BACKGROUND: Fatty acid oxidation (FAO) disorder is involved in the pathogenesis of some cases of preeclampsia (PE). Several studies show that mammalian target of rapamycin (mTOR) signaling pathway is related to FAO. Pravastatin (Pra) can promote FAO in Nω-nitro-L-arginine methyl ester (L-NAME) PE-like mouse model in our previous study. This study aimed to investigate the effect of mTOR signaling pathway in PE-like model treated with Pra. METHODS: Pregnant mice were randomly injected with L-NAME as PE-like model group or saline as control group respectively, from gestational 7th to 18th day. Giving Pra (L-NAME + Pra, Control + Pra, n = 8) or normal saline (NS; L-NAME + NS, Control + NS, n = 8) from gestational 8th to 18th day, the mice were sacrificed on day 18 and their liver and placental tissues were collected. Then the activation of mTOR and its substrates in the liver and placenta were detected. And the association between mTOR activation and serum free fatty acid (FFA) levels and the expression of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) were evaluated using Pearson correlation test. Differences between groups were analyzed using independent t-test or one-way analysis of variance (ANOVA). RESULTS: Both in the maternal liver and placenta, the activation of mTOR protein and its effect on substrates increased significantly in the L-NAME + NS group and decreased significantly in the L-NAME + Pra group. The p-mTOR/mTOR protein ratio decreased in the L-NAME + Pra group significantly than that in the L-NAME + NS group both in liver and placenta (liver: 0.74 ± 0.08 vs. 0.85 ± 0.06, t = 2.95, P < 0.05; placenta: 0.63 ± 0.06 vs. 0.77 ± 0.06, t = 4.64, P < 0.05). The activation of mTOR protein in the liver and placenta negatively correlated with the expression of LCHAD in the L-NAME + NS group (liver: r = -0.745, P < 0.05; placenta: r = -0.833, P < 0.05) and that in the maternal liver negatively correlated with the expression of LCHAD (r = -0.733, P < 0.05) and positively with the serum FFA levels (r = 0.841, P < 0.05) in the L-NAME + Pra group. CONCLUSION The inhibition of mTOR signaling pathway might be involved in the regulation of FAO in mouse model treated with Pra.
Animals ; Blotting, Western ; Fatty Acids ; metabolism ; Female ; Immunohistochemistry ; Liver ; drug effects ; metabolism ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction ; drug effects ; Placenta ; drug effects ; metabolism ; Pravastatin ; therapeutic use ; Pre-Eclampsia ; drug therapy ; Pregnancy ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; metabolism

BACKGROUND/AIMS: The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma. METHODS: High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed. RESULTS: HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice. CONCLUSIONS: These results suggest that the IL-17–leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.
Adipokines ; Adipose Tissue ; Animals ; Asthma* ; Bronchoalveolar Lavage Fluid ; Cell Differentiation ; Diet, High-Fat ; Goblet Cells ; Humans ; Inflammation* ; Interleukin-17 ; Mice ; Obesity ; Ovalbumin ; Ovum ; Oxidoreductases ; Pravastatin ; Respiratory Hypersensitivity ; Spleen

BACKGROUND: There has been evidences of ethnic differences in the low density lipoprotein cholesterol (LDL-C) lowering effect of statin. We aimed to evaluate the efficacy of moderate-intensity statins in the treatment of dyslipidemia among Korean patients with type 2 diabetes mellitus (T2DM). METHODS: We analyzed a retrospective cohort that consisted of Korean patients with T2DM aged 40 to 75 years who had been prescribed any of the moderate-intensity statins (atorvastatin 10 or 20 mg, rosuvastatin 5 or 10 mg, pitavastatin 2 mg, or pravastatin 40 mg). Among them, only patients with baseline lipid profiles before starting statin treatment were selected, and changes in their lipid profiles before and 6 months after statin therapy were analyzed. RESULTS: Following the first 6 months of therapy, the overall LDL-C reduction was −47.4% (interquartile range, −56.6% to −34.1%). In total, 92.1% of the participants achieved an LDL-C level of <100 mg/dL, 38.3% had a 30% to 50% reduction in their LDL-C levels, and 42.3% had a reduction in their LDL-C levels greater than 50%. The response rates of each drug for achieving a LDL-C level <100 mg/dL were 81.7%, 93.1%, 95.0%, 95.0%, 96.5%, and 91.7% for treatment with atorvastatin doses of 10 or 20 mg, rosuvastatin 5 or 10 mg, pitavastatin 2 mg, and pravastatin 40 mg, respectively. CONCLUSION: In conclusion, the use of moderate-intensity statins reduced LDL-C levels less than 100 mg/dL in most of the Korean patients studied with T2DM. The efficacies of those statins were higher than expected in about 42% of Korean patients with T2DM.
Atorvastatin Calcium ; Cholesterol, LDL ; Cohort Studies ; Diabetes Mellitus, Type 2* ; Dyslipidemias* ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Pravastatin ; Retrospective Studies ; Rosuvastatin Calcium

Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resistance and endothelial dysfunction. Dysregulation of the renin-angiotensin system is an important pathophysiological mechanism linking insulin resistance and endothelial dysfunction to atherogenesis. Statins are the reference standard treatment to prevent CV disease in patients with hypercholesterolemia. Statins work best for secondary CV prevention. Unfortunately, most statin therapies dose-dependently cause insulin resistance, increase new onset diabetes risk and exacerbate existing type 2 diabetes mellitus. Pravastatin is often too weak to achieve target low-density lipoprotein cholesterol levels despite having beneficial metabolic actions. Renin-angiotensin system inhibitors improve both endothelial dysfunction and insulin resistance in addition to controlling blood pressure. In this regard, combined statin-based and renin-angiotensin system (RAS) inhibitor therapies demonstrate additive/synergistic beneficial effects on endothelial dysfunction, insulin resistance, and other metabolic parameters in addition to lowering both cholesterol levels and blood pressure. This combined therapy simultaneously reduces CV events when compared to either drug type used as monotherapy. This is mediated by both separate and interrelated mechanisms. Therefore, statin-based therapy combined with RAS inhibitors is important for developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity. This combined therapy can help prevent or treat CV disease while minimizing adverse metabolic consequences.
Atherosclerosis ; Blood Pressure ; Cardiovascular Diseases ; Cholesterol ; Diabetes Mellitus, Type 2 ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Hypercholesterolemia ; Hypertension ; Insulin Resistance ; Lipoproteins ; Metabolic Diseases ; Obesity ; Pravastatin ; Renin-Angiotensin System ; Risk Factors

BACKGROUND: The effect of pravastatin on insulin resistance (IR) is controversial and poorly studied in prediabetes. METHODS: This study was performed in hyperglycemic patients at Saint Carollo Hospital from January 1, 2013 to December 31, 2015. Among them, we selected 40 patients (24 prediabetes and 16 new onset diabetes [NOD]) who had been treated with pravastatin 20 mg daily for 2 or 4 months and in whom fasting insulin and fasting glucose had been measured before and after administration of pravastatin. IR was defined as a fasting insulin level ≥ 12.94 µU/mL, homeostasis model for IR (HOMA-IR) ≥ 3.04 or quantitative insulin sensitivity check index (QUICKI) ≤ 0.32. RESULTS: Pravastatin treatment decreased total cholesterol and low-density lipoprotein cholesterol levels by 25.2% and 32.3% respectively (P = 0.000 for all), but did not affect fasting insulin level, HOMA-IR, or QUICKI in total, prediabetes, and NOD groups. Prevalence of IR was significantly different between prediabetes and NOD groups both before and after pravastatin treatment (0% versus 37.5%, P = 0.001), but pravastatin treatment did not affect the prevalence of IR in the prediabetes or NOD group. Fasting glucose level was not significantly different before and after pravastatin treatment in prediabetes (106.8 ± 6.4 mg/dL versus 103.8 ± 8.4 mg/dL, P = 0.223) but was significantly different in the NOD group (171.5 ± 70.1 mg/dL versus 124.4 ± 26.7 mg/dL, P = 0.017). CONCLUSION: Pravastatin treatment did not affect IR or fasting glucose level in hyperglycemic patients. Therefore, we suggest pravastatin can be prescribed to hypercholesterolemic patients with hyperglycemia.
Cholesterol ; Fasting ; Glucose ; Homeostasis ; Humans ; Hyperglycemia ; Insulin Resistance* ; Insulin* ; Lipoproteins ; Pravastatin* ; Prediabetic State ; Prevalence ; Saints

BACKGROUND: Non-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO) and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH), but underlying mechanisms of this prevention are largely unknown. METHODS: Seven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD) with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day), for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver. RESULTS: Statin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα) were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels. CONCLUSION: Statins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.
Animals ; Atorvastatin Calcium ; Catalase ; Cholesterol ; Developed Countries ; Diet ; Fatty Liver* ; Fibrosis ; Gene Expression ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Inflammation ; Liver Diseases ; Liver* ; Metabolism ; Mice* ; Non-alcoholic Fatty Liver Disease ; Organelles ; Peroxisomes ; Pravastatin ; Reactive Oxygen Species ; Rosuvastatin Calcium ; Simvastatin

PURPOSE: The effects of short-term intensive lipid-lowering treatment on coronary plaque composition have not yet been sufficiently evaluated. We investigated the influence of short-term intensive lipid-lowering treatment on quantitative and qualitative changes in plaque components of non-culprit lesions in patients with acute coronary syndrome. MATERIALS AND METHODS: This was a prospective, randomized, open-label, single-center trial. Seventy patients who underwent both baseline and three-month follow-up virtual histology intravascular ultrasound were randomly assigned to either an intensive lipid-lowering treatment group (ezetimibe/simvastatin 10/40 mg, n=34) or a control statin treatment group (pravastatin 20 mg, n=36). Using virtual histology intravascular ultrasound, plaque was characterized as fibrous, fibro-fatty, dense calcium, or necrotic core. Changes in plaque components during the three-month lipid-lowering treatment were compared between the two groups. RESULTS: Compared with the control statin treatment group, there was a significant reduction in low-density lipoprotein cholesterol in the intensive lipid-lowering treatment group (-20.4±17.1 mg/dL vs. -36.8±17.4 mg/dL, respectively; p<0.001). There were no statistically significant differences in baseline, three-month follow-up, or serial changes of gray-scale intravascular ultrasound parameters between the two groups. The absolute volume of fibro-fatty plaque was significantly reduced in the intensive lipid-lowering treatment group compared with the control group (-1.5±3.4 mm3 vs. 0.8±4.7 mm3, respectively; p=0.024). A linear correlation was found between changes in low-density lipoprotein cholesterol levels and changes in the absolute volumes of fibro-fatty plaque (p<0.001, R2=0.209). CONCLUSION: Modification of coronary plaque may be attainable after only three months of intensive lipid-lowering treatment.
Aged ; Cholesterol, LDL/*blood/drug effects ; Coronary Artery Disease/*diagnostic imaging ; Drug Administration Schedule ; Ezetimibe, Simvastatin Drug Combination/*administration & dosage ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*administration & dosage ; Male ; Middle Aged ; Plaque, Atherosclerotic/*diagnostic imaging ; Pravastatin/administration & dosage ; Prospective Studies ; Time Factors ; Treatment Outcome ; Ultrasonography, Interventional

PURPOSE: To evaluate the effect of statin treatment on strut coverage after drug-eluting stent (DES) implantation. MATERIALS AND METHODS: In this study, 60 patients were randomly assigned to undergo sirolimus-eluting stent (SES) or biolimus-eluting stent (BES) implantation, after which patients were randomly treated with pitavastatin 2 mg or pravastatin 20 mg for 6 months. The degree of strut coverage was assessed by 6-month follow-up optical coherence tomography, which was performed in 52 DES-implanted patients. RESULTS: The percentages of uncovered struts were 19.4+/-14.7% in pitavastatin-treated patients (n=25) and 19.1+/-15.2% in pravastatin-treated patients (n=27; p=0.927). A lower percentage of uncovered struts was significantly correlated with a lower follow-up low-density lipoprotein (LDL) cholesterol level (r=0.486; p=0.009) and a greater decline of the LDL cholesterol level (r=-0.456; p=0.015) in SES-implanted patients, but not in BES-implanted patients. In SES-implanted patients, the percentage of uncovered struts was significantly lower among those with LDL cholesterol levels of less than 70 mg/dL after 6 months of follow-up (p=0.025), but no significant difference in this variable according to the follow-up LDL cholesterol level was noted among BES-implanted patients (p=0.971). CONCLUSION: Lower follow-up LDL cholesterol levels, especially those less than 70 mg/dL, might have a protective effect against delayed strut coverage after DES implantation. This vascular healing effect of lower LDL cholesterol levels could differ according to the DES type.
Adult ; Coronary Angiography ; *Drug-Eluting Stents ; Female ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Lipoproteins, LDL/blood ; Male ; Middle Aged ; Pravastatin/therapeutic use ; *Prosthesis Implantation ; Quinolines/therapeutic use ; Tomography, Optical Coherence ; Treatment Outcome

OBJECTIVETo prepare pravastatin sodium-loaded chitosan microspheres to allow sustained drug release.

METHODSThe drug-loaded chitosan microspheres were prepared by using genipin as the cross-linker. The influences of molecular weight of chitosan, volume ratio of oil and water, reaction temperature, and stirring speed on the formation of chitosan microspheres were investigated. The morphology of the microspheres was observed using scanning electron microscopy. The encapsulation efficiency, swelling ratio under different pH conditions, and in vitro drug release were measured.

RESULTSThe in vitro release of pravastatin sodium could last for at least 31 days. The drug release rate varied with the reaction condition. The drug entrapment efficiency of the microsphere was 54.7%. The optimal processing conditions were as follows: chitosan viscosity of 200-400 mPa·s, oil-water proportion of 10:1, stirring speed of 850 r/min, and reaction temperature at 40 degrees celsius;.

CONCLUSIONThe pravastatin sodium-loaded microspheres show good sustained drug release property, and the drug release rate can be modified by controlling the cross-linking time.

Stevens-Johnson syndrome (SJS) manifests with severe cutaneous reactions, most commonly triggered by medications, which are characterized by fever and mucocutaneous lesions leading to necrosis and sloughing of the epidermis. To our knowledge, pravastatin-induced SJS has not yet been reported. Here, we describe a case of SJS due to pravastatin, which was diagnosed by a patch test. A 70-year-old woman presented with maculopapular skin rashes, which developed 2 weeks after medication of bisoprolol, amlodipine, pravastatin, spironolactone, and indobufene for cardiac problems. Various bullous-erosive mucocutaneous lesions occupied less than 10% of the total body surface area. Painful oropharyngeal mucous membrane lesions were observed. The vermilion border of the lips became denuded and developed serosanguinous crusts. With the drug withdrawal and the use of systemic corticosteroids, her manifestations resolved. Drug patch tests with bisoprolol, amlodipine, pravastatin, spironolactone, and indobufene were performed, resulting in a positive reaction to pravastatin, but not to the other drugs. To the best of our knowledge, this is the first case of pravastatin-induced SJS.
Adrenal Cortex Hormones ; Aged ; Amlodipine ; Bisoprolol ; Body Surface Area ; Epidermis ; Exanthema ; Female ; Fever ; Humans ; Lip ; Mucous Membrane ; Necrosis ; Patch Tests ; Pravastatin ; Spironolactone ; Stevens-Johnson Syndrome*