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International Journal of Pharmaceutics May 2023Atorvastatin calcium (AC), a cholesterol-lowering medication, has limited oral bioavailability (14 %) and adverse impacts on the gastrointestinal tract (GIT), liver,...
Atorvastatin calcium (AC), a cholesterol-lowering medication, has limited oral bioavailability (14 %) and adverse impacts on the gastrointestinal tract (GIT), liver, and muscle. So, in an effort to improve the poor availability and overcome the hepatotoxicity complications attendant to peroral AC administration, transdermal transfersomal gel (AC-TFG) was developed as a convenient alternative delivery technique. The impact of utilizing an edge activator (EA) and varying the phosphatidylcholine (PC): EA molar ratio on the physico-chemical characteristics of the vesicles was optimized through a Quality by Design (QbD) strategy. The optimal transdermal AC-TFG was tested in an ex-vivo permeation study employing full-thickness rat skin, Franz cell experiments, an in-vivo pharmacokinetics and pharmacodynamics (PK/PD) evaluation, and a comparison to oral AC using poloxamer-induced dyslipidemic Wister rats. The optimized AC-loaded TF nanovesicles predicted by the 2-factorial design strategy had a good correlation with the measured vesicle diameter of 71.72 ± 1.159 nm, encapsulation efficiency of 89.13 ± 0.125 %, and cumulative drug release of 88.92 ± 3.78 % over 24 h. Ex-vivo data revealed that AC-TF outperformed a free drug in terms of permeation. The pharmacokinetic parameters of optimized AC-TFG demonstrated 2.5- and 13.3-fold significant improvements in bioavailability in comparison to oral AC suspension (AC-OS) and traditional gel (AC-TG), respectively. The transdermal vesicular technique preserved the antihyperlipidemic activity of AC-OS without increasing hepatic markers. Such enhancement was proven histologically by preventing the hepatocellular harm inflicted by statins. The results showed that the transdermal vesicular system is a safe alternative way to treat dyslipidemia with AC, especially when given over a long period of time.
Topics: Rats; Animals; Administration, Cutaneous; Atorvastatin; Poloxamer; Drug Delivery Systems; Rats, Wistar; Skin; Lecithins; Dyslipidemias; Biological Availability; Particle Size
PubMed: 37019321
DOI: 10.1016/j.ijpharm.2023.122917 -
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 -
Current Opinion in Lipidology Apr 2016
Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Cholesterol; Humans; Intestinal Absorption
PubMed: 26959709
DOI: 10.1097/MOL.0000000000000283 -
Journal of Cellular Biochemistry Aug 2022Osteoarthritis (OA) is a progressive joint disease. The etiology of OA is considered to be multifactorial. Currently, there is no definitive treatment for OA, and the... (Review)
Review
Osteoarthritis (OA) is a progressive joint disease. The etiology of OA is considered to be multifactorial. Currently, there is no definitive treatment for OA, and the existing treatments are not very effective. Hypercholesterolemia is considered a novel risk factor for the development of OA. Statins act as a competitive inhibitor of the β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and are widely used to manage hypercholesterolemia. Inhibition of HMG-CoA reductase results in reduced synthesis of a metabolite named mevalonate, thereby reducing cholesterol biosynthesis in subsequent steps. By this mechanism, statins such as atorvastatin and simvastatin could potentially have a preventive impact on joint cartilage experiencing osteoarthritic deterioration by reducing serum cholesterol levels. Atorvastatin can protect cartilage degradation following interleukin-1β-stimulation. Atorvastatin stimulates the STAT1-caspase-3 signaling pathway that was shown to be responsible for its anti-inflammatory effects on the knee joint. Simvastatin had chondroprotective effects on OA in vitro by reducing matrix metalloproteinases expression patterns. In this study, we tried to review the therapeutic effects of statins on OA.
Topics: Atorvastatin; Cholesterol; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Osteoarthritis; Oxidoreductases; Simvastatin
PubMed: 35894149
DOI: 10.1002/jcb.30309 -
Free Radical Biology & Medicine Nov 2023A novel circRNA named circSQSTM1 (hsa_circRNA_075320) was screened out in atorvastatin (ATV) stimulated endothelial cells (ECs) by our group. Considering the...
A novel circRNA named circSQSTM1 (hsa_circRNA_075320) was screened out in atorvastatin (ATV) stimulated endothelial cells (ECs) by our group. Considering the anti-atherosclerotic function of ATV, we hypothesized the circSQSTM1 could protect ECs functions in AS progression. The effects of circSQSTM1 on ECs inflammation, oxidative stress and autophagy were measured by qRT-PCR, Western blotting, monocyte-endothelial adhesion assay, dichloro-dihydro-fluorescein diacetate and mCherry-GFP-LC3 labeling. A luciferase reporter assay, RNA immunoprecipitation, MS2-tagging system and fluorescence in situ hybridization were performed to identify the biological functions of circSQSTM1. The partial left carotid artery ligation model and atherosclerosis model were established to analyze the effects of circSQSTM1 on atherosclerosis progression in vivo. Our results revealed that ATV induced the accumulation of circSQSTM1 in ECs via suppressing m6A modified degradation. In the cytoplasm, circSQSTM1 could relieve Sirt1 by competitively sponging miR-23b-3p. In the nucleus, circSQSTM1 directly interacts with eIF4A3 and promoting the efficient nuclear export of FOXO1 mRNA, which encodes FOXO1 transcription factor to directly activate Sirt1 promoter activity. Hence, circSQSTM1 reduced inflammation, inhibited oxidative stress and promoted autophagy by upregulating Sirt1 in ECs. Moreover, circSQSTM1 overexpression in ECs attenuated the progression of atherosclerosis in ApoE mice. Taken together, the unique noncoding RNA known as circSQSTM1 took a protective role to the ECs in atherosclerosis.
Topics: Animals; Mice; Atherosclerosis; Endothelial Cells; In Situ Hybridization, Fluorescence; Inflammation; RNA, Circular; Sirtuin 1; Atorvastatin
PubMed: 37865306
DOI: 10.1016/j.freeradbiomed.2023.10.398 -
Nanomedicine (London, England) Jul 2023Corneal neovascularization is a sight-threatening disease. It can be treated using antiangiogenic and anti-inflammatory compounds. Therefore, atorvastatin (ATV)...
Corneal neovascularization is a sight-threatening disease. It can be treated using antiangiogenic and anti-inflammatory compounds. Therefore, atorvastatin (ATV) constitutes a suitable candidate to be administered topically. To attain suitable efficacy, ATV can be encapsulated into custom-developed nanocarriers such as peptide amphiphiles. Three peptide amphiphiles bearing one, two or four C-alkyl groups (mC-Tat, dC-Tat and qC-Tat) were synthesized, characterized and loaded with ATV. Drug release and ocular tolerance were assessed as well as anti-inflammatory and antiangiogenic properties. ATV-qC-Tat showed higher encapsulation efficiency than mC-Tat and dC-Tat and more defined nanostructures. ATV-qC-Tat showed ATV prolonged release with suitable ocular tolerance. Moreover, ATV-qC-Tat was antiangiogenic and prevented ocular inflammation. ATV-qC-Tat constitutes a promising topical medication against corneal neovascularization.
Topics: Humans; Corneal Neovascularization; Atorvastatin; Eye; Drug Liberation; Peptides
PubMed: 37610088
DOI: 10.2217/nnm-2023-0133 -
European Journal of Drug Metabolism and... Jan 2022Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly...
BACKGROUND AND OBJECTIVES
Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly atrovastatin calcium) in TCM clinics. However, the herb-drug interaction between GQD and atrovastatin calcium (AC) is still unknown. To determine whether the combination is safe, we evaluated the effects of GQD on the activities of cytochrome P450 (CYP) 3A2 enzyme and investigated the impact of GQD on the pharmacokinetics and pharmacodynamics of AC in rats.
METHODS
The pharmacokinetics of AC (10 mg/kg) with or without pretreatment with GQD (freeze-dried powder, 1.35 g/kg) were investigated using HPLC. The influence of GQD on pharmacodynamics of AC were determined by detecting the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, the probe drug method was used to explore the effect of GQD on CYP3A2 activity.
RESULTS
The pharmacokinetic parameters of AC combined with GQD were significantly affected (P < 0.05) in hyperlipidemic rats. The serum TC, TG and LDL-C levels of the combination were significantly reduced (P < 0.05), and the serum HDL-C level was significantly increased (P < 0.05) compared with AC/GQD alone. AST and ALT activities treated with both GQD and AC+GQD group were significantly reduced (P < 0.05) compared with AC group. There was a significant difference in the pharmacokinetic parameters of midazolam between control and GQD groups (P < 0.05). Maximum concentration (C), area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC) and AUC from time 0 to infinity (AUC) increased significantly in GQD group.
CONCLUSIONS
The result suggested that GQD combined with AC can improve the lipid-lowering effect of AC and reduce the damage of AC to the liver simultaneously. However, GQD can inhibit the activity of CYP3A2 in hyperlipidemic rats and increase the blood concentration of AC. Therefore, the clinical dose of AC should be adjusted when they are combined. Since the study was conducted in rats, further research should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.
Topics: Animals; Area Under Curve; Atorvastatin; Disease Models, Animal; Drugs, Chinese Herbal; Herb-Drug Interactions; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Male; Random Allocation; Rats; Rats, Sprague-Dawley
PubMed: 34855161
DOI: 10.1007/s13318-021-00738-5 -
Revista Medica Del Instituto Mexicano... Oct 2023Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary prevention of Major Cardiovascular Events (MACE).
OBJECTIVE
To evaluate the impact of high-dose atorvastatin on secondary prevention of MACE and adverse events.
MATERIAL AND METHODS
A systematic review and meta-analysis of Pubmed, Embase, Bireme and Cochrane Library Plus databases was performed, with a time scope from 1990 to July 2022. Six randomized clinical trials were included with a total of 29,333 patients who were treated with 80 mg, 10 mg or placebo doses of Atorvastatin where the main outcomes evaluated were Major Cardiovascular Events (MACE), mortality and treatment safety.
RESULTS
In the comparative study between the use of Atorvastatin 80 mg and other therapies, a relative risk (RR) of 0.8 (95%CI 0.69-0.92) was found, representing a 20% reduction in risk (RRR) and a number needed to treat (NNT) of 30-55. In the analysis of adverse effects, an RR of 2.37 (95% CI 0.86-6.53) and a number needed to harm (NNH) of 14-19 were observed. The use of 80 mg atorvastatin is associated with similar adverse events at lower doses.
CONCLUSIONS
The use of atorvastatin 80 mg is effective in the secondary prevention of Major Cardiovascular Event (MACE). The drug has adverse events that should be taken into account in secondary prevention.
Topics: Humans; Atorvastatin; Cardiovascular Diseases
PubMed: 37934798
DOI: 10.5281/zenodo.8319748 -
Asian Pacific Journal of Cancer... Mar 2022Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells....
OBJECTIVE
Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells. Among the statins, atorvastatin, and in cancers, breast malignancies have received less attention in preclinical investigations. In order to enhance the efficacy of cancer treatment, adjuvant, less expensive therapeutic strategies have been recently noticed. In this case, we investigated the in-vitro effect of atorvastatin on viability and migration of MCF7 breast cancer cell line.
METHODS
We tested the cytotoxicity of atorvastatin on breast cancer cells survival by MTT assay. Annexin-V / PI staining and then flow cytometry of cancer cells in addition to quantitative real-time PCR tests quantified the apoptosis and necrosis of cancer cells. We figured out the impact of atorvastatin on cancer cell migration capability through scratch-wound healing assay and transwell migration examination. Inverted light microscope and fluorescent imaging displayed the morphological changes following treatment of MCF7 cells with atorvastatin.
RESULT
We resulted that atorvastatin can trigger MCF7 cancer cells to undergo necrosis and caspase-dependent apoptosis based on the viable/dead cell number, mitotic cell cycle, gene expression, and morphological assays. The results were dose- and time-dependent and the half- maximal inhibitory concentration of atorvastatin for cancer cells' viability inhibition was 9.1 μM/L(nM/mL). Moreover, the migration of MCF7 cells were inhibited in the treated group as we figured out in two- and three-dimensional migration methods.
CONCLUSION
In-vitro inspection of drug-cancer cell interactions paves the way for future in-vivo research studies. These in-vitro results revealed that atorvastatin has anti-viability and anti-migration effects on breast cancer cells.
Topics: Apoptosis; Atorvastatin; Breast Neoplasms; Cell Movement; Female; Humans; MCF-7 Cells
PubMed: 35345358
DOI: 10.31557/APJCP.2022.23.3.867 -
Advances in Rheumatology (London,... Dec 2022Statins have long been extensively prescribed as effective lipid-lowering agents, but statins have also been recognized as novel immunomodulators in recent years. This...
BACKGROUND
Statins have long been extensively prescribed as effective lipid-lowering agents, but statins have also been recognized as novel immunomodulators in recent years. This study was designed to investigate the immunomodulatory effects of atorvastatin on lupus-prone MRL/lpr mice.
METHODS
A total of 30 8-week-old female MRL/lpr mice were randomly divided into three groups and orally administered vehicle, atorvastatin orhydroxychloroquine sulfate for 11 weeks. In vivo, the effects of atorvastatin on the survival rate, renal function and spleen index in MRL/lpr mice were examined. Ex vivo, splenic B-cell proliferation was assessed by a Cell Counting Kit-8.
RESULTS
Oral atorvastatin failed to prolong survival time, or reduce the levels of proteinuria, or serum anti-dsDNA antibody and complement proteins (C3, C4). Histologically, no significant improvement by atorvastatin was observed in the pathological manifestations of renal damage, while hydroxychloroquine sulfate significantly improved glomerular injury. Ex vivo, atorvastatin suppressed the proliferation of splenic B lymphocytes.
CONCLUSION
Oral atorvastatin monotherapy had no therapeutic effects on MRL/lpr mice, whereas atorvastatin inhibited splenic B-cell proliferation in vitro, suggesting that atorvastatin has a potential therapeutic effect on systemic lupus erythematosus.
Topics: Mice; Animals; Female; Humans; Mice, Inbred MRL lpr; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lupus Erythematosus, Systemic
PubMed: 36471414
DOI: 10.1186/s42358-022-00282-z