Efficacy and Mechanism of Qianshan Huoxue Gao in Acute Coronary Syndrome via Regulation of Intestinal Flora and Metabolites.

Purpose: To study the efficacy of Qianshan Huoxue Gao (QS) in treating acute coronary syndrome (ACS) and to explore the mechanism of action from the perspective of intestinal flora regulation. Methods: Male Sprague-Dawley rats were divided into control, model, QS, and atorvastatin groups; except for the control group, rats underwent ligation of the left anterior descending branch of the coronary artery. Following treatment for 28 days, cardiac function was evaluated using an echocardiographic assay; ELISAs for serum creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-2 (IL-2), IL-6, and tumor necrosis factor-α (TNF-α); assessment of cardiac enzymes and inflammatory response; hematoxylin and eosin (HE) staining for histopathological changes in the heart, skin, and viscera; 16S rRNA gene sequencing for intestinal flora diversity and structural differences analysis; and we further investigated intestinal contents using metabolomics. Results: Compared with controls, CK-MB and cTnI were increased (P<0.01); ejection factor and fractional shortening were decreased (P<0.01); left ventricular internal end-diastolic dimension and left ventricular internal end-systolic dimension were increased (P<0.01); and IL-2, IL-6, TNF-α, and hs-CRP were increased in the model group. Myocardial damage and inflammation were also observed by HE staining. QS improved these indexes, similar to the atorvastatin group; therefore, QS could effectively treat ACS. QS modulates the structure and abundance of the intestinal flora in ACS model rats, among which Bacteroides, Lactobacillus, and Rikenellaceae_RC9_gut_group are associated with cardiovascular disease. Metabolomics revealed that the intestinal metabolite content changed in ACS, with ethanolamine (EA) being the most relevant metabolite for ACS treatment by QS. EA was significantly positively correlated with Eubacterium xylanophilum group, Ruminococcus, unclassified f__Oscillospiraceae, Intestinimonas, Eubacterium siraeum group, Lachnospiraceae NK4A136 group, and norank f__Desulfovibrionaceae. Conclusion: QS can effectively treat ACS and can restore regulation of the intestinal flora. EA may be the primary metabolite of QS, exerting a therapeutic effect in ACS.

Machine-learning-based analysis of the sensitivity and specificity on lipid-lowering effect of one-month-administered statins.

Few predictive studies have been reported on the efficacy of atorvastatin in reducing lipoprotein cholesterol to be qualified after 1-month course of treatment in different individuals. A total of 14,180 community-based residents aged ≥ 65 received health checkup, 1013 of whom had low-density lipoprotein (LDL) higher than 2.6mmol/L so that they were put on 1-month course of treatment with atorvastatin. At its completion, lipoprotein cholesterol was measured again. With < 2.6 mmol/L considered as the treatment standard, 411 individuals were judged as the qualified group, and 602, and as the unqualified group. The basic sociodemographic features covered 57 items. The data were randomly divided into train sets and test ones. The recursive random-forest algorithm was applied to predicting the patients response to atorvastatin, the recursive feature elimination method, to screening all the physical indicators. The overall accuracy, sensitivity and specificity were calculated, respectively, and so were the receiver operator characteristic curve and the area under the curve of the test set. In the prediction model on the efficacy of 1-month treatment of statins for LDL, the sensitivity, 86.86%; and the specificity, 94.83%. In the prediction model on the efficacy of the same treatment for triglyceride, the sensitivity, 71.21%; and the specificity, 73.46%. As to the prediction of total cholesterol, the sensitivity, 94.38%; and the specificity, 96.55%. And in the case of high-density lipoprotein (HDL), the sensitivity, 84.86%; and the specificity, 100%. recursive feature elimination analysis showed that total cholesterol was the most important feature of atorvastatin efficacy of reducing LDL; that HDL was the most important one of its efficacies of reducing triglycerides; that LDL was the most important one of its efficacies of reducing total cholesterol; and that triglyceride was the most important one of its efficacies of reducing HDL. Random-forest can help predict whether atorvastatin efficacy of reducing lipoprotein cholesterol to be qualified after 1-month course of treatment in different individuals.

[Influence of Loading Dose Of Atorvastatin on the Risk of Contrast-Induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction].

Aim      This retrospective cohort study focused on evaluating the incidence of contrast-induced nephropathy (CIN) associated with administration of an atorvastatin loading dose (80 mg) prior to invasive coronary angiography (CAG) in patients with ST-segment elevation myocardial infarction (STEMI).Material and methods  This retrospective cohort study included 386 patients with STEMI. The patients were divided into two groups: intervention group (n=118) and control group (n=268). Patients in the intervention group, at the stage of admission to the catheterization laboratory, were administered a loading dose of atorvastatin (80 mg, p.o.) immediately before access (introducer placement). The endpoints were development of CIN, which was determined by increased serum creatinine 48 h following the intervention by at least 25% (or 44 µmol/l) of baseline value. In addition, in-hospital mortality and incidence of CIN resolution were assessed. To adjust the groups for dissimilar characteristics, a "pseudorandomization" method was used by comparing propensity scores.Results The incidence of CIN was significantly lower in the intervention group than in the control group (10.5 % vs. 24.4 %; p=0.016) with the odds for the CIN development lower than in the control group (odds ratio (OR) 0.36; 95 % confidence interval (CI), 0.16-0.85). Creatinine concentrations returned to the baseline value in 7 days more frequently than in the control group (66.3 % vs. 50.6 %, respectively; OR, 1.92; 95 % CI, 1.04-3.56; p=0.037). In-hospital mortality was higher in the control group but did not differ significantly between the groups.Conclusion      ~Administration of atorvastatin 80 mg to STEMI patients immediately before CAG was associated with a reduced risk of CIN and a higher likelihood of serum creatinine returning to the values at admission by day 7.

[Lipid-lowering Eeficacy and Safety of High Doses of Atorvastatin and Rosuvastatin].

Administration of high doses of atorvastatin 80 mg/day and rosuvastatin 40 mg/day is a part of a standard algorithm for the treatment of patients at high and very high cardiovascular risk. This treatment allows reducing atherogenic low-density lipoprotein cholesterol (LDL-C) by approximately 50 % and decreasing the risk of cardiovascular diseases. Results of prospective studies with atorvastatin and rosuvastatin demonstrated a significant (45-55 %) decrease in LDL-C and triglycerides (11-50 %). This article focuses on analysis of evidence-based retrospective database for atorvastatin and rosuvastatin in prospective studies; reviewing a retrospective database of the VOYAGER study, including subgroups of patents with type 2 diabetes mellitus or hypertriglyceridemia; evaluation of the variability of the hypolipidemic response; and analysis of the risk for development of cardiovascular diseases and their complications with the statin treatment. Rosuvastatin at the highest daily dose of 40 mg/day was superior to atorvastatin 80 mg/day by the capability for decreasing LDL-C. Both statins showed a great variability in the degree of reducing triglycerides and exerted a minimal effect on high-density lipoprotein cholesterol. According to results of completed studies, rosuvastatin 40 mg/day also was superior to high doses of atorvastatin by tolerability and safety.

Prescription of statins after acute coronary syndrome; a single-centre observational study.

There is limited information about the current use of high-intensity statins (HIS) after acute coronary syndrome (ACS) in Pakistani patients. We studied the prescription of HIS in patients admitted with ACS to Ittefaq Hospital, Lahore, Pakistan, from February 2019 to December 2019. Among the 411 patients, 221 (53.8%) patients underwent Percutaneous Coronary Intervention (PCI), 62 (15.1%) were referred for Coronary Artery Bypass Graft (CABG), and 128 (31.1%) were treated medically. Overall 408 (99.3%) patients were prescribed statins and 198 (48.2%) received HIS, with 45 (10.9%) patients receiving maximally allowed dose (Atorvastatin 80mg or Rosuvastatin 40mg). Patients treated with PCI were more likely to be prescribed HIS (73.3% vs 26.7%, p <0.001), while older patients (>75 years of age), those treated medically, and patients with severely reduced LV systolic function were significantly less likely to receive HIS (p <0.001). Our study, therefore, identifies a gap in implementation of guidelines for HIS use, particularly among the medically treated ACS patients.

Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV. METHODS: MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo. RESULTS: MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy. CONCLUSIONS: We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML.

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an 'early-stage' model in which treatment was added shortly after initiation of AML cell encapsulation, and an 'established' model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the 'established' compared to the 'early-stage' model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs.

The Role of Preoperative Chronic Statin Therapy in Heart Transplant Receipts-A Retrospective Single-Center Cohort Study.

BACKGROUND: Statin therapy has been proven to reduce the risk of cardiovascular events. The objective of our retrospective study was to investigate the relationship between preoperative chronic administration of statins to postoperative 2-month heart transplantation complications. METHODS: A total number of 38 heart transplantation recipients from the Cardiovascular and Transplant Emergency Institute of Târgu Mureș between May 2014 and January 2021 were included in our study. RESULTS: In logistic regression, we found a statistical significance between statin treatment and the presence of postoperative complications of any cause (OR: 0.06, 95% CI: 0.008-0.56; p = 0.0128), simultaneously presenting an elevated risk for early-postoperative acute kidney injury (AKI). From the statin group, atorvastatin therapy had a higher risk of type 2 diabetes mellitus (T2DM) development (OR: 29.73, 95% CI: 1.19-741.76; p = 0.0387) and AKI (OR: 29.73, 95% CI: 1.19-741.76; p = 0.0387). C-reactive protein (CRP), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) represented risk factors, atorvastatin administration being independently associated with lower CRP values. CONCLUSIONS: Chronic previous administration of statins represented a protective factor to the development of 2-month postoperative complications of any cause in heart transplant receipts.

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats.

Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6-22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.

Comparative efficacy and safety among high-intensity statins. Systematic Review and Meta-Analysis.

Aim: To summarize the evidence in terms of efficacy and safety of head-to-head studies of high-intensity statins regardless of the underlying population. Materials & methods: A systematic review and meta-analysis was conducted to summarize the effect sizes in randomized controlled trials and cohort studies that compared high-intensity statins. Results: Based on 44 articles, similar effectiveness was observed across the statins in reducing LDL levels from baseline. All statins were observed to have similar adverse drug reactions (ADRs), although higher dosages were associated with more ADRs. Based on a pooled quantitative analysis of atorvastatin 80 mg versus rosuvastatin 40 mg, rosuvastatin was statistically more effective in reducing LDL. Conclusion: This review further confirms that high-intensity statins reduce LDL by ≥50%, favoring rosuvastatin over atorvastatin. Additional data are needed to confirm the clinical significance on cardiovascular outcomes using real-world studies.

Effects of amlodipine combined with atorvastatin on Th17/Treg imbalance and vascular microcirculation in hypertensive patients with atherosclerosis: A double-blind, single-center randomized controlled trial.

OBJECTIVE: Helper T cells 17 (Th17) and regulatory T cells (Treg), as CD4+T lymphocyte subsets, play an important role in the process of atherosclerosis. However, there are few studies on the regulation and efficacy of atorvastatin combined with amlodipine on Th17/Treg balance in hypertension combined with carotid atherosclerosis. Therefore, this study aims to verify the efficacy and immunomodulatory effects of atorvastatin combined with amlodipine in the treatment of hypertension combined with carotid atherosclerosis. METHODS: A total of 260 patients with hypertension and carotid atherosclerosis were randomly divided into atorvastatin or combined treatment group. Inflammatory factors and Th17 and Treg levels were detected by enzyme-linked immunosorbent assay and flow cytometry. The messenger ribonucleic acid expression of retinoic acid receptor-related orphan receptor gamma and forkhead spiral transcription factor were detected by real-time quantitative polymerse chain reaction. RESULTS: We found that the total effective rate in the treatment group was significantly higher than that in the control group. The levels of whole blood high shear viscosity, whole blood low shear viscosity, plasma specific viscosity and fibrin content in the 2 groups were significantly decreased after treatment, and the combined group was significantly lower than the control group (all P < .05). The improvement of endothelial function in the treatment group was also significantly higher than that in the control group (all P < .05). In addition, we found that there were statistically significant differences in Th17 percentage, Treg percentage and Treg/Th17 between the treatment group and the control group (P < .05). The messenger ribonucleic acid levels of retinoic acid receptor-related orphan receptor gamma and forkhead spiral transcription factor showed the same trend. Further detection of Th17-related inflammatory factors showed that the expression of interleukin (IL)-17, IL-6, IL-23 and tumor necrosis factor-α in the treatment group was significantly decreased, which was better than that in the control group (all P < .05). CONCLUSION: These data indicate that amlodipine combined with atorvastatin can improve Th17/Treg imbalance, vascular endothelial function and efficacy in patients with hypertension and atherosclerosis.

The effect of lipid-lowering therapies on the pro-inflammatory and anti-inflammatory properties of vascular endothelial cells.

Atherosclerosis and cardiovascular events can be prevented, or treated, using statin therapy, either alone or in combination with ezetimibe. Chronic inflammation, vascular proliferation, and the development of atherosclerosis are also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe, and their combinations, on the mRNA expression of pro-inflammatory IL1ß, IL-18 and IL-23 and anti-inflammatory TGFß, IL-35 (EBI3, IL-12 subunits), IL-10 and IL-37, in endothelial cells damaged by 25-OHC. It also analyzed IL-35 expression at the protein level. HUVECs were stimulated with atorvastatin (5 µM), rosuvastatin (10 µM), ezetimibe (1.22 µM), atorvastatin-ezetimibe (5 µM + 1.22 µM) or rosuvastatin-ezetimibe (10 µM + 1.22 µM), with or without pre-incubation with 10 µg/mL 25-OHC. mRNA expression was analyzed by real-time PCR. The protein level of IL-35 was analyzed by ELISA. In the pre-stimulated HUVECs, atorvastatin and rosuvastatin decreased mRNA expression of IL1ß, IL-18, IL-23, TGFß, IL35 and increased mRNA expression of IL-10 and IL-37 compared to 25-OHC. Furthermore, only incubation with rosuvastatin and rosuvastatin-ezetimibe decreased IL-35 mRNA and protein levels. Ezetimibe down-regulated only IL1ß. Treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe reversed the effect of 25-OHC in IL1ß, IL-18 and IL-35 mRNA expression. In conclusion, rosuvastatin has the strongest anti-inflammatory effects and is the best at reducing the effect of oxysterols. Both statins exert a greater anti-inflammatory effect than ezetimibe. The anti-inflammatory effect of the combination therapies appears to be based on the effects of the statins alone and not their combination with ezetimibe.

Atorvastatin reduces contrast media-induced pyroptosis of renal tubular epithelial cells by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-acquired renal failure. However, there is no effective treatment of CI-AKI, and its mechanism is unknown. Interestingly, atorvastatin has been reported to be effective in renal injury. Therefore, the aim of this study was to explore the effect and possible molecular mechanism of atorvastatin in CI-AKI. METHODS: On the CI-AKI in vitro model, rat tubular epithelial cells (NRK-52E) were treated with 18 mg I/ml meglumine diatrizoate (MEG) and then pretreated with atorvastatin. pcDNA3.1-TLR4 treatment was performed to overexpress toll-like receptor 4 (TLR4) in NRK-52E cells. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) kits were used to detect NRK-52E cell viability as well as LDH release in each group, respectively; qRT-PCR to determine mRNA expression of TLR4 in cells; western blot to detect protein expression levels of pyroptosis-related proteins (NLRP3, caspase-1, ASC, and GSDMD) and TLR4/MyD88/NF-κB signaling pathway-related proteins (TLR4, MyD88, NF-κBp65, and p-NF-κB p65) in cells. RESULTS: MEG treatment significantly inhibited the viability of NRK-52E cells, increased pro-inflammatory factor levels and promoted pyroptosis, representing successful establishment of a rat tubular epithelial cell (NRK-52E) CI-AKI in vitro model. Notably, atorvastatin increased the activity of MEG-treated NRK-52E cells and alleviated cell injury in a concentration-dependent manner. In addition, atorvastatin significantly down-regulated the expression of TLR4 in MEG-treated NRK-52E cells. However, overexpression of TLR4 inhibited the effects of atorvastatin on increasing cell viability, alleviating cell injury, reducing pro-inflammatory factors (IL-1ß, IL-6, and TNF-α) levels, and inhibiting apoptosis (by down-regulating the expression of NLRP3, caspase-1, ASC, and GSDMD). Furthermore, atorvastatin also inhibited the expression of TLR4/MyD88/NF-κB pathway-related proteins (TLR4, MyD88, and p-NF-κB p65). CONCLUSION: Atorvastatin can attenuate CI-AKI through increasing the activity of MEG-treated renal tubular epithelial cells, relieving cell injury, as well as inhibiting pyroptosis and inflammation. More importantly, the mechanism was achieved by inhibiting the TLR4//MyD88/NF-κB signaling pathway.

[Efficacy and safety of various doses of hybutimibe monotherapy or in combination with atorvastatin for primary hypercholesterolemia: a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase â ¢ clinical trial].

Objective: To evaluate the efficacy and safety of hybutimibe monotherapy or in combination with atorvastatin in the treatment of primary hypercholesterolemia. Methods: This was a multicenter, randomized, double-blind, double-dummy, parallel-controlled phase Ⅲ clinical trial of patients with untreated primary hypercholesterolemia from 41 centers in China between August 2015 and April 2019. Patients were randomly assigned, at a ratio of 1∶1∶1∶1∶1∶1, to the atorvastatin 10 mg group (group A), hybutimibe 20 mg group (group B), hybutimibe 20 mg plus atorvastatin 10 mg group (group C), hybutimibe 10 mg group (group D), hybutimibe 10 mg plus atorvastatin 10 mg group (group E), and placebo group (group F). After a dietary run-in period for at least 4 weeks, all patients were administered orally once a day according to their groups. The treatment period was 12 weeks after the first dose of the study drug, and efficacy and safety were evaluated at weeks 2, 4, 8, and 12. After the treatment period, patients voluntarily entered the long-term safety evaluation period and continued the assigned treatment (those in group F were randomly assigned to group B or D), with 40 weeks' observation. The primary endpoint was the percent change in low density lipoprotein cholesterol (LDL-C) from baseline at week 12. Secondary endpoints included the percent changes in high density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (Apo B) at week 12 and changes of the four above-mentioned lipid indicators at weeks 18, 24, 38, and 52. Safety was evaluated during the whole treatment period. Results: Totally, 727 patients were included in the treatment period with a mean age of (55.0±9.3) years old, including 253 males. No statistical differences were observed among the groups in demographics, comorbidities, and baseline blood lipid levels. At week 12, the percent changes in LDL-C were significantly different among groups A to F (all P<0.01). Compared to atorvastatin alone, hybutimibe combined with atorvastatin could further improve LDL-C, TG, and Apo B (all P<0.05). Furthermore, there was no significant difference in percent changes in LDL-C at week 12 between group C and group E (P=0.991 7). During the long-term evaluation period, there were intergroup statistical differences in changes of LDL-C, TG and Apo B at 18, 24, 38, and 52 weeks from baseline among the statins group (group A), hybutimibe group (groups B, D, and F), and combination group (groups C and E) (all P<0.01), with the best effect observed in the combination group. The incidence of adverse events was 64.2% in the statins group, 61.7% in the hybutimibe group, and 71.0% in the combination group during the long-term evaluation period. No treatment-related serious adverse events or adverse events leading to death occurred during the 52-week study period. Conclusions: Hybutimibe combined with atorvastatin showed confirmatory efficacy in patients with untreated primary hypercholesterolemia, which could further enhance the efficacy on the basis of atorvastatin monotherapy, with a good overall safety profile.

Investigation of the effects of atorvastatin and Lactobacillus acidophilus on some hormones and oxidative stress in experimental hypercholesterolemia.

AIM: The investigation of serum leptin, ghrelin, insulin, seratonin hormones, NO, total oxidant/antioxidant status and brain cannaboid 1 receptor protein and apoptotic cell levels in atorvastatin and Lactobacillus acidophilus administrated experimental hypercholesterolemia was aimed in the project. METHODS: In the study, 5 experimental groups were formed. Group 1 was fed with standard rat chow, and Group 2 was fed with 2% cholesterol added standard rat chow for 8 weeks. Group 3 was fed with 2% cholesterol feed and received atorvastatin (20 mg/kg/day) for the last 4 weeks. Group 4 was given L. acidophilus (2 ×108 cfu/kg/day). Group 5 was given atorvastatin and L. acidophilus probiotic in the last 4 weeks of the experiment period. After the experimental period, blood samples were taken from each rat. Rats were sacrificed and brain tissues were taken for analyzes. In sera samples, leptin, ghrelin, insulin, serotonin hormones and NO levels were measured with ELISA. In brain samples, cannabinoid 1 receptor proteins and apoptosis levels were measured by ELISA. Total oxidant and antioxidant levels were investigated with using Rel Assay Kits. RESULTS: The addition of cholesterol to feeds increased the levels of serum cholesterol, insulin and leptin levels; on the other hand, reduced the levels of serotonin and ghrelin. In hypercholesterolemia, total oxidant and NO levels were increased, and total antioxidant levels were decreased. CONCLUSION: The results showed that administrations of L. acidophilus and atorvastatin might be recommended for treatment of hypercholesterolemia.

Pharmacological Action of Atorvastatin and Metformin on Non-alcoholic Fatty Liver Disease on an Experimental Model of Metabolic Syndrome.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. It is known that there is a pathogenic relation between liver damage and the inflammatory and oxidative environment present in Metabolic Syndrome (MS). OBJECTIVE: To study the pharmacological action of atorvastatin and metformin in an experimental model of MS. METHODS: We used 40 male rats (Wistar) divided into the following groups: Control (A) (n=8), induced MS (B) (n=8), MS + atorvastatin treatment (C)(n=8), MS + metformin treatment (D) (n=8) and MS + combined treatment (E) (n=8). MS was induced by administering 10% fructose in drinking water for 45 days. Atorvastatin 0.035 mg/day/rat, metformin 1.78 mg/day/rat, and a combination of both drugs were administered for 45 days. Metabolic, oxidative (nitric oxide, myeloperoxidase and superoxide dismutase) and inflammatory (fibrinogen) parameters were determined. Histological sections of liver were analyzed by light microscopy. RESULTS: The glycemia, lipid profile and TG/HDL-C index were altered in MS group. After pharmacological treatment, metabolic parameters improve significantly in all treated groups. Inflammatory and oxidative stress biomarkers increase in MS. Treated groups showed an increase in NO bioavailability, no difference in MPO activity and an increase in fibrinogen. Atorvastatin showed a decrease in SOD while Metformin and combination treatment showed an increase in SOD compared to MS. In MS, we observed histological lesions consistent with NAFLD. However, after a combined treatment, we observed total regression of these lesions. CONCLUSION: Our results showed that there is an important synergy between atorvastatin and metformin in improving liver involvement in MS.

High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4∗16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database.

Drug interactions between atorvastatin and cytochrome P450 (P450) 3A substrates/inhibitors lead to an increased incidence of skeletal muscle or hepatic toxicity. However, in this survey, among 483 Japanese subjects administered atorvastatin alone, more than half (258) experienced statin intolerance and were unable to continue using the drug. Although many factors underly atorvastatin toxicity, the intrinsic clearance rate might be a contributing causal factor. The impaired P450 3A4 p.Thr185Ser variant, CYP3A4∗16 (rs12721627), has been identified in East Asians with an allele frequency of 2.2%. Pharmacokinetically modeled plasma concentrations of atorvastatin increased after a virtual oral dose of 40 mg in CYP3A4∗16 homozygotes; the maximum concentration and area under the concentration curve, respectively, were 3.3-fold and 4.2-fold those in subjects homozygous for CYP3A4∗1. In subjects with CYP3A4∗16/∗16, the virtual hepatic concentrations of atorvastatin after daily doses of 10 mg for a week were similar to or higher than the plasma concentrations. These results suggest that the estimated high virtual plasma and hepatic exposures obtained by pharmacokinetic modeling in subjects harboring impaired allele CYP3A4∗16 may be one of the causal factors for statin intolerance in a manner similar to the well-known drug interactions caused by co-administrations of CYP3A inhibitors.

Fecal metabolomics analysis for deciphering the lipid-lowering effect of Qizhi capsule on high-fat feed induced hyperlipidemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Qizhi capsule (QZC), a Chinese patent drug, has been utilized to treat hyperlipidemia. AIM OF STUDY: The present study aims to investigate the lipid-lowering effect of QZC, as well as the mechanism of action for treating hyperlipidemia. MATERIALS AND METHODS: High-fat diet (HFD) induced hyperlipidemia rats were administrated with different doses of QZC for 28 days, and atorvastatin calcium tablets was used as the positive control. Serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were used to evaluate the effectiveness of QZC treatment. The metabolic profiles of feces were analyzed by UPLC-MS-based metabolomics approach coupled with multivariate data analysis. RESULTS: The levels of serum TC, TG, LDL-C, and HDL-C were significantly reversed in QZC treatment groups, showing a similar or even better treatment effect compared with the atorvastatin calcium group. Thirty-two potential fecal biomarkers related to hyperlipidemia were identified. QZC could partially recover the disturbed metabolic pathways of alpha-linolenic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Meanwhile, the signal pathways of regulation of lipid metabolism by peroxisome proliferator-activated receptor α (PPARα), PPARα activates gene expression, and transcriptional regulation of white adipocyte differentiation can be also regulated by QZC. CONCLUSION: The lipid-lowering effect of QZC was confirmed by both serum biochemistry and metabolomics analysis. The beneficial effects of QZC were mainly attributed to the correction of metabolic disorders and the maintenance of the dynamic balance of metabolites.

[Effect and Mechanism of Atorvastatin on Reversing Drug Resistance in Leukemia by Regulating Glycolysis through PTEN/mTOR Pathway].

OBJECTIVE: To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM. METHODS: HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected. RESULTS: CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 µmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 µmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 µmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance. CONCLUSION: Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.