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Objective: To explore the effects of Huxin formula (HXF) in curtailing atherosclerosis and its underlying mechanism. Methods: According to random number table method, 24 specific pathogen free male ApoE-/- mice were randomly divided into model group, HXF low-dose (HXF-L) group (8.4 g/kg daily), HXF high-dose (HXF-H) group (16.8 g/kg daily), and pravastatin (8 mg/kg daily) group in Experiment I (n=6 per group). C57BL/6J mice served as the control group (n=6). ApoE-/- mice in HXF-L, HXF-H, pravastatin groups were fed a Western diet and administered continuously by gavage for 12 weeks, while C57BL/6J mice in the control group were fed conventional lab mouse chow for 12 weeks. Further, Tregs were depleted by weekly intraperitoneal injection of purified anti-mouse CD25 antibody (PC61, 250 µg per mouse) for 4 weeks in Experiment II (n=6 per group). Oil Red O and Masson staining were used to evaluate the plaque area and aortic root fibrosis. The CD4+CD25+Foxp3+Treg counts in the lymph nodes and spleen cells were detected using flow cytometric analysis. The transforming growth factor-β1 (TGF-β1), interleukin (IL)-10, and IL-6 serum levels were examined by MILLIPLEX® MAP technology. Quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot were utilized to assess the expression of TGF-β mRNA and protein in the aorta. The expression of CD4+T lymphocytes, macrophages and smooth muscle cells in the aortic root were detected by immunofluorescence staining. Results: HXF reduced plaque area in ApoE-/- mice (P<0.01). HXF increased the Treg counts in the lymph nodes and spleen cells (P<0.05 or P<0.01). Moreover, HXF alleviated inflammatory response via elevating IL-10 and TGF-β 1 serum levels (P<0.05), while decreasing the IL-6 serum levels in ApoE-/- mice (P>0.05). Also, HXF upregulated the expression of TGF-β mRNA and protein in the aorta (P<0.05). Additionally, HXF attenuated CD4+T lymphocytes, macrophages and smooth muscle cells in aortic root plaque (P<0.01). Furthermore, the depletion of Tregs with CD25 antibody (PC61) curtailed the reduction in plaque area and aortic root fibrosis by HXF (P<0.01). Conclusion: HXF relieved atherosclerosis, probably by restraining inflammatory response, reducing inflammatory cell infiltration and attenuating aortic root fibrosis by increasing Treg counts. [ABSTRACT FROM AUTHOR]

There are no effective therapies to prevent preeclampsia (PE). Pravastatin shows promise by attenuating processes associated with PE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction. Methods: Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with pravastatin (1 µg/mL), while others were cotreated with pravastatin and glucose. The expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) mRNA, vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured. CTB migration was assayed using a CytoSelect migration assay kit. Statistical comparisons were performed using an analysis of variance with Duncan's post hoc test. Results: The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels > 200 mg/dL and cotreated at glucose levels > 300 mg/dL (p < 0.05). Hyperglycemia-induced decreases in VEGF and PlGF and increases in sEng and sFlt-1 were attenuated in both the pretreatment and cotreatment samples regardless of glucose dose (p < 0.05). Pravastatin attenuated hyperglycemia-induced dysfunction of CTB migration. Conclusions: Pravastatin mitigates stress signaling responses in hyperglycemic conditions, weakening processes leading to abnormal CTB migration and invasion associated with PE in pregnancy. [ABSTRACT FROM AUTHOR]

Pravastatin is a popular statin agent with applications in the treatment of cardiovascular diseases for patients with an abnormal lipid panel. The starting form of pravastatin is amorphous and following recrystallization, it becomes a crystalline solid with tert-butylamine salt molecules embedded within the lattice. Its molecular and crystal structure were elucidated based on single-crystal X-ray diffraction and characterized by ss-NMR. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pravastatin is a clinically effective drug for the treatment of hypercholesterolemia and is now found to play a beneficial role in the treatment of CNS injury; however, the mechanism remains unknown. OBJECTIVE: To ascertain the possible mechanism of action and whether pravastatin medication can expedite functional recovery following sciatic nerve crush injury. METHODS: Male Sprague-Dawley rats were randomly assigned into: pravastatin (sciatic nerve crush injury+pravastatin gavage), negative control (sciatic nerve crush injury+saline gavage), and sham operation (sciatic nerve exposure but no injury+saline gavage). While the other two groups received comparable amounts of saline gavage, the pravastatin group received postoperative pravastatin (5 mg/kg) by gavage for 1 week. The general conditions of the rats in each group were observed after operation. Sciatic function index was evaluated at the end of the 2nd, 4th, 6th, and 8th week after operation, and the wet mass ratio of the gastrocnemius muscle was measured at the end of the 8th week after operation. The levels of inflammatory cytokines in serum were measured using ELISA. Histomorphometrics was used to measure the number of myelinated nerve fibers, fiber diameter, axon diameter, and myelin sheath thickness. RT-qPCR assay was used to measure the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor, and western blot was used to measure the protein expression of growth-associated protein 43. RESULTS AND CONCLUSION: Compared with the negative control group, the sciatic function index in the pravastatin group recovered faster (P < 0.05) and was closer to the level of the sham operation group, the expression of tumor necrosis factor α and interleukin 6 in serum was lower (P < 0.05) and close to that of the sham operation group, and the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor in the sciatic nerve increased (P < 0.05 or P < 0.01), the relative protein expression of growth-associated protein 43 in the sciatic nerve was also significantly increased (P < 0.05), the number of myelinated nerve fibers was increased more, and the values of fiber diameter, axon diameter, and myelin sheath thickness were larger (P < 0.01) and closer to those of the sham operation group. To conclude, treatment with pravastatin accelerates functional recovery from sciatic nerve crush injury by a possible mechanism of inhibiting the expression of tumor necrosis factor α and interleukin 6 and promoting the secretion of neurotrophic factors nerve growth factor and brain-derived neurotrophic factor. [ABSTRACT FROM AUTHOR]

The primary intervention for pre-eclampsia (PE) remains iatrogenic delivery, which can be very preterm and not optimal for the fetus. Although many efforts have been made to prevent and manage PE, there is still a dearth of drugs to treat its pathophysiological progression. Pravastatin (PRA), a hydrophilic statin, has gained interest for the prevention and treatment of PE. The aim of the present study was to evaluate the ability of PRA to modulate factors involved in placentation, such as Epidermal Growth Factor-Like Domain 7 (EGFL7), in human chorionic villous culture from healthy controls and women with PE. A total of 18 women were enrolled: 10 controls and 8 cases. Chorionic villous explants were maintained in culture for 24 h with or without 10 μM Pravastatin, and the expression of EGFL7 and NOTCH1 pathway members was evaluated by qRT-PCR and Western blot analysis. The rationale of the present study was to establish an ex vivo model to identify potential different responses to PRA treatment of chorionic villous explants in order to clarify the molecular mechanism of PRA in the prevention and treatment of PE and to predict whether there are specific clinical conditions that modulate the response to the drug treatment. Within PE patients, two different groups were identified: the high responders, whose villous cultures exhibit significantly increased expressions of the EGFL7 and Notch pathways after PRA incubation; and the low responders, who are high-risk PE patients in which prophylaxis failed to prevent PE and PRA was not able to modulate EGFL7 expression. In conclusion, we identified EGFL7 as a new factor regulated by PRA, placing interest in early discrimination between low- and high- risk women, in which the well-known pharmacological prophylaxis seems to be ineffective, and to explore new potential prevention strategies. [ABSTRACT FROM AUTHOR]

Introduction: Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type 2 diabetes mellitus (T2DM) in clinical practice. Methods: This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week 24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks 12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48 weeks from baseline, and safety. Results: We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48 weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30–90 mL/min/1.73 m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5 years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24 weeks. Conclusion: Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function. Trial Registration Number: NCT05107063 submitted October 27, 2021. [ABSTRACT FROM AUTHOR]

Objective Our objective was to determine if treatment with pravastatin prevents preeclampsia in pregnant patients at risk of preeclampsia. Materials and Methods The study was performed in four major tertiary hospitals in Surabaya, Bandung, and Makassar between 2017 and 2021. Pregnant women at high risk of developing preeclampsia were recruited and randomized into an intervention group and control group. The control group received low-dose aspirin (80 mg) and calcium (1 g) daily, while the intervention group received additional pravastatin (20 mg twice daily) starting from 14 to 20 weeks' gestation until delivery. The pregnancy was followed until delivery, and the clinical data were collected. The primary outcome was the occurrence of preeclampsia. Result A total of 173 people participated in this study, including 86 in the control group and 87 in the pravastatin group. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8 vs. 26.7%; p = 0.034; odds ratio [OR] = 0.034, 95% confidence interval [CI] = 0.202–0.905) and preterm birth (16.1 vs. 36%; p = 0.003; OR = 0.340, 95% CI = 0.165–0.7), mostly indicated preterm birth. Preeclampsia occurred later in the pravastatin group than in the control group (36.39 + 2.32 vs. 34.89 + 3.38 weeks, p = 0.048). Overall, the pravastatin group showed better perinatal outcomes. Neonates with low Apgar scores (<7) at 1 minute (5.7 vs. 25.6%, p = 0.000) and 5 minutes (2.3 vs. 25.6%, p = 0.028) were significantly less common in the pravastatin group. Additionally, the rate of low birthweight babies (<2,500 g) was lower in the pravastatin group (27.6 vs. 40.7%; p = 0.069). Conclusion Pravastatin (20 mg bid) significantly reduces the risk of preterm preeclampsia and preterm birth in women at a high risk of developing preeclampsia. Key Points This is an open-label multicenter RCT to evaluate pravastatin effect to prevent preeclampsia. Pravastatin significantly reduces the risk of preterm preeclampsia (PE) and preterm birth in high risk PE women. Pravastatin had a beneficial effect on perinatal outcomes, including Apgar scores and birth weight. [ABSTRACT FROM AUTHOR]

This research endeavour primarily aimed to optimize and establish a model for the recovery of pravastatin, a well‐known statin drug recognized for its cholesterol‐lowering properties, from aqueous solutions using reactive extraction. This study used the Box–Behnken design to investigate extraction parameters and create a concise model equation illustrating the relationship between variables and responses. The investigation showed a strong agreement between the model equation and experimental outcomes. It highlighted a positive correlation, demonstrating that higher concentrations of reactant and pravastatin led to notable improvements in extraction efficiency. Two out of 90 experiments had extraction efficiencies below 10%, both with constant factors except for solvent type, while 14 experiments exceeding 80% efficiency highlighted the positive impact of a 50% reactant concentration on extraction efficiency. According to a statistical second‐order polynomial, the predicted extraction efficiency stands at 75.14%. In the culminating phase of the study, optimal extraction conditions were meticulously determined, resulting in the identification of an optimal set of parameters: a pravastatin concentration of 35 mg · L−1, an adogen concentration of 20.91% (v/v), and a butanol phase ratio of 0.2% (v/v). Under optimal conditions, the experimental extraction efficiency reached 72.69%, closely aligning with values predicted through numerical optimization employing response surface methodology. [ABSTRACT FROM AUTHOR]

Background: Pravastatin is an oral lipid‐lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear. Methods: In this study, 16S rRNA sequencing and qRT‐PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT‐PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification. Results: We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5‐trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA. Conclusions: Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis. [ABSTRACT FROM AUTHOR]

Cell-to-cell propagation of protein aggregates has been implicated in the progression of neurodegenerative diseases. However, the underlying mechanism and modulators of this process are not fully understood. Here, we screened a small-molecule library in a search for agents that suppress the propagation of α-synuclein and mutant huntingtin (mHtt). These screens yielded several molecules, some of which were effective against both α-synuclein and mHtt. Among these molecules, we focused on simvastatin and pravastatin. Simvastatin administration in a transgenic model of synucleinopathy effectively ameliorated behavioral deficits and α-synuclein accumulation, whereas pravastatin had no effect. Because only simvastatin enters the brain effectively, these results suggest that inhibition of brain cholesterol synthesis is important in simvastatin effects. In cultured cells, accumulation of intracellular cholesterol, induced by genetic ablation of the NPC1 gene or by pharmacological treatment with U18666A, increased α-synuclein aggregation and secretion. In contrast, lowering cholesterol using methyl-β-cyclodextrin or statins reversed α-synuclein aggregation and secretion in NPC1-knockout cells. Consistent with these observations, feeding a high-fat diet aggravated α-synuclein pathology and behavioral deficits in the preformed fibril-injected mouse model, an effect that was also reversed by simvastatin administration. These results suggest that statins suppress propagation of protein aggregates by lowering cholesterol in the brain.

IntroductionFamilial hypercholesterolemia, the highly prevalent form of dyslipidemia, is a well-known risk factor for premature heart disease and stroke worldwide. Statins, which inhibit 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the first-choice treatment for dyslipidemias, and have been effective in reducing the risk of stroke and myocardial infarction. However, emerging evidence indicates that statins may increase the incidence of new-onset type 2 diabetes by reducing β-cell mass and function. Notably, past in vitro reports studying the effects of statins on β-cells were performed without including free fatty acids in the model. This factor should have been addressed since these agents are used to treat individuals with hyperlipidemia.MethodsHere, we used a mouse insulinoma MIN6 β-cell culture model to assess the efficacy, cytotoxicity, and insulin-suppressive effects of simvastatin and pravastatin in the presence of palmitic, linoleic, and oleic acids cocktail to mimic mixed lipids challenge in a biologically relevant setting.Results and discussionOur findings indicate that simvastatin was more effective in lowering intracellular cholesterol but was more cytotoxic as compared to pravastatin. Similarly, simvastatin exhibited a higher suppression of total insulin content and insulin secretion. Both drugs suppressed insulin secretion in phases 1 and 2, dose-dependently. No significant effect was observed on mitochondrial respiration. More importantly, elution experiments showed that insulin content diminution by simvastatin treatment was reversible, while exogenous mevalonate did not improve total insulin content. This suggests that simvastatin's influence on insulin content is independent of its specific inhibitory action on HMG-CoA reductase. In conclusion, our study identified that simvastatin was more effective in lowering intracellular cholesterol, albeit it was more toxic and suppressive of β-cells function. Notably, this suppression was found to be reversible.

Pravastatin is a popular statin agent with applications in the treatment of cardiovascular diseases for patients with an abnormal lipid panel. The starting form of pravastatin is amorphous and following recrystallization, it becomes a crystalline solid with tert-butylamine salt molecules embedded within the lattice. Its molecular and crystal structure were elucidated based on single-crystal X-ray diffraction and characterized by ss-NMR.

An identical group of disorders has been called “interstitial granulomatous dermatitis” and “palisaded neutrophilic and granulomatous dermatitis.” In addition, a drug-induced subset of this condition has been named “interstitial granulomatous drug reaction (IGDR).” More recently, “reactive granulomatous dermatitis (RGD)” has been proposed as an umbrella term encompassing these three disorders. A considerable number of RGD cases are associated with systemic conditions, including autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, inflammatory bowel disease, and malignancies. IGDR has also been shown to be caused by certain medications. We present a case of a 74-year-old Japanese man showing an asymptomatic, well-demarcated erythema eruption on the bilateral inguinal region extending to the lower abdomen and proximal thigh area. He had hyperlipidemia and had been taking pravastatin for 4 years. A biopsy specimen taken from the erythematous lesion revealed infiltration of lymphocytes and histiocytes in the upper and lower dermis. Interstitial infiltrates of histiocytes and lymphocytes were found as they were dispersed between collagen bundles. Immunostaining showed CD68+ macrophages intermingled with CD4+ and CD8+ T cells. Based on the clinical and histologic findings, the eruption was diagnosed as RGD. Because of the possibility of IGDR, pravastatin was stopped. His eruption completely disappeared within 6 months after the discontinuation. The list of drugs that cause RGD includes angiotensin-converting enzyme inhibitors, antihistamines, β-blockers, antidepressants, anticonvulsants, tocilizumab and ustekinumab. In addition, various statins have been reported to induce drug eruptions. The eruption types are mainly eczematous or lichenoid reactions, with psoriasiform or ichthyosiform reactions occurring rarely. There was only one report documenting that RGD occurred in patients administered rosuvastatin, with annular, violaceous plaques distributed on the extremities, proximal trunk and intertriginous areas. Pravastatin induces lichenoid eruption, but RGD has not been documented. Our case suggests that RGD is underestimated as an adverse effect of statins possibly because of its unusual cutaneous manifestations.

Context: Preeclampsia prevention is important for reducing maternal mortality and morbidity worldwide. Recent studies have explored the use of to prevent preeclampsia and improve maternal, perinatal, or neonatal outcomes. However, the results are still debatable. Aims: To evaluate the role of pravastatin in the prevention of preeclampsia in pregnant women. Methods: This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) involving studies with healthy pregnant women receiving pravastatin vs. control to observe the risk of preeclampsia. Literature searching was conducted in PubMed, Science Direct, EBSCO/CINAHL, PROQUEST, and SCOPUS. Statistical analyses were performed using the Review Manager 5.4.1 software. Results: Five studies were initially identified for meeting the inclusion criteria; 2 studies were treatment studies and had to be excluded, and one small study only used pravastatin for a few weeks, leaving only two studies for statistical analysis. Administration of pravastatin was associated with a reduced risk of preeclampsia (OR: 0.51; 95% CI: 0.29-0.90; p= 0.02) and preterm delivery (OR: 0.31; 95% CI: 0.16-0.58; p

Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg−1 day−1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg−1 day−1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg−1 day−1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg−1 day−1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg−1 day−1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg−1 day−1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg−1 day−1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.

BackgroundMaternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.MethodsA total of 19 obese mothers were assigned to either one of the two intervention groups (n = 5 for calorie restriction; n = 7 for pravastatin) or an obese control group (n = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers (n = 6) using metabolomics methods.ResultsGestational calorie restriction normalized one-carbon metabolism dysregulation in obese mothers, but altered energy metabolism in her offspring. Although administration of pravastatin during pregnancy tended to normalize blood cholesterol in the mothers, it potentially impacted the gut microbiome and kidney function of their offspring. In the offspring, both calorie restriction and pravastatin administration during pregnancy tended to normalize the activity of AMPK in the brain at 6 months, and while results of the Visual Paired-Comparison test, which measures infant recognition memory, was not significantly impacted by either of the interventions, gestational pravastatin administration, but not calorie restriction, tended to normalize anxiety assessed by the Human Intruder test.ConclusionsAlthough the two interventions tested in a non-human primate model led to some improvements in metabolism and/or infant brain development, negative impacts were also found in both mothers and infants. Our study emphasizes the importance of assessing gestational interventions for maternal obesity on both maternal and offspring long-term outcomes.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor–dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated antimicrobial activity of atorvastatin, pravastatin, rosuvastatin, and simvastatin against oral bacteria, and the interaction of simvastatin with standard antimicrobials (amoxicillin and metronidazole). Methods: Minimal inhibitory concentration assays were performed with Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Actinomyces odontolyticus, Streptococcus oralis, Streptococcus mitis, Streptococcus salivarius, Streptococcus sanguinis, and Streptococcus gordonii; checkerboard microdilution assays between simvastatin and standard antimicrobials; monospecies and multispecies biofilms. Results: Simvastatin showed the best antimicrobial activity against most species (MIC range from 3.12 to 25 μg/ml), highlighting the sensitivity of P. gingivalis. In the checkerboard assay, synergistic interaction was found between simvastatin and amoxicillin against S. oralis and S. sanguinis. P. gingivalis biofilm was inhibited by simvastatin at 10 and 50× Minimal inhibitory concentration, with similar effects to metronidazole. For multispecies biofilm, SMV reduced the biofilm metabolic activity (79%) and total counts (87%), comparable to amoxicillin. Simvastatin also reduced bacterial counts of Veilonnella parvula, P. gingivalis, Streptococcus mutans, Actinomyces naeslundii, P. intermedia, and Capnocytophaga ochracea in the multispecies biofilm. Conclusions: Simvastatin showed antimicrobial and antibiofilm activity against oral bacteria and may contribute to the control of dysbiosis, and may be considered in clinical studies as an adjuvant in the treatment of periodontitis. [ABSTRACT FROM AUTHOR]

• Pravastatin treatment improved hypertension, oxidative stress, vascular increased contractility and pup weight in an experimental model of preeclampsia. • The pravastatin vascular improvements in contractility are more noticeable in the thoracic segment of the aorta and are dependent of the endothelium viability. 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. [ABSTRACT FROM AUTHOR]

Abstract Background Pravastatin is an oral lipid‐lowering drug, commonly used by patients with diabetes that is positively correlated with the occurrence of vascular calcification (VC), but the mechanism is unclear. Methods In this study, 16S rRNA sequencing and qRT‐PCR wereused to detect the differential gut bacteria. Metabolomics and ELISA were used to analyze the differential metabolites. qRT‐PCR and western blotting (WB) were used to detect genes expression. Flow cytometry was used to analyze macrophage phenotype. Immunohistochemistry was used to analyze aortic calcification. Results We found that gut Bacteroides fragilis (BF) increased significantly in patients who took pravastatin or type 2 diabetes (T2D) mice treated with pravastatin. In vitro experiments showed that pravastatin had little effect on BF but significantly promoted BF proliferation in vivo. Further analysis showed that ArsR was an important gene for pravastatin to regulate the activation of BF, and overexpression of ArsR significantly promoted the secretion of 3,4,5‐trimethoxycinnamic acid (TMCA). Importantly, pravastatin significantly promoted BF secretion of TMCA and significantly increased TMCA secretion in T2D patients or T2D mice. TMCA had little effect on vascular smooth muscle cell calcification but significantly promoted macrophage M1 polarization, which we had demonstrated that M1 macrophages promoted T2D VC. In vivo studies found that pravastatin significantly upregulated TMCA levels in the feces and serum of T2D mice transplanted with BF and promoted the macrophage M1 polarization in bone marrow and the osteoblastic differentiation of aortic cells. Similar results were obtained in T2D mice after intravenous infusion of TMCA. Conclusions Promoting intestinal BF to secrete TMCA, which leads to macrophage M1 polarization, is an important mechanism by which pravastatin promotes calcification, and the result will be used for the optimization of clinical medication strategies of pravastatin supplying a theoretical basis and experimental basis.

There are no effective therapies to prevent preeclampsia (PE). Pravastatin shows promise by attenuating processes associated with PE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction. Methods: Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with pravastatin (1 µg/mL), while others were cotreated with pravastatin and glucose. The expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) mRNA, vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured. CTB migration was assayed using a CytoSelect migration assay kit. Statistical comparisons were performed using an analysis of variance with Duncan’s post hoc test. Results: The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels > 200 mg/dL and cotreated at glucose levels > 300 mg/dL (p < 0.05). Hyperglycemia-induced decreases in VEGF and PlGF and increases in sEng and sFlt-1 were attenuated in both the pretreatment and cotreatment samples regardless of glucose dose (p < 0.05). Pravastatin attenuated hyperglycemia-induced dysfunction of CTB migration. Conclusions: Pravastatin mitigates stress signaling responses in hyperglycemic conditions, weakening processes leading to abnormal CTB migration and invasion associated with PE in pregnancy.

Objectives This study aimed to evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing PE and the maternal and perinatal outcomes and the soluble fms-like tyrosine kinase 1/placental growth factor (sFlt1/PlGF) ratio. Study Design This is an open-labeled randomized controlled trial (RCT), a part of INOVASIA (Indonesia Pravastatin to Prevent Preeclampsia study) trial. Pregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery Doppler examination at 10 to 20 weeks' gestational age. The control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20-mg twice daily) starting from 14 to 20 weeks' gestation until delivery. Research blood samples were collected before the first dose of pravastatin and before delivery. The main outcome was the rate of maternal PE, maternal–perinatal outcomes, and sFlt-1, PlGF, sFlt-1/PlGF ratio, and soluble endoglin (sEng) levels. Results The rate of PE was (nonsignificantly) lower in the pravastatin group compared with the control group (17.5 vs. 35%). The pravastatin group also had a (nonsignificant) lower rate of severe PE, HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, acute kidney injury, and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly (p = 0.048) lower in the pravastatin group (n = 4) compared with the controls (n = 12). Neonates in the pravastatin group had significantly higher birth weights (2,931 ± 537 vs. 2,625 ± 872 g; p = 0.006), lower Apgar's scores < 7 (2.5 vs. 27.5%, p = 0.002), composite neonatal morbidity (0 vs. 20%, p = 0.005), and NICU admission rates (0 vs. 15%, p = 0.026). All biomarkers show a significant deterioration in the control group compared with nonsignificant changes in the pravastatin group. Conclusion Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes by improving the angiogenic imbalance. Key Points Prophylactic pravastatin was associated with a significantly lower rate of adverse perinatal outcome. The sFlt1/PlGF ratio stabilized in the pravastatin group compared with a deterioration in the control group. Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Background: Compounding solid oral dosage forms into liquid preparations is a common practice for administering drug therapy to patients with swallowing difficulties. This is particularly relevant for those on enteral nutrition, where factors such as the administration procedure and co-administration of enteral nutrition play crucial roles in effective drug delivery. Due to the limited studies focused on this practice, the impact of co-administered nutrition remains unclear. Methods: Pravastatin tablets were compounded into two liquid formulations and administered through three independent tubes for ten cycles. The drug amount was quantified upstream and downstream of the tubes both with and without different (fiber content) nutritional boluses. Results: The compounding procedure did not lower the drug amount with respect to the original tablets. However, when the liquid formulation was pumped through the tubes, a statistically significant reduction in the pravastatin administered (between 4.6% and 11.3%) was observed. The co-administration of different nutritional boluses or the compounding procedure did not affect the general results. Conclusions: Pravastatin loss appears unavoidable when administered via the enteral tube. Although, in this case, the loss was of limited clinical relevance, it is important not to underestimate this phenomenon, especially with drugs having a narrow therapeutic index. [ABSTRACT FROM AUTHOR]

We investigated the effects of pravastatin (PRAVA) on isoprenaline (ISP) induced cardiac fibrosis using four groups of mice: untreated control, PRAVA, ISP, ISP + PRAVA groups. ISP, 20 mg/kg, was administered subcutaneously daily for 14 days. PRAVA, 20 mg/kg, was administered orally daily for 14 days. Mice were sacrificed on day15 and heart and blood samples were collected to investigate cardiac injury markers. The mean body weight for the ISP group on day 15 was decreased significantly compared to day 0; PRAVA increased the mean body weight slightly on day 15 of treatment compared to day 0. The heart:body weight ratio was increased in the ISP group compared to the control group, but the ratio was returned to near control ratio in the PRAVA + ISP group. The serum creatine kinase-myocardial band (CK-MB) level was reduced significantly in the PRAVA + ISP group compared to the ISP group. Serum triglyceride level was decreased significantly in ISP + PRAVA group compared to the ISP group. PRAVA administration significantly reduced tissue collagen I and III levels in the ISP + PRAVA group compared to the ISP group. Lipid oxidation was decreased and reduced glutathione activity was increased in the PRAVA + ISP group compared to the ISP group. IL-6, α-SMA, CTGF, TGF-β and SMAD-3 gene expressions were decreased in the PRAVA + ISP group compared to the ISP group. We found fewer inflammatory cells and less fibrosis in heart tissue in the PRAVA + ISP group compared to the ISP group. PRAVA decreased ISP induced cardiac fibrosis by reducing oxidative stress, collagen deposition and inflammation, as well as by decreasing expression of TGF-β, SMAD-3 and CTGF genes. [ABSTRACT FROM AUTHOR]

Rationale: Decision curve analysis (DCA) helps integrate prediction models with treatment assessments to guide personalised therapeutic choices among multiple treatment options. However, the current versions of DCA do not explicitly model treatment effects in the analysis but implicitly or holistically assess therapeutic benefits and harms. In addition, the existing DCA cannot allow the comparison of multiple treatments using a standard metric. Aims and Objectives: To develop a generalised version of DCA (gDCA) by decomposing holistically assessed net benefits and harms into patient preferences versus empirical evidence (as obtained in the trials, meta‐analyses of clinical studies, etc.) to allow individualised comparison of single or multiple treatments using a common metric. Methods: We reformulated DCA by (1) decomposing holistic, implicit utilities into specific utilities related to treatment effects and patient's relative values (RV) about disease outcomes versus treatment harms, (2) explicitly modelling each treatment effect at the level of probabilities and/or utilities (outcomes) in a decision tree, and (3) avoiding scaling effects employed in the original DCA to enable comparison of treatment effects against the common metrics. We used data from a published network meta‐analysis of randomised trials to inform the use of statin treatment according to Framingham Risk Model. Results: We illustrate the analysis by modelling the effects of three statins in the primary prevention of cardiovascular disease. We performed simultaneous comparisons against standard metrics (RV) for all treatments. We examined for which RV values, a predictive model for guiding personalised treatment, outperformed the strategies of treating everyone or treating no one. We found that the magnitude of benefits (efficacy) seems more important than the simple ratio of efficacy/harms. Conclusion: We describe gDCA for evaluating single or multiple treatments to help tailor therapy toward individual risk characteristics. gDCA further helps integrate the principles of evidence‐based medicine with decision analysis. [ABSTRACT FROM AUTHOR]

Background: While statin therapy is the preferred treatment for hyperlipidemia, literature supports the low-density lipoprotein (LDL) lowering effects associated with red yeast rice, berberine, and Silybum marianum. Dietary supplements may be perceived as a more affordable alternative to prescription medication. Objective: We determined cost-effectiveness of generic pravastatin versus single-ingredient dietary supplements in relation to LDL lowering effect. Methods: Data from meta-analyses and systematic reviews was extracted to calculate pooled weighted mean LDL differences amongst generic pravastatin and single ingredient dietary supplements. The effect was then divided by average 30-day costs and compared amongst agents. Results: The greatest difference was seen in pravastatin 40 mg [MD -57.88 mg/dL (95%CI: - 64.80 to −50.96)], followed by pravastatin 10 mg [MD -41.30 mg/dL (95%CI: 63.30 to - 19.40)], red yeast rice [MD -25.39 (95%CI: −32.98 to −17.81)], berberine [MD -15.13 (95%CI: −21.78 to −8.48)], and Silybum marianum [MD -9.51 mg/dL (95%CI: −22.13 to - 0.10)]. were divided by mean difference to calculate cost per mg/dL reduction in LDL. Cost-effectiveness was greatest for pravastatin 10 mg [$0.66/mg/dL LDL reduction (range: $0.39 to $1.13)], followed by pravastatin 40 mg [$0.74/mg/dL LDL reduction (range: $0.66 to $0.84)], berberine [$0.81/mg/dL LDL reduction (range: $0.56 to $1.44)], red yeast rice [$0.84/mg/dL reduction (range: $0.67 to $1.13)], and Silybum marianum [$0.88/mg/dL LDL reduction (range: $0.38 to $82.02)]. Conclusion: Pravastatin is most cost-effective in each scenario whether or not prescription insurance is utilized.

The primary intervention for pre-eclampsia (PE) remains iatrogenic delivery, which can be very preterm and not optimal for the fetus. Although many efforts have been made to prevent and manage PE, there is still a dearth of drugs to treat its pathophysiological progression. Pravastatin (PRA), a hydrophilic statin, has gained interest for the prevention and treatment of PE. The aim of the present study was to evaluate the ability of PRA to modulate factors involved in placentation, such as Epidermal Growth Factor-Like Domain 7 (EGFL7), in human chorionic villous culture from healthy controls and women with PE. A total of 18 women were enrolled: 10 controls and 8 cases. Chorionic villous explants were maintained in culture for 24 h with or without 10 μM Pravastatin, and the expression of EGFL7 and NOTCH1 pathway members was evaluated by qRT-PCR and Western blot analysis. The rationale of the present study was to establish an ex vivo model to identify potential different responses to PRA treatment of chorionic villous explants in order to clarify the molecular mechanism of PRA in the prevention and treatment of PE and to predict whether there are specific clinical conditions that modulate the response to the drug treatment. Within PE patients, two different groups were identified: the high responders, whose villous cultures exhibit significantly increased expressions of the EGFL7 and Notch pathways after PRA incubation; and the low responders, who are high-risk PE patients in which prophylaxis failed to prevent PE and PRA was not able to modulate EGFL7 expression. In conclusion, we identified EGFL7 as a new factor regulated by PRA, placing interest in early discrimination between low- and high- risk women, in which the well-known pharmacological prophylaxis seems to be ineffective, and to explore new potential prevention strategies.

BACKGROUND: Statin treatment has decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid level is higher in patients with acute coronary syndrome. This study aimed to evaluate the effect of pravastatin on the erythrocyte membrane fatty acid (FA) contents in patients with CKD. METHODS: Sixty-two patients were enrolled from January 2017 to March 2019 (NCT02992548). Pravastatin was initially administered at a dose of 20 mg for 24 weeks. The pravastatin dose was increased to 40 mg after 12 weeks if it was necessary to control dyslipidemia. The primary outcome was change in erythrocyte membrane FA, including oleic acid, after pravastatin treatment for 24 weeks. RESULTS: Forty-five patients finished this study, and there was no adverse effect related to pravastatin. Compared with baseline, total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased after pravastatin treatment. Compared with baseline, saturated FA, oleic acid, and arachidonic acid levels were significantly increased and polyunsaturated FA and linoleic acid (LA) levels were significantly decreased after pravastatin treatment. There was also a decrease in eicosapentaenoic acid after pravastatin treatment in CKD patients with estimated glomerular filtration rate

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. [ABSTRACT FROM AUTHOR]

Throughout the history of medicine, preeclampsia has remained an enigmatic field of obstetrics. In 2023, despite its prevalence and impact, preeclampsia's exact cause and effective treatment remain elusive; the current options are limited to delivery. The purpose of this review is to summarize the knowledge of the possible novel prophylactic therapies and screening methods for preeclampsia, thereby providing valuable insights for healthcare professionals and researchers. Aspirin and LMWH have already been widely used; meanwhile, calcium, vitamin D, and pravastatin show promise, and endothelin receptor antagonists are being explored. Stress reduction, dietary changes, and lifestyle modifications are also being investigated. Another interesting and fast-growing area is AI- and software-based screening methods. It is also key to find novel biomarkers, which, in some cases, are not only able to predict the development of the disease, but some of them hold promise to be a potential therapeutic target. We conclude that, while a definitive cure for preeclampsia may not be eligible in the near future, it is likely that the assessment and enhancement of preventive methods will lead to the prevention of many cases. However, it is also important to highlight that more additional research is needed in the future to clarify the exact pathophysiology of preeclampsia and to thus identify potential therapeutic targets for more improved treatment methods. [ABSTRACT FROM AUTHOR]

Background: Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence of VTE. Aims: To perform a network meta-analysis to determine which lipid-lowering agent was more efficacious in and had more evidence regarding reducing the VTE risk. Study Design: Network meta-analysis of the randomized controlled trials (RCTs). Methods: RCTs that assessed the effectiveness and safety of statins or fibrates and compared them to a placebo or another statin were eligible for the study. The outcomes examined in the study were deep vein thrombosis, pulmonary embolism, and/or VTE. We conducted a comprehensive search of the Medline database from 1966 to February 2017, using specific search terms related to VTE and statins. Additionally, we screened, and cross-checked relevant systematic reviews and meta-analyses. We performed a network meta-analysis to compare the different lipid-lowering agents to each other and the placebo and their effectiveness. Results: Twenty-seven RCTs were included in the network meta-analysis (n = 137,940). Pairwise meta-analysis revealed a statistically significant lower incidence of VTE with statins than with placebos (0.79% vs 0.99%, respectively; risk ratios: 0.87, 0.77-0.98; p = 0.022). Rosuvastatin had the most favorable effect in reducing VTE risk than the other statins, fenofibrate, and placebo. Fenofibrate was ranked the worst drug choice, because it increased risk of VTE when compared with the other statins. Rosuvastatin was the best choice for reducing the VTE risk when compared with the placebo (OR: 0.56, 0.42-0.75), atorvastatin (OR: 0.64, 0.44-0.95), pravastatin (OR: 0.50, 0.34-0.74), simvastatin (OR: 0.60, 0.42-0.86) and fenofibrate (OR: 0.37, 0.25-0.56). Compared with a placebo, rosuvastatin reduced the VTE risk by around 45% and fenofibrate increased the risk by 65%. Conclusion: Rosuvastatin is significantly reduces the risk of VTE when compared with a placebo, other statin subtypes, and fibrate. Furthermore, fenofibrate increased the VTE risk when compared with a placebo and statins. [ABSTRACT FROM AUTHOR]

[Figure: see text].

Abstract Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims.

Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia. Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (No EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cellspecific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers. Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001). Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease. [ABSTRACT FROM AUTHOR]

Background: The "coronary heart disease risk equivalent" of diabetes is now widely accepted as a medical fact. This is mostly attributable to the prevalence of dyslipidemia in the diabetic population, which is thought to be a primary contributor to the disproportionately high number of fatalities in this group caused by cardiovascular disease. Aim and objectives: To compare the efficacy and safety of rosuvastatin, atorvastatin and pravastatin among dyslipidemic diabetic patients. Materials and methods: 90 men and women with type II diabetes. People were divided up into groups. Atorvastatin 20 mg was given to Group 1 patients, rosuvastatin 20 mg was given to Group 2, and pravastatin 20 mg was given to Group 3. Total cholesterol, good cholesterol (HDL), bad cholesterol (LDL), and triglyceride (TG) levels were all assessed. The metric for safety was also evaluated. Results: In groups 1, 2, and 3, the mean percent reduction in LDL was -20.02, -30.78, and -11.02, respectively. TG was reduced by -20.87, - 26.11, and -13.22 in groups 1, 2, and 3, respectively. TC was -14.11, -23.14, and -16.14 in groups 1, 2, and 3, respectively, and the percentage increase in HDL was -6.55, -5.11, and -6.41 in groups 1, 2, and 3, respectively. The difference was significant (P< 0.05). No patients in the current study showed elevated ALT levels greater than 3, the upper limit of normal. So far, none of the statins used in the study have been associated with any adverse events that could have affected hepatic function. Conclusion: Rosuvastatin, in contrast to atorvastatin and pravastatin, was shown to be the most effective statin in lowering LDL-C. [ABSTRACT FROM AUTHOR]

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing. [ABSTRACT FROM AUTHOR]

Water clover (Marsilea crenata C. Presl.) is a widely available plant in Indonesia and often utilized as a traditional food ingredient. This plant is also traditionally believed to contain compounds that can decrease blood cholesterol. This study aimed to determine the compounds in water clover which have the potential to decrease blood cholesterol through inhibition of the HMG-CoA enzyme using in silico approach. This research was done in several steps, i.e., extraction using ethyl acetate solvent, identification of chemical compounds using GC-MS, and screening of compounds with potential to be a nticholesterolemic agent through in silico using PyRx 0.8 (AutoDockVina and Open Babel GUI version 2.4.1), Discovery Studio Visualizer 2021, and PyMOL™ 1.7.4.5 software. Results showed that ethyl acetate extract of water clover contained 26 compounds, 6 of which were potential to be anticholesterolemic agent, i.e., phytol, 1,2-benzenedicarboxylic acid, 2,4-di-tert-butylphenol, diethyl phthalate, 1,2,3,4-tetramethylbenzene, and dipentene. Binding affinity values of those six compounds were lower than the native ligand of the HMG-CoA reductase, although still higher compared to pravastatin. The binding affinity value of pravastatin was -7.13 kcal/mol and the binding affinity value of 3-methyl glutaric acid as a native ligand was -5.33 kcal/mol, meanwhile, the lowest binding affinity value of compounds in water clover was phytol (-6.37 kcal/mol) and the highest was dipentene (-5.40 kcal/mol). Through in silico study, there were six compounds from water clover leaf's ethyl acetate extract that could inhibit the HMG-CoA reductase. Therefore, water clover leaf has the potential to become an anticholesterolemic functional food ingredient. [ABSTRACT FROM AUTHOR]

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8–10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12–14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1. [ABSTRACT FROM AUTHOR]

• Preeclampsia is the leading cause of premature delivery worldwide. • Pravastatin given in the second trimester may increase the duration of early severe preeclampsia. • Our data suggest a role of pravastatin in stabilizing the progression of preeclampsia. • No differences in infant follow-up are observed between treated and not-treated pregnancies. Preeclampsia (PE) is the major cause of maternal morbidity and mortality and the leading cause of premature delivery worldwide. As well as intrauterine growth restriction (IUGR), PE is associated with pathogenic evidence of placental malperfusion and ischemia. Recent literature has highlighted the potential of pravastatin in the prevention and treatment of these conditions. Aim of this study is to describe perinatal outcomes and placental histopathological findings in a small series of pregnant women with severe PE and IUGR treated with pravastatin on compassionate grounds. Two-year follow up of these babies is provided. Between October 2017 and October 2019 in Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy, women with singleton pregnancy between 19.6 and 27.6 gestational weeks, who presented with severe PE and IUGR were counselled for a compassionate treatment with Pravastatin 40 mg a day. Treated women were compared with controls identified with similar data in terms of gestational age at diagnosis, clinical maternal data, Doppler severity findings. Neonates were followed up for two years. The median time from diagnosis to delivery was 39 days (IQR 20) for women in the pravastatin group and 20 days (IQR 20.5) for controls. Looking to maternal blood exams, in the group of women treated with pravastatin, maximum transaminase, creatinine levels were lower than in controls, where the minimum platelet count was higher. Placenta examination did not reveal any significant differences in placental histopathological findings. No significant differences were observed in the investigated perinatal data, as well as in infant follow-up, although an increased prenatal weight gain was found in treated pregnancies in comparison to controls. Our data did not allow us to find significant differences in pregnancy outcome and infant follow-up, as well as in placental histological picture in preeclamptic patients when pravastatin is administered in the late second trimester. However, we suggest its possible role in stabilizing the disease, increasing the prenatal weight gain and prolonging the duration of pregnancy, thus preventing the progression to a more severe maternal disease. [ABSTRACT FROM AUTHOR]

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy and has been associated with placental growth restriction. The pre-eclamptic placenta releases free radicals to maternal circulation, thus increasing oxidative stress. An impaired redox state leads to reduction in circulating nitric oxide (NO) levels and activation of extracellular matrix metalloproteinases (MMPs). However, activation of MMPs induced by oxidative stress is still unclear in PE. Antioxidant effects have been demonstrated with the use of pravastatin. Therefore, we hypothesized that pravastatin protects against oxidative stress-induced activation of MMPs in a rat model of PE. The animals were divided into four groups: normotensive pregnant rats (Norm-Preg); pregnant rats treated with pravastatin (Norm-Preg + Prava); hypertensive pregnant rats (HTN-Preg); and hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava). The deoxycorticosterone acetate (DOCA) and sodium chloride (DOCA-salt) model was used to induce hypertension in pregnancy. Blood pressure, and fetal and placental parameters were recorded. The gelatinolytic activity of MMPs, NO metabolites and lipid peroxide levels were also determined. Endothelium function was also examined. Pravastatin attenuated maternal hypertension, prevented placental weight loss, increased NO metabolites, inhibited increases in lipid peroxide levels, and reduced the activity of MMP-2, and these effects were observed along with enhanced endothelium-derived NO-dependent vasodilation. The present results provide evidence that pravastatin protects against activation of MMP-2 induced by oxidative stress in pre-eclamptic rats. These findings may also involve improvement in endothelial function related to NO and antihypertensive effects of pravastatin, thus suggesting pravastatin as a therapeutic intervention for PE. [ABSTRACT FROM AUTHOR]

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 (μHbO2) 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 µHbO2 in liver and colon deteriorated over time (µHbO2: −9.8 ± 7.5%* and −7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment μHbO2 remained constant (liver: µHbO2 pravastatin: −4.21 ± 11.7%, pravastatin + GW6471: −0.08 ± 10.3%; colon: µHbO2 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. [ABSTRACT FROM AUTHOR]

Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p =.004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p =.0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims. [ABSTRACT FROM AUTHOR]

Introduction: Elevated plasma levels of extracellular vesicles have been associated with impaired placentation, angiogenesis imbalance, intravascular inflammation, and endothelial dysfunction in women with preeclampsia, thus suggesting that circulating vesicles may be a good therapeutic target for the treatment of the disease. Recently, statins have been considered a potential treatment for the prevention of preeclampsia because of their pleiotropic effects, including the improvement of endothelial dysfunction and inhibition of inflammatory responses. However, the effects of these drugs on circulating vesicles concentration in women at risk of preeclampsia have not been established. Herein, we aimed to assess the effects of pravastatin on circulating extracellular vesicle generation in women at high risk of term preeclampsia.Methods: In a sample of 68 singleton pregnant women participating in the multicenter, double-blind, placebo-controlled STATIN trial (Nº EducraCT 2016-005206-19 ISRCTN), 35 women received a placebo and 33 women received a 20 mg/day dose of pravastatin for approximately 3 weeks (from 35 to 37 weeks of gestation until delivery). Large extracellular vesicles were characterized and quantified by flow cytometry using annexin V and cell-specific antibodies directed against platelet, endothelial, leukocyte, and syncytiotrophoblast cell surface markers.Results: In women who received the placebo, a significant increase in the plasma levels of large extracellular vesicles from platelets (34%, p < 0.01), leukocytes (33%, p < 0.01), monocytes (60%, p < 0.01), endothelial cells (40%, p < 0.05), and syncytiotrophoblast cells (22%, p < 0.05) were observed. However, treatment with pravastatin significantly reduced the plasma levels of large extracellular vesicles from platelets (42%, p < 0.001), leukocytes (25%, p < 0.001), monocytes (61%, p < 0.001), endothelial cells (69%, p < 0.001), activated endothelial cells (55%, p < 0.001), and syncytiotrophoblast cells (44%, p < 0.001).Discussion: These results indicate that pravastatin reduces the levels of activated cell-derived membrane vesicles from the maternal vasculature, blood, and placental syncytiotrophoblast of women at high risk of term preeclampsia, suggesting that this statin may be beneficial in reducing endothelial dysfunction and pro-inflammatory and pro-coagulatory state characteristics of the disease.

Understanding transporter-mediated drug-drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)-I, and CP-III as clinical biomarkers for evaluating organic anion-transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1-Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP-I, and CP-III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) was similar among the four biomarkers (1.8-2.5-fold, paired t-test P value C genotype is significantly associated with CP-I but not CP-III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.

Accurately predicting hepatic clearance is an integral part of the drug-development process, and yet current in vitro to in vivo (IVIVE) extrapolation methods yield poor predictions, particularly for highly protein-bound transporter substrates. Explanations for error include inaccuracies in protein-binding measurements and the lack of recognition of protein-facilitated uptake, where both unbound and bound drug may be cleared, violating the principles of the widely accepted free drug theory. A new explanation for protein-facilitated uptake is proposed here, called a transporter-induced protein binding shift High-affinity binding to cell-membrane proteins may change the equilibrium of the nonspecific binding between drugs and plasma proteins, leading to greater cellular uptake and clearance than currently predicted. The uptake of two lower protein-binding organic anion transporting polypeptide substrates (pravastatin and rosuvastatin) and two higher binding substrates (atorvastatin and pitavastatin) were measured in rat hepatocytes in incubations with protein-free buffer versus 100% plasma. Decreased unbound K m values and increased intrinsic clearance values were seen in the plasma incubations for the highly bound compounds, supporting the new hypothesis and mitigating the IVIVE underprediction previously seen for highly bound transporter substrates.

PURPOSE:To compare effects of lipid-soluble statins (simvastatin, lovastatin, atorvastatin) and water-soluble statin (pravastatin) on growth and invasiveness of human endometrial stromal (HES) cells. METHODS:Endometrial biopsies were collected during the proliferative phase from five volunteers. HES cells were isolated and cultured in the absence or in the presence of simvastatin, lovastatin, atorvastatin, and pravastatin. Effects of statins on DNA synthesis, cell viability, activity of caspases 3/7 and invasiveness were evaluated. RESULTS:The proliferation of HES cells was significantly decreased by simvastatin (by 47-89%), lovastatin (by 46-78%), and atorvastatin (by 21-48%) in a concentration-dependent manner. Activity of executioner caspases 3/7 was significantly increased by simvastatin (by 10-25%), lovastatin (by 19%) and atorvastatin (by 7-10%) in a concentration-dependent manner. The greatest effects were observed in response to simvastatin. Accounting for the effects of statins on cell number, the invasiveness of HES cells was significantly decreased in cells treated with simvastatin (by 49%), lovastatin (by 54%), and atorvastatin (by 53%). Pravastatin had little or no effects on any of the tested endpoints. CONCLUSIONS:Present findings demonstrate that only lipid-soluble among tested statins were effective in inhibition of growth and invasiveness of HES cells. These findings may have clinical relevance in treatment of endometriosis.

Statins, which reduce LDL-cholesterol by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are among the most widely prescribed drugs. Skeletal myopathy is a known statin-induced adverse effect associated with mitochondrial changes. We hypothesized that similar effects would occur in cardiac myocytes in a lipophilicity-dependent manner between 2 common statins: atorvastatin (lipophilic) and pravastatin (hydrophilic). Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48 h. Both statins induced endoplasmic reticular (ER) stress, but only atorvastatin inhibited ERK1/2T202/Y204, AktSer473, and mammalian target of rapamycin signaling; reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor, and insulin receptor-β; decreased Ras homolog gene family member A activation; and induced apoptosis. In cardiomyocyte-equivalent HL-1 cells, atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption. When male mice underwent atorvastatin and pravastatin administration per os for up to 7 mo, only long-term atorvastatin, but not pravastatin, induced elevated serum creatine kinase; swollen, misaligned, size-variable, and disconnected cardiac mitochondria; alteration of ER structure; repression of mitochondria- and endoplasmic reticulum-related genes; and a 21% increase in mortality in cardiac-specific vinculin-knockout mice during the first 2 months of administration. To our knowledge, we are the first to demonstrate in vivo that long-term atorvastatin administration alters cardiac ultrastructure, a finding with important clinical implications.-Godoy, J. C., Niesman, I. R., Busija, A. R., Kassan, A., Schilling, J. M., Schwarz, A., Alvarez, E. A., Dalton, N. D., Drummond, J. C., Roth, D. M., Kararigas, G., Patel, H. H., Zemljic-Harpf, A. E. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes.