Atorvastatin Treatment Research Articles

Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study.

Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell. mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers. All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters. Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.

Prophylactic and therapeutic effects of EsV3 on atherosclerotic lesions in ApoE−/− mice

BackgroundAtherosclerosis (AS) is a major contributor to vascular disorders and represents a significant risk to human health. Currently, first-line pharmacotherapies are associated with substantial side effects, and the development of atherosclerosis is closely linked to dietary factors. This study evaluated the effects of a dietary supplement, EsV3, on AS in apolipoprotein E (ApoE) −/− model mice.MethodsThe study utilized a high-fat diet-induced ApoE−/− hyperlipidemic mouse model. EsV3 was administered in prophylactic (P-EsV3) and therapeutic regimens for 16 and 12 weeks, respectively, with distinct high- and low-dose groups (0.36 and 1.8 g/kg/day). Serum lipid levels were measured and monitored for body weight and food consumption alterations in murine models. Aortic oil red O staining was conducted to assess plaque formation and calculate the plaque-to-vessel area ratio. Liver tissue changes were examined via HE staining. Moreover, serum oxidative stress markers (MDA, GSH, SOD) were measured to evaluate oxidative damage and lipid metabolism.ResultsBoth atorvastatin and P-EsV3 treatments significantly lowered TC, TG, and LDL-C levels, with P-EsV3-H enhancing HDL-C levels (P < 0.05). Prophylactic EsV3 administration was more effective than therapeutic administration in regulating TG and LDL-C levels and had comparable effects to atorvastatin on TC and HDL-C. All treatment groups exhibited reduced body weight compared to the model group, with no significant differences in food intake. Additionally, EsV3 administration significantly reduced the aortic plaque area and liver lipid droplets compared to the model group, while mitigating oxidative stress, as evidenced by decreased MDA levels and increased SOD and GSH levels, with outcomes comparable to those observed with atorvastatin.ConclusionsIn ApoE−/− hyperlipidemic mice, EsV3 improved lipid profiles and reduced aortic plaque formation. EsV3's effects, attributed partly to its antioxidant properties, were comparable to atorvastatin, suggesting its potential as a preventive and therapeutic agent for hyperlipidemia and atherosclerosis.

Inactivation of notch1-TGF-β-smads signaling pathway by atorvastatin improves cardiac function and hemodynamic performance in acute myocardial infarction rats.

To determine the effects of atorvastatin on cardiac function and hemodynamics and to investigate its functional mechanism on cardiac fibrosis in acute myocardial infarction (AMI) rats. Cardiac functions and hemodynamic changes were evaluated in each group on day 28. Quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry were performed to detect the expression of notch1, transforming growth factor-β (TGF-β), Smad2, Smad7, as well as myocardial fibrosis factors (i.e. collagen I, collagen III, and galectin-3) in the myocardial tissues of AMI rats. The changes of myocardial cell structure and myocardial collagen fibers of AMI rats were observed with hematoxylin and eosin staining and Masson staining. Atorvastatin improved the cardiac function and hemodynamic performance. Atorvastatin down-regulated the expression of notch1, smad2, collagen I, and collagen III in AMI rats. Atorvastatin treatment decreased the transcription of notch1, TGF-β, and smad2, while increased smad7 in AMI rats. Atorvastatin induced the down-regulation of collagen I, collagen III, and galectin-3. Myocardial immunohistochemical analysis showed atorvastatin inhibited the expression of notch1, TGF-β, and smad2 in myocardial tissues. Atorvastatin inhibited myocardial fibrosis by interfering with notch1-TGF-β-smads signal pathways. In addition, it could mitigate myocardial remodeling, and improve cardiac functions and hemodynamics.

Kidney function, bone health, and vascular calcifications in patients with CKD II - IV: A 2 - 3 year prospective study with bone biopsies.

Patients with chronic kidney disease (CKD) have serum, bone, and vascular abnormalities presenting as chronic kidney disease-mineral bone disorder (CKD-MBD) syndrome. This study sought to identify the parameters with the greatest relative impact on progression of CKD-MBD abnormalities. This prospective study measured 237 parameters including serum markers, clinical variables, dual-energy X-ray absorptiometry (DXA) measurements, vascular calcifications, and histomorphometric results from bone samples obtained at baseline and after 2-3 years. Relative impact of these parameters on kidney function, bone changes, and vascular calcification were assessed using machine learning, a subset of artificial intelligence analyses. Baseline estimated glomerular filtration rate (eGFR) values ranged from 18 to 70 mL/min and declined in 52% of subjects by at least 3.3% annually during the study. These declines in eGFR were associated with changes in specific serum markers, bone quantity decreases, and bone quality alterations, but not with arterial calcifications. Arterial calcifications were associated with collagen crosslinking heterogeneity, serum phosphorus, diuretics and atorvastatin treatment, but not with kidney function. Baseline collagen crosslinking heterogeneity was an important factor impacting progression of coronary, but not aortic calcification. Baseline serum phosphorus was a factor primarily associated with progression of aortic calcification. Machine learning revealed specific bone and vascular abnormalities occurring early during loss of kidney function. Bone, vascular, blood, medication use, and other parameters were identified impacting the presence and progression of arterial calcification and altering bone quality and quantity in this understudied patient population. Serum phosphorus levels considered normal impacted progression of arterial calcification. Identification of these parameters and their relative importance enhances our understanding of CKD progression and should improve patient care.

Anti-Dyslipidemic Potential of Sulfated Glycosaminoglycan from Rock Oyster Saccostrea cucullata: An in vivo study.

The rock oyster, Saccostrea cucullata, native to the Indo-Pacific region, is renowned for its nutritional and therapeutic benefits. A sulfated glycosaminoglycan (SCP-2) with β-(1→3)-GlcNSp and α-(1→4)-GlcAp as recurring units isolated from S. cucullata. SCP-2 exhibited substantial 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibition potential (IC50 0.65 mg/mL) in comparison with atorvastatin (IC50 0.72 mg/mL). An in vitro study of SCP-2 (0.1-160 μg/dL) revealed a 77-89% reduction in triglyceride levels in control Caco-2 cells after 4 days of incubation, similar to atorvastatin-treated cells (90%). The acute dyslipidemic efficacy of SCP-2 (at 90 mg/kg body weight) showed timely alleviation of triglyceride and cholesterol levels in tyloxapol-induced rats (∼43% and 81% inhibition at 5 h), which was analogous to the atorvastatin treatment group (∼66% and 71%). Furthermore, SCP-2 (at 90 mg/kg body weight) showed mitigation in triglyceride (> 50%) and cholesterol levels (> 25%) in high-fat high-cholesterol (HFHC) diet-induced rats, similar to the lovastatin treatment group (approximately 62% and 33% inhibition on the 45th day). Histopathological studies of SCP-2 also showed recovery in steatosis, inflammation, and ballooning degradation in liver tissues. Structure-activity relationship analysis suggested the sulfate groups in SCP-2 enhance its anti-dyslipidemic efficacy. The capability of SCP-2 to mitigate cholesterol, triglyceride, and HMGCR levels makes it a prospective functional food against dyslipidemia-related disorders.

Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells

Statins are cholesterol-lowering drugs often used for the treatment of dyslipidemia. Statins also exert anti-cancer effects by inhibiting hydroxymethylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We previously reported that the susceptibility to statin treatment differs among cancer cells and that functional E-cadherin expression on the plasma membrane could be a biomarker of statin sensitivity in cancer cells. However, the detailed qualitative and molecular differences between statin-sensitive and statin-resistant cancer cells remain unclear. Here, we explored novel parameters related to statin sensitivity by comparing gene expression profiles and metabolite contents between statin-sensitive and statin-resistant lung cancer cell lines. We found that the expression of most cholesterol synthesis genes was lower in the statin-sensitive cancer cell line, HOP-92, than in the statin-resistant cancer cell line, NCI-H322M. Moreover, HOP-92 cells originally exhibited lower levels of CoA and HMG-CoA. Additionally, atorvastatin decreased the mRNA expression of PANK2, a rate-limiting enzyme in CoA synthesis. Atorvastatin also reduced the mRNA levels of the cholesterol esterification enzyme SOAT1, which was consistent with a decrease in the ratio of cholesterol ester to total cholesterol in HOP-92 cells. Our data suggest that the cholesterol synthetic flow and CoA content may be limited in statin-sensitive cancer cells. We also suggest that CoA synthesis and cholesterol storage may fluctuate with atorvastatin treatment in statin-sensitive cancer cells.

Mechanism of atorvastatin in treating hepatocellular carcinoma: a study based on network pharmacology, molecular docking, and bioinformatics analysis.

Hepatocellular carcinoma (HCC) is a tumor with high morbidity and mortality. Current research suggests that statins may aid in its prevention and treatment, while studies on the associated mechanisms remain limited. Therefore, we aim to reveal the mechanism of atorvastatin treatment for HCC by using network pharmacology and bioinformatics methods. The databases SwissTargetPrediction, PharmMapper, and DrugBank were utilized to obtain targets of atorvastatin, while GSE169289, GSE135631, and GSE207435 were used to identify differentially expressed genes (DEGs) for HCC. The overlap between the two groups was used to identify atorvastatin's target for treating HCC. Following protein-protein interaction (PPI) analysis, hub genes were identified using Cytoscape software and LASSO analysis. The hub genes were further validated using data from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) databases. To evaluate the clinical significance of the hub genes, Kaplan-Meier (KM) survival analysis and Cox analysis were conducted. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to investigate potential mechanisms. Finally, molecular docking analysis was performed to validate the interaction between atorvastatin and the hub genes. A total of 1948 DEGs of HCC and 380 targets of atorvastatin were identified, respectively. After taking the intersection, 79 genes were identified as potential targets of atorvastatin for HCC treatment. After multiple screening methods, CYP2C9 was ultimately identified as the hub gene. Analysis of data from TCGA and HPA databases showed reduced expression of CYP2C9 in HCC tissues. KM and Cox analysis showed a favorable prognosis for HCC patients with high CYP2C9 expression. KEGG and GSEA indicated that metabolism of xenobiotics by cytochrome P450, and PPAR signaling pathway could be the potential mechanisms for atorvastatin in treating HCC. Molecular docking analysis revealed that atorvastatin binds to CYP2C9 with a binding energy of - 8.837, indicating highly stable binding. CYP2C9 is associated with the prognosis of HCC patients and could serve as a potential target for atorvastatin treatment in HCC.

CYP3A4*1B and CYP3A5*3 SNPs significantly impact the response of Egyptian candidates to high-intensity statin therapy to atorvastatin

BackgroundA single nucleotide polymorphism (SNP) is a variation in the DNA sequence that results from the alteration of a single nucleotide in the genome. Atorvastatin is used to treat hypercholesterolemia. It belongs to a class of drugs called statins, which lower elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Research findings on the associations between the response to atorvastatin and genetic polymorphisms in CYP3A4 and CYP3A5 are inconclusive. The effects of CYP3A4*1B (rs2740574 C/T) and CYP3A5*3 (rs776746 T/C) on atorvastatin therapy have not been previously studied among Egyptians.ObjectiveThis research aimed to investigate the effects of the genetic polymorphisms CYP3A4*1B and CYP3A5*3 on atorvastatin treatment in Egyptians.MethodsIn this prospective cohort study, 100 subjects were genotyped for these SNPs. All participants were screened for serum lipid profiles, liver enzymes, total bilirubin (TB), and creatine kinase (CK) before and after 40 mg postatorvastatin therapy. Atorvastatin plasma levels were assessed posttreatment; atorvastatin pharmacokinetics were evaluated in five carriers of the CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes.ResultsThe allele frequencies of the CYP3A4*1B and CYP3A5*3 SNPs were 86% and 83%, respectively. The CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes significantly improved the serum triglyceride (TG) level (P < 0.05) and elevated the TB level (P < 0.001). Atorvastatin plasma levels were greater in CYP3A4*1B (T/T) (P < 0.05) and CYP3A5*3 (C/C) (P < 0.001) genotype carriers. Both SNPs significantly affected the pharmacokinetics of atorvastatin compared with those of Egyptian volunteers and various ethnic populations.ConclusionsThe CYP3A4*1B and CYP3A5*3 variants were prevalent in the study participants and could impact the effectiveness and safety of atorvastatin therapy. The mutant genotype of the CYP3A4*1B SNP and the CYP3A5*3 SNP led to high atorvastatin levels. Both variants had a notable effect on the pharmacokinetics of atorvastatin among Egyptians compared with healthy Egyptians and volunteers from other ethnic populations. Overall, clinicians can learn more about the impact of both variants in response to atorvastatin.Graphical

The Influence of Atorvastatin Treatment on Homocysteine Metabolism and Oxidative Stress in an Experimental Model of Diabetic Rats.

In our experimental study, we evaluated the influence of treatment with atorvastatin on the antioxidant activity of intracellular and extracellular systems factors, homocysteine levels (Hcy), and lipid profiles in obese and diabetic rats. Twenty-one male Wistar rats, aged 6 months, 450-550 g, were allocated into three groups. From the beginning of the study, the first group (G-I, control) received only standard food, while the second and third groups (G II-obese, G III-diabetic) were administered a high-fat diet (HFD) with 2% cholesterol. After 2 weeks of accommodation, the specimens in G-III were injected intraperitoneal (i.p.) streptozotocin (35 mg of body weight, pH 4.5), intervention followed by the onset of type 2 diabetes mellitus. Following confirmation of diabetes onset, the specimens in G III were administered concomitantly with the HFD a daily gavage of atorvastatin 20 mg of body weight/day for 20 days. We measured, at the beginning and the end of the study, the Hcy levels, lipid profile, vitamin B12, B6, folic acid, and various parameters of oxidative stress (OS)-total antioxidant status (TAS), glutathione peroxidase (GPX) and superoxide dismutase (SOD). After treatment with atorvastatin, the lipid profile in G III significantly improved compared to the other two groups, but enzymatic markers of oxidative stress did not closely parallel this trend. However, after the treatment of statin, we observed an important reduction in Hcy values. Our results demonstrate that treatment with atorvastatin can be used not only for its lipid-lowering properties and antioxidant effects but also to reduce Hcy concentration in this experimental model of diabetic rats. Moreover, atorvastatin therapy improves lipid profiles, reduces inflammation, suppresses oxidation, and decreases Hcy levels, potentially preventing major adverse cardiovascular events.

Investigating the presence, distribution and risk of pharmaceutically active compounds (PhACs) in wastewater treatment plants, river sediments and fish

The increasing consumption of medicines and the lack of efficient technologies in wastewater treatment plants (WWTPs) can release pharmaceutically active compounds (PhACs) into any given river with the subsequent risk to the environment and human health. To assess the occurrence and transfer pathways of PhACs through the river ecosystem, 22 PhACs and one metabolite were analyzed in WWTPs, river sediments and fish collected alongside the Tagus River basin between 2020 and 2022. All the matrices presented at least two drugs being azithromycin the only one quantified in all of them. Analgesics, anti-inflammatories, antihypertensives, antidepressants and beta-blockers were the main PhACs in influents, with median concentrations up to 19 μg/L. In effluents, antihypertensives and antidepressants were the PhACs with the highest contribution. For acetaminophen, ibuprofen, ketoprofen, naproxen, atorvastatin, azithromycin, clarithromycin, sulfamethoxazole, trimethoprim, and valsartan WWTPs treatments reached removal efficiencies above 75%. Compounds with a high tendency to bind to organic matter were retained in sludge (clotrimazole, 96 ng/g before digester, 100%). However, results showed that applied treatments were not effective in removing PhACs from this matrix. Although the total mass balance revealed a high removal rate of some PhACs, many of them were still present in the effluent and their release into rivers became the main source of PhAC pollution of the aquatic ecosystem. The most hydrophobic ones (irbesartan, 24 ng/g, 61%), positively charged (o-desmethylvenlafaxine, 95 ng/g, 68%) and those with affinity to organic matter (clotrimazole, 21 ng/g, 61%) reached sediment samples. Only clotrimazole (7.8 ng/g) and azithromycin (160 ng/g) were found in fish samples. Risk assessment revealed a high risk for (i) acetaminophen, clarithromycin, erythromycin A, and venlafaxine in phototrophic organisms and (ii) acetaminophen and venlafaxine in fish.

Combined administration of atorvastatin and mesenchymal stem cells synergizes to attenuate inflammation and promote efferocytosis in atherosclerotic mice

Abstract Background Atherosclerosis (AS), characterized by chronic systemic and lesional inflammation, is by far the most frequent underlying cause of cardio-cerebrovascular diseases. Recently, impaired efferocytosis, referring to defective removal of dead cells, was identified as another essential factor contributing to the development of AS, which is partly attributed to upregulation of CD47 and explain the benefits of atorvastatin (ATV). Mesenchymal stem cells (MSCs) were reported to protect against AS by inhibiting inflammation; while whether ATV and MSCs could synergize to attenuate inflammation and promote efferocytosis and consequently, reduce AS burden, remains unclear. Methods To establish the AS model, 6-week-old male ApoE-/- mice fed with Western diet for 12 weeks were used and grouped randomly (n=15 per group). The scheme of administration of ATV and human umbilical cord MSCs was shown in Figure 1A. After 6-week treatment, mice were sacrificed, and hearts and aortas were harvested. Oil Red O staining was used to evaluate the lesional burden. Immunofluorescence staining was used to assess the inflammation and efferocytosis in the plaque. A high level of CD11b+ cells (macrophages) infiltration was considered an indicator of inflammation; a high level of cleaved caspase 3 puncta unmerged with macrophages (Mac3+ area) was considered an indicator of impaired efferocytosis. Results Human umbilical cord MSCs were identified as CD73+CD90+CD105+CD45-CD14- cells. Evoked inflammation and defective clearance of apoptotic cells in the plaque were observed (Figure 1B, C). ATV and MSC treatment inhibited macrophage infiltration and activated efferocytosis. Given the mechanistic idea that upregulated CD47 blocks the Signal regulatory protein α (SIRPα) / src homology-2 (SH2)-domain-containing protein tyrosine phosphatases (SHP) signal and leads to efferocytosis impairment, we evaluated the expression levels of CD47 in plaque and phosphorylated SHP (p-SHP) in lesional macrophages (Figure 2A, B). The elevation of CD47 expression and consequent downregulation of p-SHP was reversed by both ATV and MSCs, with a lower lesion burden observed in NS+MSC, ATV+PBS and ATV+MSC groups. All benefits were more pronounced in the group received combined treatment (ATV+MSC). Conclusions The results indicated ATV and MSC administration could synergizes to attenuate inflammation and promote efferocytosis in AS plaque, and the combined treatment led to the lowest lesion burden. CD47/p-SHP signal plays an essential role in the activation of efferocytosis. The mechanisms underlying the inhibition of CD47 are currently under investigation.

Prolonged treatment of compactin, atorvastatin, lovastatin or simvastatin decreased glucose consumption and expressions of proteins for glucose metabolism and insulin signaling in L6 skeletal muscle cells

Statins inhibit mevalonate synthesis and successfully lower plasma cholesterol levels and decrease the risk of cardiovascular diseases in humans, but also lead to myalgia in some patients. We hypothesize that statins may modulate glucose metabolism and insulin signaling in the skeletal muscle cells during and after differentiation, and in turn lead to side effects. Here, differentiating and differentiated L6 muscle cells were treated with 1 μM of different class of statins (compactin, pravastatin, atorvastatin, lovastatin and simvastatin) with or without insulin or mevalonate for extended periods of time. The glucose consumption and expression levels of proteins for glucose metabolism and insulin receptor (IR)/Akt signaling were determined. The prolonged statin treatments (except pravastatin) decreased glucose consumption in L6 skeletal muscle cells. In differentiating L6 cells, compactin, lovastatin or simvastatin decreased the expression levels of proteins involved in glucose metabolism and insulin signaling, including glucose transporter 4 (GLUT4), pyruvate dehydrogenase (PDH), glycogen synthase (GS), glycogen synthase kinase 3β (GSK3β) and insulin receptor β subunit (IRβ). In differentiated L6 cells, long-term treatment of compactin or simvastatin also decreased levels of proteins in glucose metabolism and IR/Akt signaling, including GLUT4, GSK3β, IRβ and PI3K p110α. Insulin treatment restored statin-mediated impairments in L6 cells. The insulin-mediated phosphorylation of Akt Ser473 was attenuated in differentiating and differentiated L6 cells in the presence of atorvastatin (differentiated only), compactin, lovastatin or simvastatin. In addition, mevalonate supplementation reversed the statin-mediated impairments in differentiated and differentiating L6 cells. Statin affected glucose usage and insulin signaling by inhibiting mevalonate synthesis in L6 cells. Our results provides a possible mechanism of adverse effects of statins in skeletal muscle and calls for cautious use of the medication in patients with impaired insulin sensitivity and glucose metabolism.

The Impact of Atorvastatin Treatment on the Distribution of Low-Density Lipoprotein Subfractions and the Level of Vitamin D in Patients After Acute Myocardial Infarction: Preliminary Findings

Clinical trial results indicate that statin therapy aimed at normalising the lipid profile can prevent and reduce the risk of cardiovascular events. Both LDL and HDL consist of several subfractions, with only the smallest and densest subfractions being the most atherogenic. We examine the effect of Atorvastatin treatment not only on basic lipid profile parameters but also atherogenic lipoprotein subfractions and 25(OH)D levels in patients after the first acute myocardial infarction. The study population had not previously received lipid-lowering medications. Serum 25(OH)D concentration was determined by direct competitive immunochemiluminescent assays. Lipoprotein subfractions, including VLDL, IDL-C, IDL-B, and IDL-A, as well as LDL1, LDL2 (large LDL), and LDL3-7 (sdLDL), were measured in serum (Lipoprint® system). Almost all patients had 25(OH)D deficiency. Atorvastatin primarily reduced strongly atherogenic sdLDL and decreased the less atherogenic large LDL subfractions. A statistically significant reduction in VLDL cholesterol and IDL fractions was also observed. Analysing LDL subfractions provides a more detailed insight into lipid metabolism and enables the identification of patients with a more atherogenic phenotype. LDL subfractions may thus become not only more accurate prognostic biomarkers but also targets for lipid-lowering therapy. Vitamin D deficiency is associated with atherogenic dyslipidaemia, particularly high levels of sdLDL.

Comparison of Atorvastatin Alone and its Combination with Ezetimibe among Mixed Hyperlipidemic Patients

Background: Lowering the lipid levels remains the basis of recent medical therapy for preventing cardiovascular events. Statin treatment to attain target low-density lipoprotein cholesterol (LDL-C) levels is still associated with residual risk. Objective: To compare the efficacy of Atorvastatin and Atorvastatin combined with Ezetimibe among mixed hyperlipidemic patients. Methodology: This was a prospective interventional study among the 58 diagnosed mixed hyperlipidemic patients in the outpatient department (OPD) of the Department of Cardiology at the Sylhet MAG Osmani Medical College Hospital during February to November, 2023. Patients were divided into two groups. Group I had a combination of Atorvastatin 10mg and Ezetimibe 10mg, whereas Group II took Tab. Atorvastatin 20mg once daily at night for 12 weeks. Results: After 12 weeks of treatment, a comparison of lipid profile changes between the combination therapy group and the Atorvastatin group revealed a significant reduction (p&lt;0.05) in total cholesterol (35.7% vs. 30.1%), triglycerides (30.6% vs. 16%), and LDL-C (47.5% vs. 40.1%). In the combination therapy group, ALT levels increased by 4.6%, compared to a 3.8% increase with Atorvastatin treatment alone. Combination therapy led to a 2.07% elevation in CK levels, while the Atorvastatin treatment group showed a 1.9% increase in CK values. The differences in HDL-C, ALT, and CK levels between the two groups were not statistically significant (p&gt;0.05). Conclusion: The study revealed that combination therapy of Atorvastatin with Ezetimibe is more effective in reducing LDL-C, TG, and total cholesterol in patients with mixed hyperlipidemia compared to Atorvastatin alone. Journal of Monno Medical College June, 2024; 10 (1):23-29

Mevalonate in blood and muscle: Response to atorvastatin treatment and the relationship to statin intolerance in patients with coronary heart disease.

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. Invitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference -38%, range -77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range -47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho -0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference -8.1 (-22 to 3.5) nmol/L versus -25 (-93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.

Impact of Long-Term Atorvastatin Therapy on the Development of Chronic Lung Allograft Dysfunction in Patients with Azithromycin Prophylaxis after Lung Transplantation

ObjectiveTo assess the impact of long-term atorvastatin (ATO) therapy on reducing recipient inflammation and immune response, thus lowering the risk of chronic lung allograft dysfunction (CLAD) in lung transplant recipients. This study aimed to investigate the effects of ATO on overall survival, lung function recovery, and its influence on inflammatory factors alongside azithromycin (AZI) prophylaxis. MethodsThis retrospective single-center study included lung transplant recipients from January 2017 to December 2022. Patients who survival >1 year after lung transplantation and who were receiving AZI prophylaxis for >6 months were selected. Outcome measures involved pulmonary function assessments at various time points after AZI treatment, complete blood cell analysis, and inflammatory factor evaluations. ResultsThe incidence of CLAD was significantly lower in the long-term ATO group compared with those not on ATO (P = .011). Long-term ATO treatment significantly delayed CLAD onset after lung transplantation (850 days vs. 630 days; P = .041), with patients showing notably enhanced lung function recovery within 6 months of AZI therapy compared with the non-ATO group. Neutrophil levels decreased in patients with CLAD, and interleukin-6 concentrations significantly decreased in the AZI + ATO group compared with the AZI group. Overall patient survival was significantly better in the AZI+ATO group than in the AZI group (P = .02). ConclusionIn cases where CLAD develops despite AZI prophylaxis, long-term ATO treatment may lead to short-term improvements in lung function. It could also decrease inflammation levels in lung transplant recipients and enhance overall survival. The combination of AZI and long-term ATO therapy may be beneficial for CLAD prevention.

Pharmacodynamics of Qingxin Jieyu Granules for treatment of atherosclerosis and its regulatory mechanism for lipid metabolism

To elucidate the therapeutic mechanism of Qingxin Jieyu Granule (QXJYG) against atherosclerosis (AS) based on network pharmacology. The major targets and pathways of QXJYG against AS were analyzed using network pharmacology. Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline, atorvastatin (13.15 mg/kg), or QXJYG at 0.99, 1.98, and 3.96 g/kg for 8 weeks (n=6). Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta. Blood lipids and serum levels of Ang Ⅱ, ET-1, TXA2, PGI2, and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA. The expressions of LOX-1, PPARγ, RXRα, p-P65, VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry. The rat models of AS showed obvious abdominal aorta wall thickening, increased pulse wave velocity and pulse index, decreased inner diameter of the abdominal aorta, elevated levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and lowered levels of HDL-C and PGI2. QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta, decreased serum levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and increased the levels of HDL-C and PGI2. Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism, PPAR and NF-κB pathways. Consistently, treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1, P-P65, VCAM-1 and ICAM-1 protein expressions while increasing PPARγ and RXRα expressions in the aorta of AS rats. QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level, reducing LOX-1 expression, activating PPARγ and RXRα, and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.

Effects of in utero benzo[a]pyrene exposure on the testis of rats during puberty and the protective effect of atorvastatin.

Benzo[a]pyrene (BaP) is a contaminant that is generated in the environment through processes such as smoke, incomplete combustion of fossil fuels, vehicle exhaust emissions, entry into the body is through inhalation, and consumption of contaminated food. It is an omnipresent environmental pollutant with unavoidable exposure. BaP metabolites are observed in the male reproductive system, especially in the testes and epididymis of animals, and are responsible for reduced testicular and epididymal function. The protective effect of atorvastatin (ATV) on testicular damage was investigated previously. The aim of the present study was to investigate the protective effect of ATV on testicular toxicity induced by benzo[a]pyrene (BaP) during pregnancy in Wistar rats. This experimental laboratory study involved 40 adult rats, divided into seven groups and maintained under standard environmental conditions. The groups received different diets [control, corn oil, ATV (10 mg/kg), BaP (10 and 20 mg/kg), and ATV + BaP (10 and 20 mg/kg)] at gestation Days 7-16, orally. Male offspring were examined 10 weeks after birth. Testis and serum samples were collected, and testosterone level, malondialdehyde (MDA), and glutathione (GSH) were measured. Histological and immunohistochemical assays were performed under a light microscope. Statistical analysis was conducted using SPSS, with analysis of variance and Tukey tests to assess significant differences between groups. ATV significantly reduced MDA, a marker of lipid peroxidation and oxidative stress in rat testes following BaP administration. Treatment with ATV at doses of 10 mg/kg increased GSH levels, correcting disruptions in the antioxidant system caused by BaP. Testosterone concentration in rats treated with ATV and BaP substantially prevented the decrease induced by BaP. Histomorphometry revealed that ATV significantly prevented the detrimental effects of BaP on the thickness of spermatogenic epithelium and the diameter of seminiferous tubules. Under ATV treatment, testicular tissue histopathology improved, and spermatogenesis returned to a almost back to normal state. Caspase-3 expression decreased, and apoptosis activity in testicular tissue improved under ATV treatment, indicating a positive effect of ATV in reducing apoptotic damage caused by BaP. In conclusion, exposure to BaP can induce oxidative stress-related damage to testicular tissue, as evidenced by an increase in MDA levels, which ATV treatment can mitigate. Additionally, ATV enhances intracellular antioxidant GSH and protects the testes against BaP-induced damage while increasing testosterone levels, which are reduced due to exposure to BaP.

Short-Term Atorvastatin Therapy in Healthy Individuals Results in Unaltered Plasma MMP Levels and Disrupted MMP-7 Correlation with Blood Lipids and Blood Count-Derived Inflammatory Markers.

Background: Matrix metalloproteinases (MMPs) play an important role in the pathophysiology of atherosclerosis. Reportedly, statins can decrease MMP activity in patients with atherosclerotic cardiovascular disease, but this effect has not been studied in healthy individuals. Methods: MMPs 2, 7, and 9 and several other parameters were measured before and after a four-week course of moderate-dose atorvastatin (20 mg/day) in 21 healthy individuals. Results: Atorvastatin treatment resulted in lower total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and triglycerides (p < 0.001 for all), but higher levels of plasma enzymes AST, ALT, CK, and LDH (p < 0.05 for all). No effect of atorvastatin on plasma MMP median concentrations was recorded. Before treatment, moderate positive significant correlations were found between MMP-7 and age, blood lipids, and blood count-derived inflammatory markers. Pre-treatment MMP-7 was best predicted by the total cholesterol-to-HDL cholesterol ratio in a remnant cholesterol-weighted least squares regression model. After atorvastatin treatment, MMP-7 no longer correlated with these markers. Conclusions: While the effect of statins on plasma MMPs in atherosclerosis is controversial, short-term moderate-dose atorvastatin treatment does not seem to affect levels of MMPs 2, 7, and 9 in healthy individuals. However, an intriguing correlation between MMP-7 and atherosclerosis-related blood lipids and neutrophil-associated inflammatory biomarkers seems to be disrupted by atorvastatin independently of hsCRP, possibly via pleiotropic effects.

Effect of rosuvastatin versus atorvastatin on new-onset diabetes mellitus in patients treated with high-intensity statin therapy for coronary artery disease: a post-hoc analysis from the LODESTAR randomized clinical trial

BackgroundThe impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial.MethodsIn the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest.ResultsAmong 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was < 70 mg/dL (13.9% versus 8.0%; HR = 1.79, 95% CI 1.18 to 2.73, P = 0.007).ConclusionsAmong CAD patients receiving high-intensity statin therapy, the incidence of NODM was not significantly different between rosuvastatin and atorvastatin. However, a drug effect of the statin type on NODM was observed when the achieved LDL-C level was < 70 mg/dL.Trial registrationClinicalTrials.gov, Identifier: NCT02579499.Graphical abstract