment Outcome; Twins, Dizygotic; Ultrasonography, Prenatal; Umbilical Arteries; Vascular Resistance; Vasodilation; Vasodilator Agents
PubMed: 29879462
DOI: 10.1016/j.vph.2018.06.001 -
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 -
Acta Parasitologica Sep 2019Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the...
Pravastatin and Simvastatin Pretreatment in Combination with Pyrimethamine and Sulfadiazine Reduces Infection Process of Toxoplasma gondii Tachyzoites (RH Strain) in HeLa Cells.
PURPOSE
Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast.
METHODS
To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (10) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 10) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine.
RESULTS
Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control.
CONCLUSION
Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.
Topics: Antiprotozoal Agents; Cell Survival; Drug Synergism; HeLa Cells; Humans; Life Cycle Stages; Pravastatin; Pyrimethamine; Simvastatin; Sulfadiazine; Toxoplasma; Toxoplasmosis
PubMed: 31286354
DOI: 10.2478/s11686-019-00076-2 -
Journal of Clinical Biochemistry and... Jan 20193-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used for preventing cardiovascular and cerebrovascular diseases by controlling blood...
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used for preventing cardiovascular and cerebrovascular diseases by controlling blood cholesterol level. Additionally, previous studies revealed the scavenging effects of statins on free radicals. We assessed direct scavenging activities of two water-soluble statins, fluvastatin and pravastatin, on multiple free radicals using electron spin resonance spectrometry with spin trapping method. We estimated reaction rate constants ( for fluvastatin, and for pravastatin). Superoxide anion was scavenged by fluvastatin and pravastatin with and of 4.82 Ms and 49.0 Ms, respectively. Scavenging effects of fluvastatin and pravastatin on hydroxyl radical were comparable; both and were >10 Ms. Fluvastatin also eliminated -butyl peroxyl radical with relative of 2.63 to that of CYPMPO, whereas pravastatin did not affect -butyl peroxyl radical. Nitric oxide was scavenged by fluvastatin and pravastatin with and of 68.6 Ms and 701 Ms, respectively. Both fluvastatin and pravastatin had scavenging effects on superoxide anion, hydroxyl radical and nitric oxide radical. On the other hand, -butyl peroxyl radical was scavenged only by fluvastatin, suggesting that fluvastatin might have more potential effect than pravastatin to prevent atherosclerosis and ischemia/reperfusion injury via inhibiting oxidation of lipids.
PubMed: 30705508
DOI: 10.3164/jcbn.18-48 -
BJOG : An International Journal of... Mar 2020Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia.
DESIGN
Blinded (clinician and participant), proof of principle, placebo-controlled trial.
SETTING
Fifteen UK maternity units.
POPULATION
We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 -31 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth.
PRIMARY OUTCOME
Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation.
RESULTS
The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI -1175 to 592; P = 0.5), and over days 1-14 was 48 pg/ml (95% CI -1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50-1.40; P = 0.6). The median time from randomisation to childbirth was 9 days (interquartile range [IQR] 5-14 days) for the pravastatin group and 7 days (IQR 4-11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin.
CONCLUSIONS
We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects.
TWEETABLE ABSTRACT
Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.
Topics: Adult; Double-Blind Method; Female; Gestational Age; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pravastatin; Pre-Eclampsia; Pregnancy; Vascular Endothelial Growth Factor Receptor-1
PubMed: 31715077
DOI: 10.1111/1471-0528.16013 -
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 -
Biomedicines Sep 2023Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin....
Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.
PubMed: 37893059
DOI: 10.3390/biomedicines11102685 -
Experimental and Therapeutic Medicine May 2017Pravastatin is an inhibitor of 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory...
Pravastatin is an inhibitor of 3-hydroxy-3-methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory conditions. The aim of the present study was to assess the radioprotective effects of pravastatin in an experimental animal model. Mice were divided into two groups: The control group received ionizing radiation with no prior medication, while the pravastatin group received pravastatin prior to ionizing radiation. Pravastatin was administered orally at 30 mg/kg body weight in drinking water at 24 and 4 h before irradiation. Intestinal crypt epithelial cell survival and the incidence of apoptosis in the intestine and lung were measured post-irradiation. The effect of pravastatin on intestinal DNA damage was determined by immunohistochemistry. Finally, the effect of pravastatin on tumor response to radiotherapy was examined in a mouse mesothelioma xenograft model. Pravastatin increased the number of viable intestinal crypts and this effect was statistically significant in the ileum (P<0.0001). The pravastatin group showed significantly lower apoptotic indices in all examined parts of the intestine (P<0.0001) and tended to show reduced apoptosis in the lung. Pravastatin reduced the intestinal expression of ataxia-telangiectasia mutated and gamma-H2AX after irradiation. No apparent pravastatin-related differences were observed in the response of xenograft tumors to irradiation. In conclusion, pravastatin had radioprotective effects on the intestine and lung and reduced radiation-induced DNA double-strand breaks. Pravastatin may increase the therapeutic index of radiotherapy.
PubMed: 28565765
DOI: 10.3892/etm.2017.4192 -
Translational Research : the Journal of... Aug 2016Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are...
Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8-7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity.
Topics: Acid-Base Imbalance; Animals; Cell Death; Cell Differentiation; Cell Line; Cell Membrane Permeability; Chromatography, High Pressure Liquid; Culture Media; Humans; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; L-Lactate Dehydrogenase; Membrane Transport Proteins; Mice; Microsomes, Liver; Muscle Development; Muscles; Plasma; Pravastatin; Simvastatin; Time Factors
PubMed: 27083388
DOI: 10.1016/j.trsl.2016.03.015 -
Clinical Journal of the American... Sep 2015Disease-specific treatment options for autosomal dominant polycystic kidney disease are limited. Clinical intervention early in life is likely to have the greatest... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Disease-specific treatment options for autosomal dominant polycystic kidney disease are limited. Clinical intervention early in life is likely to have the greatest effect. In a 3-year randomized double-blind placebo-controlled phase 3 clinical trial, the authors recently showed that pravastatin decreased height-corrected total kidney volume (HtTKV) progression of structural kidney disease over a 3-year period. However, the underlying mechanisms have not been elucidated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Participants were recruited nationally from July 2007 through October 2009. Plasma and urine samples collected at baseline, 18 months, and 36 months from 91 pediatric patients enrolled in the above-mentioned clinical trial were subjected to mass spectrometry-based biomarker analysis. Changes in biomarkers over 3 years were compared between placebo and pravastatin-treated groups. Linear regression was used to evaluate the changes in biomarkers with the percent change in HtTKV over 3 years.
RESULTS
Changes in plasma concentrations of proinflammatory and oxidative stress markers (9- hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, and 15-hydroxyeicosatetraenoic acid [HETE]) over 3 years were significantly different between the placebo and pravastatin-treated groups, with the pravastatin group showing a lower rate of biomarker increase. Urinary 8-HETE, 9-HETE, and 11-HETE were positively associated with the changes in HtTKV in the pravastatin group.
CONCLUSIONS
Pravastatin therapy diminished the increase of cyclooxygenase- and lipoxygenase-derived plasma lipid mediators. The identified biomarkers and related molecular pathways of inflammation and endothelial dysfunction may present potential targets for monitoring of disease severity and therapeutic intervention of autosomal dominant polycystic kidney disease.
Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adolescent; Biomarkers; Child; Female; Humans; Hydroxyeicosatetraenoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Linoleic Acids; Male; Organ Size; Oxidative Stress; Polycystic Kidney, Autosomal Dominant; Pravastatin; Time Factors; Young Adult
PubMed: 26224879
DOI: 10.2215/CJN.11331114