Atorvastatin Group Research Articles

Abstract 11456: Elevated Lipoprotein(a) is Associated with Statin Resistance

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p < 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) > 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) <30 mg/dL (50.4% [33.3-61.1%]), p < 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) <30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and > 100 mg/dL (p < 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis.

Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoE−/−Fbn1C1039G+/−), a model of advanced atherosclerosis, statins do not lower cholesterol. Consequently, studying cholesterol-independent effects of statins can be achieved more straightforwardly in these mice. Female ApoE −/−Fbn1C1039G+/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided into a WD group (receiving WD only) and a WD + atorvastatin group (receiving 10 mg/kg/day atorvastatin +WD) group. After 15 weeks, blood was collected from the retro-orbital plexus, and the mice were sacrificed. Total plasma cholesterol and C-reactive protein (CRP) were measured with commercially available kits. Plasma proCPU levels were determined with an activity-based assay. Total plasma cholesterol levels were not significantly different between both groups, while proCPU levels were significantly lower in the WD + atorvastatin group. Interestingly proCPU levels correlated with CRP and circulating monocytes. In conclusion, our results confirm that atorvastatin downregulates proCPU levels in ApoE−/−Fbn1C1039G+/− mice on a WD, and evidence was provided that this downregulation is a pleiotropic effect of atorvastatin treatment.

Effect of Atorvastatin on Knee Cartilage Volume in Patients With Symptomatic Knee Osteoarthritis: Results From a Randomized Placebo-Controlled Trial.

To determine whether atorvastatin slows tibial cartilage volume loss in patients with symptomatic knee osteoarthritis (OA) in a multicenter, randomized, double-blind, placebo-controlled trial. Participants ages 40-70 years were randomized to receive oral atorvastatin (40 mg once daily) (n = 151) or matching placebo (n = 153). The primary end point was annual percentage change in tibial cartilage volume over 2years, assessed using magnetic resonance imaging (MRI). The prespecified secondary end points were progression of cartilage defects and bone marrow lesions over 2 years, which were assessed using MRI and change in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index pain, stiffness, and function scores. A total of 248 of 304 participants (81.6%) completed the trial (mean age 55.7 years; 55.6% women). The annual change in tibial cartilage volume differed minimally between the atorvastatin and placebo groups (mean change -1.66% versus -2.17%, between-group difference 0.50% [95% confidence interval (95% CI) -0.17%, 1.17%]). There were no significant differences in the progression of cartilage defects (odds ratio [OR] 0.86 [95% CI 0.52, 1.41]) or progression of bone marrow lesions (OR 1.00 [95% CI 0.62, 1.63]). Moreover, there were no significant differences in change in WOMAC pain, stiffness, or function scores over 2 years between the atorvastatin and placebo groups (mean change in pain score -36.0 versus -29.5, adjusted difference -2.7 [95% CI -27.1, 21.7]; mean change in stiffness score -14.2 versus -11.8, adjusted difference -0.2 [95% CI -12.2, 11.8]; mean change in function score -89.4 versus -87.5, adjusted difference 0.3 [95% CI -83.1, 83.6]). The incidence of adverse events (AEs) was similar between the atorvastatin and placebo groups (57 [37.7%] versus 52 [34.0%] experiencing AEs). Treatment with oral atorvastatin (40 mg once daily), compared to placebo, did not significantly reduce cartilage volume loss over 2 years in patients with symptomatic knee OA. These findings do not support the use of atorvastatin for the treatment of knee OA.

Atorvastatin therapy in COVID-19 adult inpatients: A double-blind, randomized controlled trial.

IntroductionEfficacious therapies are urgently required to tackle the coronavirus disease 2019 (COVID-19). This trial aims to evaluate the effects of atorvastatin in comparison with standard care for adults hospitalized with COVID-19.MethodsWe conducted a randomized controlled clinical trial on adults hospitalized with COVID-19. Patients were randomized into a treatment group receiving atorvastatin + lopinavir/ritonavir or a control group receiving lopinavir/ritonavir alone. The primary outcome of the trial was the duration of hospitalization. The secondary outcomes were the need for interferon or immunoglobulin, receipt of invasive mechanical ventilation, and O2 saturation (O2sat), and level of C-reactive protein (CRP) which were assessed at the onset of admission and on the 6th day of treatment.ResultsForty patients were allocated and enrolled in the study with a 1 to 1 ratio in atorvastatin + lopinavir/ritonavir and lopinavir/ritonavir groups. Clinical and demographic characteristics were similar between the two groups. CRP level was significantly decreased in the lopinavir/ritonavir + atorvastatin group (P < 0.0001, Cohen’s d = 0.865) so that there was a significant difference in CRP level on the 6th day between the two groups (P = 0.01). Nevertheless, there was no significant difference in O2sat on day 6. Although the duration of hospitalization in the lopinavir/ritonavir + atorvastatin group was significantly reduced compared to the control group (P = 0.012), there was no significant difference in the invasive mechanical ventilation reception and the need for interferon and immunoglobulin.ConclusionAtorvastatin + lopinavir/ritonavir may be more effective than lopinavir/ritonavir in treating COVID-19 adult hospitalized patients.

Development of the Binary and Ternary Atorvastatin Solid Dispersions: In Vitro and In Vivo Investigations.

The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.

Pioglitazone combined with atorvastatin promotes plaque stabilization in a rabbit model.

It is not yet clear whether plaque inflammation and cardiovascular events are reduced further when pioglitazone and atorvastatin are combined. Our study aimed to determine whether pioglitazone combined with atorvastatin can restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model. Thirty rabbits were randomly divided into an atherosclerosis group, an atorvastatin group, and an atorvastatin plus pioglitazone group. The atherosclerosis model was induced using balloon injury and feeding a high-fat diet. Plasma samples were then used to analyze glucose, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and matrix metalloproteinase-9 (MMP-9). The area percentage of atherosclerotic plaques was analyzed by hematoxylin-eosin staining. The relative reductions in TG and LDL-C and the increase in HDL-C levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (TG: -33.60 ± 7.17% vs -24.16 ± 8.04%, p < 0.001; LDL-C: -42.89 ± 1.63% vs -37.13 ± 1.35%, p < 0.001; and HDL-C: 25.18 ± 5.53% vs 10.43 ± 6.31%, p < 0.001). The relative reductions in hs-CRP and MMP-9 levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (-69.38 ± 1.06% vs-53.73 ± 1.92%, p < 0.001; -32.77 ± 2.49% vs -13.36 ± 1.66%, p < 0.001). The area percentage of atherosclerotic plaques was significantly smaller in the atorvastatin group (47.75%, p < 0.05) and in the atorvastatin plus pioglitazone group (22.57%, p < 0.05) than in the atherosclerosis group (84.08%, p < 0.05). We can thus conclude that the combination treatment of atorvastatin and pioglitazone provided additive benefits on inflammatory parameters and lipid metabolism. Pioglitazone combined with atorvastatin can further restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model.

Hyperleptinaemia and its Association with Postprandial Hypertriglyceridemia and Glucose Intolerance.

Introduction:Leptin resistance is believed to cause insulin resistance though the exact mechanism is not fully understood. The present study aims to investigate the temporal profile of postprandial triglyceride (PPTG) and leptin levels, and their association with each other as well as with markers of metabolic syndrome.Materials and Methods:Serum leptin and PPTG levels were measured longitudinally till 26 weeks in Wistar rats fed on controlled diet (group 1) and high sucrose diet (HSD) (group 2). Two additional groups fed on HSD were taken and treated with pioglitazone (group 3) and atorvastatin (group 4). Body weight, homeostasis model assessment of insulin resistance (HOMA-IR), and glucose intolerance were also measured during this period. Comparison of the groups were done and Pearson's correlation coefficient was used to ascertain the association.Results:Leptin levels were significantly higher in all three groups receiving HSD compared to controlled diet group from week 2 to week 26 (P < 0.01). The postprandial triglyceride area under the curve (PPTG AUCs) were significantly higher in group 2 than controls during this period (P < 0.001). Body weight, HOMA-IR and glucose AUC were found to be significantly higher in group 2 rats than controls only from week 6, 8, and 12 respectively. In HSD-fed rats, but not in control, mean serum leptin levels from 2-26 weeks as well as peak (10th week) and 26th week were strongly associated with corresponding as well as preceding PPTG levels. Leptin levels significantly predicted HOMA-IR and prediabetes in group 2.Conclusion:This study found significant hyperleptinemia associated with postprandial hypertriglyceridemia that predicted insulin resistance and prediabetes in high sucrose diet–fed rats.

Prospective, randomized, open label comparative study of efficacy of atorvastatin versus atorvastatin with vitamin D3 in patients with dyslipidemia attending tertiary care hospital

Background: Cardiovascular diseases are one of the most important group of diseases causing premature mortality and morbidity. Dyslipidemia is an independent risk factor for cardiovascular diseases and is a disorder of lipoprotein metabolism. Various research studies support role of vitamin D against dyslipidemia. Vitamin D concentration positively correlates with HDL cholesterol and negatively with serum LDL and triglyceride levels. Vitamin D supplementation to Atorvastatin appeared to have increased cholesterol lowering activity more than either substance did alone.Methods: The study was conducted in an outpatient department of general medicine for a duration of 12 weeks in a tertiary care hospital. Total of 100 patients with dyslipidemia were selected based on measurement of lipid profile. Out of 100 patients, 50 patients under group A were treated with atorvastatin 10mg and balance 50 patients under group B treated with atorvastatin and Vitamin D3 1000 IU/day orally. Patients were followed up monthly for 3 months and lipid profile was assessed at baseline and at the end of study. The baseline characteristics were similar in both study groups.Results: On comparing groups at the end of 12 weeks mean LDL, triglycerides and VLDL were significantly reduced in group B than group A with p&lt;0.001. The mean HDL level too increased in group B than group A with p&lt;0.001.Conclusions: Fasting plasma lipid profile improvement was higher in the atorvastatin with vitamin D3 group compared to atorvastatin group.

Probiotics Alleviated Nonalcoholic Fatty Liver Disease in High-Fat Diet-Fed Rats via Gut Microbiota/FXR/FGF15 Signaling Pathway

Gut microbiota (GM) dysbiosis and bile acid (BA) metabolism disorder play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Probiotics had a beneficial effect on NAFLD, but further study is needed to explore probiotics as a potential therapeutic agent to NAFLD. The aim of this study was to investigate the regulatory effect of probiotics on gut microbiota in NAFLD rats and to explore the possible mechanism of probiotics regulating the bile acid receptor farnesoid X receptor/growth factor 15 (FXR/FGF15) signaling pathway in rats. We established a rat model of NAFLD fed with a high-fat diet (HFD) for 14 weeks, which was given different interventions (312 mg/kg/day probiotics or 10 mg/kg/day atorvastatin) from the 7th week. Serum lipids and total bile acids (TBA) were biochemically determined; hepatic steatosis and lipid accumulation were evaluated with HE staining. The expression levels of FXR, FGF15 mRNA, and protein in rat liver were detected. 16S rDNA was used to detect the changes of gut microbiota in rats. Compared with the HFD group, probiotics and atorvastatin significantly reduced serum lipids and TBA levels. And probiotics increased dramatically the expression of FXR, FGF15 mRNA, and protein in the liver. But there were no significant changes in the atorvastatin group. Probiotics and atorvastatin can upregulate the diversity of gut microbiota and downregulate the abundance of pathogenic bacteria in NAFLD model rats. In summary, probiotics alleviated NAFLD in HFD rats via the gut microbiota/FXR/FGF15 signaling pathway.

Atorvastatin attenuates intermittent hypoxia-induced myocardial oxidative stress in a mouse obstructive sleep apnea model.

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is associated with various cardiovascular diseases. In the present study, we assessed the effect of the lipid reducing agent atorvastatin on CIH-induced myocardial oxidative stress and apoptosis in a mouse OSA model. Forty-eight C57BL/6J mice were evenly divided among normoxia + vehicle, normoxia + atorvastatin, CIH + vehicle, and CIH + atorvastatin groups. CIH consisted of a hypoxia-reoxygenation cycle in which oxygen concentrations fluctuated from 21% to 6% and back over two minutes for 8 hours each day (30 events/hour). CIH exposure continued for 12 weeks. Atorvastatin (5 mg/kg) was administered from week 6 through the end of the experiment. CIH increased malondialdehyde levels and decreased superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 levels in cardiac tissue, indicating a reduction in antioxidant activity. Atorvastatin significantly reversed those effects (p < 0.05). CIH also increased B-cell lymphoma 2-associated protein X and cleaved caspased-3 levels as well as the myocardial apoptotic rate, as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Atorvastatin had no effect on those changes (p > 0.05). Thus, atorvastatin administration exerts antioxidant but not anti-apoptotic effects after CIH and may therefore have therapeutic potential in OSA patients with cardiovascular comorbidities.

Effects of atorvastatin on sevoflurane postconditioning in in vivo rabbit hearts

ObjectivesMyocardial ischemia-reperfusion injury is a phenomenon that promotes myocardial damage when the blood supply returns to the tissue after a period of ischemia. Anesthetic postconditioning involves myocardial protection against myocardial I/R injury. The effects of atorvastatin (ATV) on sevoflurane postconditioning against myocardial ischemia-reperfusion injury have not been thoroughly studied. The present study aimed to investigate if ATV interacts synergistically with sevoflurane postconditioning against myocardial infarction in rabbit hearts in vivo. MethodsTwenty-eight male rabbits underwent 30 min of left anterior descending coronary artery occlusion that was followed by reperfusion for 180 min under ketamine/xylazine (K/X) anesthesia. Rabbits were randomly assigned to four groups that included Group K/X (under K/X anesthesia only), Group POST (sevoflurane exposure at initial reperfusion), Group ATV (ATV 5 mg/kg/day administered before ischemia), and Group ATV + POST (POST intervention with atorvastatin administered once daily for 3 days). At the end of reperfusion, the myocardial infarct size and the area at risk were both measured. ResultsThe mean infarct sizes in the POST, ATV, and ATV + POST groups were significantly smaller compared to those in the K/X group. Furthermore, the mean infarct size in Group ATV + POST was significantly smaller than was that in Group POST and significantly smaller compared to that in Group ATV. ConclusionThe combination of sevoflurane postconditioning and pre-administration of ATV further reduced the myocardial infarction size compared to that observed with sevoflurane postconditioning alone or ATV alone. Our data suggest that sevoflurane postconditioning and ATV may function additively to enhance cardioprotection.

Effect of statins on post-contrast acute kidney injury: a multicenter retrospective observational study

BackgroundPost-contrast acute kidney injury (PC-AKI) is a severe complication of coronary angiography (CAG) and percutaneous coronary intervention (PCI). Currently, the effect of statins on PC-AKI and its mechanism remains unclear.MethodsThis multicenter retrospective observational study included 4386 patients who underwent CAG or PCI from December 2006 to December 2019 in Sir Run Run Shaw Hospital and its medical consortium hospitals. Serum creatinine pre- or post-procedure within 72 h after PCI was recorded. Multivariate logical regression was used to explore whether preoperative use of statins was protective from PC-AKI. The path analysis model was then utilized to look for the mediation factors of statins.ResultsFour thousand three hundred eighty-six patients were enrolled totally. The median age of the study population was 68 years old, 17.9% with PC-AKI, and 83.3% on preoperative statins therapy. The incidence of PC-AKI was significantly lower in group of patients on statins therapy. Multivariate regression indicated that preoperative statins therapy was significantly associated with lower percentage of elevated creatinine (β: -0.118, P < 0.001) and less PC-AKI (OR: 0.575, P < 0.001). In the preoperative statins therapy group, no statistically significant difference was detected between the atorvastatin and rosuvastatin groups (OR: 1.052, P = 0.558). Pathway model analysis indicated a direct protective effect of preoperative statins therapy on PC-AKI (P < 0.001), but not through its lipid-lowering effect (P = 0.277) nor anti-inflammatory effect (P = 0.596). Furthermore, it was found that “low-density lipoprotein cholesterol (LDL-C)→C-reactive protein (CRP)” mediated the relationship between preoperative statins therapy and PC-AKI (P = 0.007). However, this only explained less than 1% of the preoperative protective effects of statins on PC-AKI.ConclusionPreoperative statins therapy is an independent protective factor of PC-AKI, regardless of its type. This protective effect is not achieved by lipid-lowering effect or anti-inflammatory effect. These findings underscore the potential use of statins in preventing PC-AKI among those at risk.

Potential Effect of Curcumin versus Atorvastatin on Hepatic and Metabolic Changes in Rat Model of Metabolic Syndrome

Background: Metabolic syndrome is defined as a cluster of metabolic disorders, including hypertension, insulin resistance, dyslipidemia, diabetes, cardiovascular disease and abdominal [central] obesity. It is also found under different names, such as syndrome X, “deadly quartet” and insulin resistance syndrome. The aim of the work: to investigate the potential effect of curcumin and compare it with the effect of metformin and atorvastatin on hepatic and metabolic changes in metabolic syndrome. Materials and Methods: Fifty male Sprague–Dawley [8 weeks old] weighting 150-200 g obtained from animal house of the department of pharmacology, Al-Azhar Faculty of Medicine. Rats were kept in regular dark – light cycle with free access to groups [specific diet and water] that were renewed daily and were observed for water intake, food intake, changes in body weight and abdominal circumference during 16-week study period. Results: Histopathological changes after administration of high carbohydrate high fat [HCHF] diet, revealed fatty changes, ballooning degeneration [vacuoles] and fibrosis. Infiltration by large numbers of inflammatory cells was detected in the portal area and there was an inflammatory reaction dividing the hepatic parenchyma into lobules. On the other side, the treated rats with curcumin showed improved inflammation [few inflammatory cells, slight ballooning and fibrosis, but still present moderate steatosis in liver samples. The atorvastatin group revealed comparable results to the curcumin group. However, when combined together, they were able to restore hepatic tissue to nearly its normal structure. Conclusions: Combination therapy by curcumin and atorvastatin was more effective in the management of non-alcoholic fatty liver/non-alcoholic steatohepatitis [NAFL/NASH]. However, further studies are required to evaluate the applicability of the present results in human beings and to judge the safety and efficacy of curcumin, atorvastatin and their combination.

Imperatae rhizoma-Hedyotis diffusa Willd. herbal pair alleviates nephrotic syndrome by integrating anti-inflammatory and hypolipidaemic effects

BackgroundNephrotic syndrome (NS) is a common nephropathy with a complex and diverse aetiology. Both Imperatae rhizoma and Hedyotis diffusa Willd. are herbs that are widely used as medicine and functional food. In traditional Chinese medicine theory, they are used as an herbal pair (HP) to treat inflammation-related diseases in the clinic, especially disorders of the kidney. PurposeThis study aimed to investigate the anti-inflammatory and hypolipidaemic effects of HP in an NS rat model and provide scientific data for its clinical application. MethodsAn NS model was established by two-dose injection of Sprague-Dawley rats with adriamycin. Seven groups, including the sham, model, HP treatment (0.25, 0.5 and 1.0 g/kg/d), prednisone (positive control, 5 mg/kg/d), and atorvastatin (positive control, 4 mg/kg/d) groups, were tested. The biochemical indexes of renal function and inflammatory cytokines were determined by ELISA kits and/or qPCR assays, and the crucial protein involved in the signalling pathway were subsequently tested by qPCR and/or Western blotting. Based on specific compounds identified by LC-Q-TOF-MS, network pharmacological study was carried out. ResultsThe levels of BUN, Scr, Upro, UA, Alb, TC, TG, and LDL-C were significantly elevated in model rats. HP treatment for four weeks improved the renal function and the dyslipidaemia by decreasing the levels of all parameters, except BUN and Scr. HP treatment (0.5 and 1.0 g/kg/d) upregulated the expression of PPARγ, CYP7b1, and LDLR in the liver, while it down-regulated PCSK9, showing a regulatory effect on lipid metabolism disorder. The levels of TNF-α and IL-1β in the plasma and the mRNA expression of TNF-α, IL-1β, MCP-1, and TGF-β1 in the kidney were decreased in HP groups, revealing its anti-inflammatory effect in NS rats. The HP exerted an alleviation effect on the inflammatory response through the NF-κB pathway by inhibiting the mRNA and protein expression of p50 and p65. There were 34 compounds identified or tentatively characterized in HP. In the network pharmacological study, PPARG(PPARγ), PCSK9, RELA(p65), and NF-κB1(p50) were the top 20 targets for HP, supporting the animal experimental results. Conclusion: HP exhibited protective effects on NS rats. These effects might be closely related to the inhibition of NF-κB and PCSK9-LDLR and activation of the PPARγ-CYP7B1 signalling pathways.

Effects of atorvastatin on the insulin resistance in women of polycystic ovary syndrome: A systematic review and meta-analysis.

Background:Atorvastatin treatment has been suggested as a therapeutic method for women with polycystic ovary syndrome (PCOS) in many clinical studies. Nonetheless, the effects of atorvastatin on insulin resistance in PCOS patients still remain controversial.Objective:The aim of this report was to evaluate the effects of atorvastatin therapy on the insulin resistance in the treatment of PCOS compared to that of placebo, in order to confer a reference for clinical practice.Methods:Randomized controlled trials (RCTs) of atorvastatin for PCOS published up to August, 2020 were searched. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was measured by the I2 test. Sensitivity analysis was also carried out. The outcomes of interest were as follows: fasting glucose concentration, fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) or body mass index (BMI) value.Results:Nine RCTs with 406 participants were included. The difference of fasting glucose concentration in PCOS patients between atorvastatin group and placebo group was not statistically significant (8 trials; SMD −0.06, 95% CI −0.31 to 0.20, P = .66). PCOS patients in atorvastatin group had lower fasting insulin level than those in placebo group (7 trials; SMD −1.84, 95% CI −3.06 to −0.62, P < .003). The homeostasis model assessment of insulin resistance (HOMA-IR) value showed significant decrease in the atorvastatin therapy compared to placebo (6 trials; SMD −4.12, 95% CI −6.00 to −2.23, P < .0001). In contrast to placebo, atorvastatin therapy did not decrease the BMI value significantly in PCOS patients (7 trials; SMD 0.12, 95% CI −0.07 to 0.31, P = .22).Conclusions:Atorvastatin therapy can reduce insulin resistance in the treatment of patients with PCOS. In addition, further large-sample, multi-center RCTs are needed to identify these findings.

Atorvastatin Promotes Macrocalcification, But Not Microcalcification in Atherosclerotic Rabbits: An 18F-NaF PET/CT Study.

Our study aimed to investigate the effect of atorvastatin on plaque calcification by matching the results obtained by 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) with data from histologic sections. The rabbits were divided into 2 groups as follows: an atherosclerosis group (n = 10) and an atorvastatin group (n = 10). All rabbits underwent an abdominal aortic operation and were fed a high-fat diet to induce atherosclerosis. Plasma samples were used to analyze serum inflammation markers and blood lipid levels. 18F-NaF PET/CT scans were performed twice. The plaque area, macrophage number and calcification were measured, and the data from the pathological sections were matched with the 18F-NaF PET/CT scan results. The mean standardized uptake value (0.725 ± 0.126 vs. 0.603 ± 0.071, P < 0.001) and maximum standardized uptake value (1.024 ± 0.116 vs. 0.854 ± 0.091, P < 0.001) significantly increased in the atherosclerosis group, but only slightly increased in the atorvastatin group (0.616 ± 0.103 vs. 0.613 ± 0.094, P = 0.384; 0.853 ± 0.099 vs.0.837 ± 0.089, P < 0.001, respectively). The total calcium density was significantly increased in rabbits treated with atorvastatin compared with rabbits not treated with atorvastatin (1.64 ± 0.90 vs. 0.49 ± 0.35, P < 0.001), but the microcalcification level was significantly lower. There were more microcalcification deposits in the areas with increased radioactive uptake of 18F-NaF. Our study suggests that the anti-inflammatory activity of atorvastatin may promote macrocalcification but not microcalcification within atherosclerotic plaques. 18F-NaF PET/CT can detect plaque microcalcifications.

Evaluation of locally delivered 1.2% Atorvastatin gel versus 2% Evaluation of locally delivered 1.2% Atorvastatin gel versus 2% melatonin gel as adjunctive to non-surgical periodontal therapy on melatonin gel as adjunctive to non-surgical periodontal therapy on GCF osteocalcin level in stage II periodontitis patients: a GCF osteocalcin level in stage II periodontitis patients: a randomized controlled trial

Objective: Atorvastatin (ATV) and melatonin have antioxidant and anti- inflammatory properties and were suggested to have positive effect when used in periodontitis cases. In periodontitis, osteocalcin (OC) was suggested to be a bone formation marker. Regarding bone turnover in periodontium, gingival crevicular fluid (GCF) osteocalcin levels are more accurate than salivary or serum levels. Aim: The aim of the present study was to assess the effectiveness of local delivery of ATV gel and melatonin gel as adjuncts to scaling and root planning (SRP) in the treatment of stage II periodontitis patients. Subjects and method: Thirty-six patients having stage II periodontitis were included in this study. They were divided into three groups: SRP plus placebo gel, SRP plus 1.2% ATV gel and SRP plus melatonin gel. Clinical parameters (Plaque Index (PI), Gingival Index (GI), Probing Depth (PD) and Clinical Attachment Level (CAL)) were recorded and GCF samples to assess the osteocalcin level were collected at baseline and at 3 months follow up. Results: All three groups showed statistically significant changes in all clinical parameters, PI, GI, PD and CAL. However, these changes were more significant in the ATV and melatonin groups. Reduction in OC was only significant in the ATV and melatonin groups. Melatonin group showed greater mean OC reduction level than the ATV group at 3 months follow up. Conclusion: The adjunctive use of topical ATV gel and melatonin gel with nonsurgical periodontal therapy have showed to be effective in treatment of stage II periodontitis patients. Melatonin gel proved to be more potent in reducing the OC level in the GCF than the ATV gel.

Adjuvant Low-dose Statin Use after Radical Prostatectomy: The PRO-STAT Randomized Clinical Trial.

Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy. In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose atorvastatin (20 mg/day, n = 183) or placebo (n = 181) for 1 year after radical prostatectomy. The primary endpoint was the 1-year biochemical recurrence rate. The secondary endpoints included the 5-year biochemical recurrence-free survival and changes in lipid, testosterone, and sex hormone binding globulin levels. From October 2012 through January 2019, a total of 364 patients underwent randomization. Among 59 total primary end points, 30 (16.4%) and 29 (16.0%) occurred in the atorvastatin and placebo groups, respectively. Atorvastatin did not significantly reduce the primary endpoint of 1-year biochemical recurrence [HR, 0.96; 95% confidence interval (CI), 0.58-1.60]. During a median follow-up of 24 months, 131 patients experienced biochemical recurrence (68 in the atorvastatin group and 63 in the placebo group), representing Kaplan-Meier estimated event rates of 24.0% and 25.4% in the atorvastatin and placebo groups, respectively, at 24 months (HR, 1.00; 95% CI, 0.71-1.41). We observed no significant between-group differences in the testosterone and sex hormone binding globulin levels. Among patients with high-risk pathologic features after radical prostatectomy for prostate cancer, 1-year adjuvant use of atorvastatin was not associated with a lower risk of disease recurrence compared with that for placebo. (ClinicalTrials.gov number, NCT01759836).See related commentary by Murtola and Siltari, p. 4947.

The Effect of Atorvastatin in Knee Osteoarthritis

The aim of this, randomized, double-blind, placebo-controlled study is to evaluate the effect of using 40mg atorvastatin on the progression of joint structural changes and symptoms over 3months in Iraqi patients with symptomatic knee osteoarthritis.This study was performed at Department of Rheumatology, Baghdad Teaching Hospital during the period from September 2020 to January 2021.A total of 44 patients with knee osteoarthritis were assigned to the placebo group (n=21) and atorvastatin group (n=23)that was received atorvastatin 40mg once daily. Both groups received etoricoxib tablets 60mg as a rescue medicine on need. Both groups were treated continuously for 12 weeks.Serum levels of C-terminal telopeptide of type II collagen CTXII, high sensitive c-reactive protein HS-CRP and Western Ontario and McMaster Universities Osteoarthritis Index WOMAC was measured before and after three months of treatment.Resultsshowed that after three months of treatment, the atorvastatin group showeda significant symptomatic improvement in total WOMAC scoring (P&lt;0.0001) associated with a significant reduction (P&lt;0.001) in serum CTXII, HS-CRP level.These results confirmed that the atorvastatin treatment in patients with knee osteoarthritis has clinical efficacy in reducing symptoms through the improvement of WOMAC index and reduction of serum level of CTXII and HS-CRP. In conclusions: Atorvastatin in a dose of 40mg daily can reduce the symptoms of OA.

Effect of Si-Miao-Yong-An decoction on the differentiation of monocytes, macrophages, and regulatory T cells in ApoE−/− mice

Ethnopharmacological relevanceSi-Miao-Yong-An decoction (SMYAD) is a renowned traditional Chinese medicinal formula. SMYAD was originally recorded in the “Shi Shi Mi Lu”, which was edited by medical scientist Chen Shi'duo during the Qing Dynasty. SMYAD has been traditionally used to treat thromboangiitis obliterans. At present, it is mainly used in clinical applications and research of cardiovascular diseases. Aim of the studyTo explore the effects of SMYAD on the pathological changes of atherosclerosis (AS) and the differentiation of monocytes, macrophages, and regulatory T (Treg) cells in apolipoprotein E knockout (ApoE−/−) mice. Materials and methodsEight C57BL/6J mice, which were fed with normal diet for 16 weeks, were used as control group. Forty ApoE−/− mice were randomly divided into model group, atorvastatin group, SMYAD low-dose (SMYAD-LD) group, SMYAD medium-dose (SMYAD-MD) group, and SMYAD high-dose (SMYAD-HD) group. ApoE−/− mice were fed with western diet (WD) for 8 weeks, and the drugs were continuously administered for 8 weeks. The levels of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured by the esterase method. Morphological changes of the aortic sinus in mice were observed by hematoxylin-eosin (HE) staining, the lipid infiltration of the aorta and aortic sinus were observed by oil red O staining, and the spleen index was calculated. The proportion of Ly6Chigh and Ly6Clow monocyte subsets, macrophages, and their M1 phenotype, as well as Treg cells in spleen were measured by flow cytometry. The expressions of cluster of differentiation 36 (CD36), scavenger receptor A1 (SRA1), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), F4/80, and fork head frame protein 3 (FOXP3) in aortic sinus were assessed by immunohistochemical staining. The serum levels of oxidized low density lipoprotein (ox-LDL), interleukin-1β (IL-1β), IL-18, transforming growth factor-β (TGF-β), and IL-10 were measured by enzyme-linked immunosorbent assays (ELISA). ResultsCompared with the model group, the level of serum TC and LDL-C decreased in the SMYAD group, the pathological changes of aortic sinus decreased, and lipid infiltration of aorta and aortic sinus also decreased. These decreases were accompanied by a significant downregulation of CD36, SRA1, and LOX-1. Furthermore, the proportions of Ly6Chigh pro-inflammatory monocyte subsets, macrophages, and their M1 phenotypes in spleen decreased significantly, while the proportion of Treg cells increased. In addition, while the expression of F4/80 decreased, the expression of FOXP3 increased in the aorta sinus. The levels of serum pro-inflammatory factors IL-1β and IL-18 decreased. ConclusionsSMYAD can improve the pathological changes associated with AS and can inhibit lipid deposition in ApoE−/− mice induced by WD diet. The likely mechanism is the inhibition of the differentiation and recruitment of monocytes and macrophages, the promotion of the differentiation and recruitment of Treg cells, as well as the reduction of the secretion of pro-inflammatory factors.