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Acta Pharmaceutica (Zagreb, Croatia) Sep 2023The advancements in proteomics have provided a better understanding of the functionality of apolipoproteins and lipoprotein-associated proteins, with the HDL lipoprotein...
The advancements in proteomics have provided a better understanding of the functionality of apolipoproteins and lipoprotein-associated proteins, with the HDL lipoprotein fraction being the most studied. The focus of this study was to evaluate the HDL proteome in dyslipidemic subjects without an established cardiovascular disease, as well as to test whether rosuvastatin treatment alters the HDL proteome. Patients with primary hypercholesterolemia or mixed dyslipidemia were assigned to 20 mg/day rosuvastatin and blood samples were drawn at study entry and after 12 weeks of treatment. A label-free LC-MS/MS protein profiling was conducted, coupled with bioinformatics analysis. Sixty-nine HDL proteins were identified, belonging to four main biological function clusters: lipid transport and metabolism; platelet activation, degranulation, and aggregation, wound response and wound healing; immune response; inflammatory and acute phase response. Five HDL proteins showed statistically significant differences in the abundance (Anova ≤ 0.05), before and after rosuvastatin treatment. Platelet factor 4 variant (PF4V1), Pregnancy-specific beta-1-glycoprotein 2 (PSG2), Profilin-1 (PFN1) and Keratin type II cytoskeletal 2 epidermal (KRT2) showed decreased expressions, while Integrin alpha-IIb (ITGA2B) showed an increased expression after treatment with rosuvastatin. The ELISA validation of PFN1 segregated the subjects into responders and non-responders, as PFN1 levels after rosuvastatin were shown to mostly depend on the subjects' inflammatory phenotype. Findings from this study introduce novel insights into the HDL proteome and statin pleiotropism.
Topics: Female; Pregnancy; Humans; Proteome; Rosuvastatin Calcium; Chromatography, Liquid; Tandem Mass Spectrometry; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Profilins
PubMed: 37708957
DOI: 10.2478/acph-2023-0034 -
International Journal of Molecular... May 2023Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate...
Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas.
Topics: Male; Animals; Rabbits; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Interleukin-10; Myeloid Differentiation Factor 88; Fluvastatin; Tumor Necrosis Factor-alpha; Interleukin-2; Interleukin-4; Interleukin-8; Atherosclerosis; Aortic Diseases; Aorta, Abdominal; Inflammation; Chemokines
PubMed: 37298199
DOI: 10.3390/ijms24119248 -
Yonsei Medical Journal Jan 2024There are few studies in the literature on the dosage of statin that equivalently reduces low-density lipoprotein cholesterol (LDL-C) compared to an ezetimibe... (Meta-Analysis)
Meta-Analysis
PURPOSE
There are few studies in the literature on the dosage of statin that equivalently reduces low-density lipoprotein cholesterol (LDL-C) compared to an ezetimibe combination and whether such regimens have differences in safety. We compared the lipid-modifying efficacy and safety of 5 mg rosuvastatin/10 mg ezetimibe to those of 20 mg rosuvastatin.
MATERIALS AND METHODS
A literature search was conducted using the PubMed, EMBASE, Cochrane, Web of Sciences, and SCOPUS databases up to December 2021. Human studies investigating the two aforementioned regimens with a randomized controlled design were selected. Outcome variables included the percentage reduction in LDL-C and other lipid parameters and rates of composite adverse events (AEs), including muscle-related symptoms. A random-effects meta-analysis was performed after heterogeneity testing between studies.
RESULTS
Seven studies were included in this meta-analysis. The percentage LDL-C reduction did not differ between the combination and monotherapy groups [standardized mean difference (SMD) 0.08; 95% confidence interval (CI) -0.09 to 0.26; =0.35]. The risk of composite AEs (odds ratio 0.50; 95% CI 0.15 to 1.72; =0.27) of the combination was not different compared to the monotherapy group. The percentage of total cholesterol reduction was greater in the combination group (SMD 0.22; =0.02), whereas that of triglyceride reduction and high-density lipoprotein cholesterol elevation did not differ between the two groups.
CONCLUSION
This meta-analysis showed that 5 mg rosuvastatin/10 mg ezetimibe had largely comparable lipid-modifying efficacy and tolerability as 20 mg rosuvastatin.
Topics: Humans; Rosuvastatin Calcium; Ezetimibe; Cholesterol, LDL; Anticholesteremic Agents; Hypercholesterolemia; Drug Therapy, Combination; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Treatment Outcome
PubMed: 38154476
DOI: 10.3349/ymj.2023.0285 -
Diabetes & Metabolism Journal Jan 2024Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparative Efficacy of Rosuvastatin Monotherapy and Rosuvastatin/Ezetimibe Combination Therapy on Insulin Sensitivity and Vascular Inflammatory Response in Patients with Type 2 Diabetes Mellitus.
BACKGRUOUND
Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present study aimed to compare the effects of rosuvastatin monotherapy and rosuvastatin/ezetimibe combination therapy on lipid profile, insulin sensitivity, and vascular inflammatory response in patients with T2DM.
METHODS
A total of 101 patients with T2DM and dyslipidemia were randomized to either rosuvastatin monotherapy (5 mg/day, n=47) or rosuvastatin/ezetimibe combination therapy (5 mg/10 mg/day, n=45) and treated for 12 weeks. Serum lipids, glucose, insulin, soluble intercellular adhesion molecule-1 (sICAM-1), and peroxiredoxin 4 (PRDX4) levels were determined before and after 12 weeks of treatment.
RESULTS
The reduction in low density lipoprotein cholesterol (LDL-C) by more than 50% from baseline after treatment was more in the combination therapy group. The serum sICAM-1 levels increased significantly in both groups, but there was no difference between the two groups. The significant changes in homeostasis model assessment of insulin resistance (HOMA-IR) and PRDX4 were confirmed only in the subgroup in which LDL-C was reduced by 50% or more in the combination therapy group. However, after adjusting for diabetes mellitus duration and hypertension, the changes in HOMA-IR and PRDX4 were not significant between the two groups.
CONCLUSION
Although rosuvastatin/ezetimibe combination therapy had a greater LDL-C reduction effect than rosuvastatin monotherapy, it had no additional effects on insulin sensitivity and vascular inflammatory response. Further studies are needed on the effect of long-term treatment with ezetimibe on insulin sensitivity and vascular inflammatory response.
Topics: Humans; Anticholesteremic Agents; Cholesterol, LDL; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; Rosuvastatin Calcium; Treatment Outcome
PubMed: 38173371
DOI: 10.4093/dmj.2022.0402 -
PloS One 2018Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate...
PURPOSE
Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate and bioavailability. Therefore, the aim of the current study is to prepare ROSCa nanoparticles by wet milling technique using planetary ball mill. The codesign between formulation and stabilization of nanoparticles was studied to achieve both high dissolution as well as bioavailability.
METHODOLOGY
ROSCa nanosuspensions was prepared by wet milling technique using planetary ball mill, by applying milling ball size of 0.1 mm at speed of 800 rpm for 3 cycles each cycle composed of 10 minutes. HPMC, PVP k-30, pluronic F-127, Tween 80 and PEG 6000 were used as stabilizers. The nanosuspensions were then freeze-dried, and the dried nanoparticles were evaluated for particle size, zeta potential, in-vitro dissolution test, XRPD and in-vivo study.
RESULTS
ROSCa nanoparticles stabilized with 10% PVP (P3) had a good stability with smallest particle size, which in turn enhanced the dissolution rate. The particle size of the leading formula was 461.8 ± 16.68 nm with zeta potential of -31.8 ± 7.22 mV compared to untreated drug that has a particle size of 618μm. The percent of ROSCa dissolved after 1 hour enhanced significantly which reached 72% and 58.25% for leading nanoparticle formula and untreated ROSCa, respectively (P < 0.05). The in-vivo study of ROSCa from the leading nanoparticle formula showed a significant enhancement in the Cmax after 2 h (82.35 ng/ml) compared to 9.2 ng/ml for untreated drug.
CONCLUSION
Wet milling technique is a successful method to prepare ROSCa nanoparticles. From different stabilizer used, PVP (10%) was able to produce stable nanoparticle with small particle size which significantly enhance the dissolution rate and pharmacokinetics parameters of ROSCa.
Topics: Animals; Anticholesteremic Agents; Biological Availability; Drug Compounding; Drug Design; Nanoparticles; Particle Size; Rabbits; Rosuvastatin Calcium
PubMed: 29985967
DOI: 10.1371/journal.pone.0200218 -
The Journal of Antimicrobial... Dec 2023Global emergence of rapidly developing resistance to multiple antifungal drugs and high mortality pose challenges to the treatment of invasive Candida auris infections....
BACKGROUND
Global emergence of rapidly developing resistance to multiple antifungal drugs and high mortality pose challenges to the treatment of invasive Candida auris infections. New therapeutic approaches are needed, such as repurposing drugs including combination with antifungals. Statins have been reported to exert antifungal effects against various Candida species.
OBJECTIVES
Our study investigated potential synergy between the statins (rosuvastatin and fluvastatin) and azoles (voriconazole, posaconazole and isavuconazole) on clinical isolates of C. auris.
METHODS
Twenty-one clinical isolates of C. auris were obtained. Chequerboard assays based on the CLSI broth microdilution method were used to assess synergy based on FIC index (FICI) calculations of MICs of individual drugs and in combinations.
RESULTS
Single drug geometric mean (GM) MICs of fluvastatin and rosuvastatin were ≥128 mg/L in all 21 isolates. GM (range) MICs of posaconazole, voriconazole and isavuconazole were 0.259 (0.016-1 mg/L), 0.469 (0.016-2 mg/L) and 0.085 (0.004-1 mg/L), respectively. Combination of azoles with fluvastatin showed synergy in 70%-90% of C. auris isolates. In particular, voriconazole/fluvastatin resulted in 16-fold reduction in voriconazole MIC and synergy in 14/21 (67%) isolates. Posaconazole/fluvastatin resulted in 8-fold reduction in posaconazole MIC and synergy in 19/21 (90%) isolates.Combining rosuvastatin with the azoles also showed synergy against C. auris in 40%-60% of the isolates and additive effect in 40%-50%. None of the combinations was antagonistic.
CONCLUSIONS
Our results provide a rationale for pursuing in vivo synergy tests as well as clinical studies to explore tolerability, treatment outcomes, optimal dose and exposure targets.
Topics: Antifungal Agents; Voriconazole; Candida auris; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Fluvastatin; Rosuvastatin Calcium; Azoles; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37823357
DOI: 10.1093/jac/dkad303 -
CPT: Pharmacometrics & Systems... Jan 2021Physiologically-based pharmacokinetic (PBPK) modeling is increasingly used to predict drug disposition and drug-drug interactions (DDIs). However, accurately predicting... (Review)
Review
Physiologically-based pharmacokinetic (PBPK) modeling is increasingly used to predict drug disposition and drug-drug interactions (DDIs). However, accurately predicting the pharmacokinetics of transporter substrates and transporter-mediated DDIs (tDDIs) is still challenging. Rosuvastatin is a commonly used substrate probe in DDI risk assessment for new molecular entities (NMEs) that are potential organic anion transporting polypeptide 1B or breast cancer resistance protein transporter inhibitors, and as such, several rosuvastatin PBPK models have been developed to try to predict the clinical DDI and support NME drug labeling. In this review, we examine five representative PBPK rosuvastatin models, discuss common challenges that the models have come across, and note remaining gaps. These shared learnings will help with the continuing efforts of rosuvastatin model validation, provide more information to understand transporter-mediated drug disposition, and increase confidence in tDDI prediction.
Topics: Animals; Computer Simulation; Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Biological; Rosuvastatin Calcium
PubMed: 33220025
DOI: 10.1002/psp4.12571 -
Yonsei Medical Journal Mar 2023Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with diabetes and/or dyslipidemia. However, statins and antidiabetic agents have opposite pharmacological effects, because statins, particularly atorvastatin and rosuvastatin, impair glucose homeostasis, increasing the risk of new-onset diabetes, whereas antidiabetic drugs improve glycemic homeostasis. The aim of this study was to investigate the effect of atorvastatin, rosuvastatin, and pitavastatin on glucose homeostasis in patients with type 2 diabetes mellitus (T2DM) and dyslipidemia during stable treatment with hypoglycemic drugs.
MATERIALS AND METHODS
The study was conducted as a pilot, prospective, randomized, open label, parallel group with blinded-endpoints (PROBE) study. Of 180 recruited patients with T2DM and dyslipidemia, 131 were randomized to atorvastatin (n=44), rosuvastatin (n=45), and pitavastatin (n=42) and treated for 6 months.
RESULTS
Fasting plasma glucose (FPG) marginally decreased in patients assigned to atorvastatin (-3.5 mg/dL, =0.42) and rosuvastatin (-6.5 mg/dL, =0.17), while it decreased much more in patients treated with pitavastatin (-19.0 mg/dL, <0.001). Mean glycated hemoglobin A1c (HbA1c ) values remained unchanged during treatment with atorvastatin (-0.10%, =0.53) and rosuvastatin (0.20%, =0.40), but were significantly reduced with pitavastatin (-0.75%, =0.01). Atorvastatin, rosuvastatin, and pitavastatin significantly lowered (<0.001) plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and triglycerides, while high-density lipoprotein-cholesterol (HDL-C) levels increased significantly (=0.04) only in the pitavastatin group.
CONCLUSION
The results of the present study suggest that pitavastatin affects FPG and HbA1c less than atorvastatin and rosuvastatin in patients with T2DM and concomitant dyslipidemia. Lipid-lowering efficacies were not significantly different among the three statins, with the exception of HDL-C, which increased significantly with pitavastatin. Although the pharmacological mechanism of pitavastatin on glucose homeostasis in patients with T2DM during stable antidiabetic therapy is not known, it can be assumed that pitavastatin has less drug interaction with hypoglycemic agents or that it increases plasma levels of adiponectin.
Topics: Humans; Atorvastatin; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Glycated Hemoglobin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Prospective Studies; Pyrroles; Rosuvastatin Calcium; Treatment Outcome
PubMed: 36825343
DOI: 10.3349/ymj.2022.0287 -
Mediators of Inflammation 2017Recent studies have shown that overweight and obesity play an important role in the development of osteoarthritis (OA). However, joint overload is not the only risk... (Review)
Review
Recent studies have shown that overweight and obesity play an important role in the development of osteoarthritis (OA). However, joint overload is not the only risk factor in this disease. For instance, the presence of OA in non-weight-bearing joints such as the hand suggests that metabolic factors may also contribute to its pathogenesis. Recently, white adipose tissue (WAT) has been recognized not only as an energy reservoir but also as an important secretory organ of adipokines. In this regard, adipokines have been closely associated with obesity and also play an important role in bone and cartilage homeostasis. Furthermore, drugs such as rosuvastatin or rosiglitazone have demonstrated chondroprotective and anti-inflammatory effects in cartilage explants from patients with OA. Thus, it seems that adipokines are important factors linking obesity, adiposity, and inflammation in OA. In this review, we are focused on establishing the physiological mechanisms of adipokines on cartilage homeostasis and evaluating their role in the pathophysiology of OA based on evidence derived from experimental research as well as from clinical-epidemiological studies.
Topics: Adipokines; Adipose Tissue, White; Adiposity; Animals; Humans; Osteoarthritis; Rosiglitazone; Rosuvastatin Calcium; Thiazolidinediones
PubMed: 28490838
DOI: 10.1155/2017/5468023 -
Clinical and Translational Science Jun 2022The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic...
The accurate prediction of OATP1B-mediated drug-drug interactions (DDIs) is challenging for drug development. Here, we report a physiologically-based pharmacokinetic (PBPK) model analysis for clinical DDI data generated in heathy subjects who received oral doses of cyclosporin A (CysA; 20 and 75 mg) as an OATP1B inhibitor, and the probe drugs (pitavastatin, rosuvastatin, and valsartan). PBPK models of CysA and probe compounds were combined assuming inhibition of hepatic uptake of endogenous coproporphyrin I (CP-I) by CysA. In vivo K of unbound CysA for OATP1B (K ), and the overall intrinsic hepatic clearance per body weight of CP-I (CL ) were optimized to account for the CP-I data (K , 0.536 ± 0.041 nM; CL , 41.9 ± 4.3 L/h/kg). DDI simulation using K reproduced the dose-dependent effect of CysA (20 and 75 mg) and the dosing interval (1 and 3 h) on the time profiles of blood concentrations of pitavastatin and rosuvastatin, but DDI simulation using in vitro K failed. The Cluster Gauss-Newton method was used to conduct parameter optimization using 1000 initial parameter sets for the seven pharmacokinetic parameters of CP-I (β, CL , F F , R , f , f , and v ), and K and K of CysA. Based on the accepted 546 parameter sets, the range of CL and K was narrowed, with coefficients of variation of 12.4% and 11.5%, respectively, indicating that these parameters were practically identifiable. These results suggest that PBPK model analysis of CP-I is a promising translational approach to predict OATP1B-mediated DDIs in drug development.
Topics: Coproporphyrins; Drug Interactions; Humans; Liver-Specific Organic Anion Transporter 1; Models, Biological; Rosuvastatin Calcium
PubMed: 35421902
DOI: 10.1111/cts.13272