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Pharmacogenetics and Genomics Sep 2023The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport...
OBJECTIVE
The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.
METHODS
We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.
RESULTS
We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P = 0.047).
CONCLUSION
The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Pravastatin; Cytochrome P-450 CYP2C9; Fluvastatin; Pharmacogenetics; Simvastatin; Liver-Specific Organic Anion Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins
PubMed: 37490620
DOI: 10.1097/FPC.0000000000000504 -
Molecules (Basel, Switzerland) Jan 2023Many studies have shown that alterations in the gut microbiota are associated with hypertension. Our study aimed to observe the characteristics of the gut microbiota in...
Many studies have shown that alterations in the gut microbiota are associated with hypertension. Our study aimed to observe the characteristics of the gut microbiota in hypertension and to further explore whether drug molecules can play a therapeutic role in hypertension by interfering with the gut microbiota. We evaluated the differences in the composition of the gut microbiota in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Meanwhile, three first-line cardiovascular disease (CVD) drugs, losartan, atorvastatin, and aspirin, were used to treat the SHR in order to observe their effects on the gut microbiota in SHR. The 16S rDNA results showed that the diversity and richness of the gut microbiota in SHR were significantly reduced compared with that of the WKY, the Firmicutes/Bacteroidetes ratio was increased, the abundances of and short chain fatty acids (SCFAs)-producing bacteria decreased, and the abundance of lactate-producing bacteria increased. In addition to lowering the blood pressure, losartan increased the abundances of , and in SHR, reduced the abundances of , and , reduced the Firmicutes/Bacteroidetes ratio, and rebalanced the gut microbiota. Losartan also increased the abundances of and SCFAs-producing bacteria and reduced the abundance of lactate-producing bacteria. However, atorvastatin and aspirin had no significant effect on the gut microbiota in SHR. The above results showed that losartan could change the characteristics of the gut microbiota in hypertension and rebalance the gut microbiota, which may be related to lowering the blood pressure. Atorvastatin and aspirin have no significant influence on the gut microbiota in SHR.
Topics: Rats; Animals; Losartan; Blood Pressure; Rats, Inbred SHR; Atorvastatin; Gastrointestinal Microbiome; Aspirin; Hypertension; Rats, Inbred WKY
PubMed: 36677668
DOI: 10.3390/molecules28020612 -
Fundamental & Clinical Pharmacology Feb 2021
Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signalling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuate progression of oxazolone-induced colitis.
Topics: Anti-Inflammatory Agents; Atorvastatin; Colitis; Gene Expression; Humans; Interleukin-10; Interleukin-6; Mesalamine; Oxazolone
PubMed: 33289917
DOI: 10.1111/fcp.12638 -
The Journal of International Medical... Jun 2023Evidence of therapy for dysfunctional coronary circulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary...
OBJECTIVE
Evidence of therapy for dysfunctional coronary circulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) is limited. This study was performed to compare the effects of atorvastatin and rosuvastatin on dysfunctional coronary circulation.
METHODS
This retrospective study enrolled 597 consecutive patients with STEMI who underwent pPCI in 3 centers from June 2016 to December 2019. Dysfunctional coronary circulation was defined by the thrombolysis in myocardial infarction (TIMI) grade and the TIMI myocardial perfusion grade (TMPG). Logistic regression analysis was used to evaluate the impact of different statin types on dysfunctional coronary circulation.
RESULTS
The incidence of TIMI no/slow reflow did not differ between the two groups, but the incidence of TMPG no/slow reflow was significantly lower in the atorvastatin than rosuvastatin group (44.58% vs. 57.69%, respectively). After multivariate adjustment, the odds ratio with 95% confidence interval of rosuvastatin was 1.72 (1.17-2.52) for after pretreatment TMPG no/slow reflow and 1.73 (1.16-2.58) for after stenting TMPG no/slow reflow. Atorvastatin and rosuvastatin showed no significant differences in clinical outcomes during hospitalization.
CONCLUSIONS
Compared with rosuvastatin, atorvastatin was associated with better coronary microcirculatory perfusion in patients with STEMI who underwent pPCI.
Topics: Humans; ST Elevation Myocardial Infarction; Atorvastatin; Rosuvastatin Calcium; Treatment Outcome; Retrospective Studies; Microcirculation; Myocardial Infarction; Percutaneous Coronary Intervention; Coronary Circulation; Coronary Angiography; No-Reflow Phenomenon
PubMed: 37377087
DOI: 10.1177/03000605231182547 -
Cell Communication and Signaling : CCS May 2023Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in...
BACKGROUND
Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain-Barré syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.
METHODS
We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.
RESULTS
Autophagy increases in virus-infected cells as early as 6 h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.
CONCLUSIONS
We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD. Video Abstract.
Topics: Humans; Atorvastatin; Autophagy; Lipid Metabolism; Virus Replication; Zika Virus; Zika Virus Infection; Madin Darby Canine Kidney Cells; Animals; Dogs
PubMed: 37208782
DOI: 10.1186/s12964-022-01026-8 -
Cellular Physiology and Biochemistry :... 2017Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular lesions, such as atherosclerosis and restenosis. PDGF-ββ, an isoform of PDGF...
Atorvastatin Calcium Inhibits PDGF-ββ-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRβ-PI3K-Akt Signaling Cascade.
BACKGROUND/AIMS
Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular lesions, such as atherosclerosis and restenosis. PDGF-ββ, an isoform of PDGF (platelet-derived growth factor), has been demonstrated to induce proliferation and migration of VSMCs. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has favorable protective effects on VSMCs. This study examined the effects of atorvastatin calcium on the proliferation and migration of PDGF-ββ-treated VSMCs, as well as its underlying mechanisms.
METHODS
MTT assays, Edu imaging, cell cycle analysis, wound healing assays, transwell migration assays, and western blot analysis were performed.
RESULTS
Atorvastatin calcium significantly inhibited cell proliferation, DNA synthesis and cell migration of PDGF-ββ-treated VSMCs. We demonstrated that atorvastatin calcium induced cell cycle arrest in the G0/G1 phase in response to PDGF-ββ stimulation and decreased the expression of G0/G1-specific regulatory proteins, including proliferating cell nuclear antigen (PCNA), CDK2, cyclin D1, cyclin E and CDK4 in PDGF-ββ-treated VSMCs. Moreover, pretreatment with atorvastatin calcium inhibited the PDGF-ββ-treated phosphorylation of PDGFRβ and Akt, whereas atorvastatin calcium did not affect the phosphorylation of PLC-γ1 or (ERK) 1/2.
CONCLUSION
Our data suggested that atorvastatin calcium inhibited abnormal proliferation and migration of VSMCs through G0/G1 cell cycle arrest and suppression of the PDGFRβ-Akt signaling cascade.
Topics: Animals; Atorvastatin; Becaplermin; Cell Movement; Cell Proliferation; Cells, Cultured; Cyclin D1; Cyclin E; G1 Phase Cell Cycle Checkpoints; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction
PubMed: 29131001
DOI: 10.1159/000484648 -
Biomedicine & Pharmacotherapy =... Mar 2023Atherosclerosis is associated with inflammation in the arteries, a significant cause of heart attacks and strokes. Although statin therapy can reduce the chances of...
Atherosclerosis is associated with inflammation in the arteries, a significant cause of heart attacks and strokes. Although statin therapy can reduce the chances of atherosclerotic plaque formation, they need to be administered in high doses due to low systemic bioavailability and encountered with side effects. To overcome these challenges, we developed nanoparticles using biocompatible and biodegradable lipids and polymers for improving systemic drug absorption and therapeutic response. The polymeric nanoparticles were prepared using PLGA and PVA, while hybrid nanoparticles were prepared using PLGA and Phospholipon 90 G. Both nanoparticles were systematically optimized by I-optimal response surface design. The optimum formulation composition exhibited particle size of less than 250 nm, polydispersity index of less than 0.3, entrapment efficiency of more than 70%, and sustained drug release up to 6 h. In vivo pharmacokinetic evaluation in rats indicated multi-fold improvement in the extent of drug absorption (C and AUC) for atorvastatin from the nanoparticles vis-à-vis the pure drug suspension. In vivo pharmacodynamic studies also indicated the excellent ability of nanoparticles to lower the elevated levels of lipids (total cholesterol, triglycerides, and low-density lipoproteins) and increase the level of high-density lipoproteins as compared to that of the pure drug suspension.
Topics: Rats; Animals; Atorvastatin; Rats, Wistar; Drug Carriers; Lipids; Polymers; Biological Products; Nanoparticles; Drug Liberation; Atherosclerosis; Particle Size; Biological Availability
PubMed: 36689837
DOI: 10.1016/j.biopha.2023.114261 -
Current Opinion in Infectious Diseases Feb 2016To evaluate evidence that statins reduce cardiovascular risk in patients living with HIV. (Review)
Review
PURPOSE OF REVIEW
To evaluate evidence that statins reduce cardiovascular risk in patients living with HIV.
RECENT FINDINGS
Moderate to high-dose atorvastatin and rosuvastatin appear to reduce noncalcified coronary plaque volume and slow progression of carotid intima-media thickness in patients with treated HIV infection. Expected lipoprotein changes with statins on the background of modern antiretroviral therapy are similar to the general population. In addition to lipids, the statin benefit may be mediated in part by improvements in vascular inflammation and levels of T-cell and monocyte activation. One concern is the potential for rosuvastatin to cause insulin resistance. Decisions to prescribe statins must be done in the context of global risk assessment, but traditional risk calculators such as the Framingham Risk Score or the American College of Cardiology/American Heart Association pooled-risk equations underestimate risk in this population. Furthermore, many patients with subclinical disease would not be recommended for statins according to the most recent American College of Cardiology/American Heart Association guidelines.
SUMMARY
Statins are likely to improve cardiovascular outcomes for patients with HIV, but results of the first outcome study are not expected until 2020. In the meantime, clinicians should individualize statin prescriptions, and should consider using more potent statins (rosuvastatin, atorvastatin, and pitavastatin) when possible.
Topics: Atorvastatin; Carotid Intima-Media Thickness; Coronary Disease; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; Practice Guidelines as Topic; Practice Patterns, Physicians'; Precision Medicine; Primary Prevention; Randomized Controlled Trials as Topic; Rosuvastatin Calcium; Treatment Outcome; United States
PubMed: 26658651
DOI: 10.1097/QCO.0000000000000223 -
International Journal of Pharmaceutics Nov 2022In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API...
Process intensification of atorvastatin calcium crystallization for target polymorph development via continuous combined cooling and antisolvent crystallization using an oscillatory baffled crystallizer.
In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API manufacturing, ASC is manufactured batchwise and the pure API is recovered via batch combined cooling and antisolvent crystallization (CCAC) process, which has the challenges of low productivity, wide crystal size distribution (CSD) and sometimes polymorphic form contamination. To overcome the limitations of the batch crystallization, continuous crystallization of ASC was studied in a NiTech (United Kingdom) DN15 COBC, manufactured by Alconbury Weston Ltd. (AWL, United Kingdom), with the aim to improve productivity and CSD of the desired polymorph. The COBC has the advantage of high heat transfer rates and improved mixing that significantly reduces the crystallization time. It also has the advantage of spatial temperature distribution and multiple addition ports to control supersaturation and hence the crystallization process. This work uses an array of process analytical technology (PAT) tools to assess key process parameters that affect the polymorphic outcome and CSD. Two parameters were found to have significant impact on the polymorph, they are ratio of solvent to antisolvent at the point of mixing of the two streams and presence of seeds. The splitting of antisolvent into two addition ports in the COBC was found to give the desired form. The CCAC of ASC in COBC was found to be -30-fold more productive than the batch CCAC process. The cycle time for generating 100 g of desired polymorphic form of ASC also significantly reduced from 22 h in batch process to 12 min in the COBC. The crystals obtained using a CCAC process in a COBC had a narrower CSD compared to that from a batch crystallization process.
Topics: Crystallization; Atorvastatin; Phase Transition; Solvents; United Kingdom; Particle Size
PubMed: 36084877
DOI: 10.1016/j.ijpharm.2022.122172 -
Oxidative Medicine and Cellular... 2022Abdominal or pelvic radiotherapy (RT) often results in small intestinal injury, such as apoptosis of epithelial cells and shortening of the villi. Atorvastatin, a...
Abdominal or pelvic radiotherapy (RT) often results in small intestinal injury, such as apoptosis of epithelial cells and shortening of the villi. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has many biological effects including cholesterol reduction, protection from cell damage, and autophagy activation. To reduce the extent of radiotherapy- (RT-) induced enteritis, we investigated the protective effects of atorvastatin against RT-induced damage of the intestinal tract. In this study, C57BL/6 mice were randomly distributed into the following groups ( = 8 per group): (1) control group: mice were fed water only, (2) atorvastatin group (Ator): mice were administered atorvastatin, (3) irradiation group (IR): mice received abdominal RT, (4) Ator+IR group: mice received abdominal RT following atorvastatin administration, and (5) Ator+IR+3-MA group: abdominal RT following atorvastatin and 3-methyladenine (an autophagy inhibitor) administration. Based on the assessment of modified Chiu's injury score and villus/crypt ratio, we found that atorvastatin administration significantly reduced intestinal mucosal damage induced by RT. Atorvastatin treatment reduced apoptosis (cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase), DNA damage (H2AX and 53BP1), oxidative stress (OS, 4-hydroxynonenal), inflammatory molecules (phospho-NF-B p65 and TGF-), fibrosis (collagen I and collagen III), barrier leakage (claudin-2 and fluorescein isothiocyanate-dextran), disintegrity (fatty acid-binding protein 2), and dysfunction (lipopolysaccharide) caused by RT in small intestinal tissue. In addition, atorvastatin upregulated the expression of autophagy-active molecules (LC3B), antioxidants (heme oxygenase 1 and thioredoxin 1), and tight junction proteins (occludin and zonula occludens 1). However, the biological functions of atorvastatin in decreasing RT-induced enteritis were reversed after the administration of 3-MA; the function of antioxidant molecules and activity of thioredoxin reductase were independent of autophagy activation. Our results indicate that atorvastatin can effectively relieve RT-induced enteritis through autophagy activation and associated biological functions, including maintaining integrity and function and decreasing apoptosis, DNA damage, inflammation, OS, and fibrosis. It also acts via its antioxidative capabilities.
Topics: Animals; Antioxidants; Atorvastatin; Autophagy; Fibrosis; Mice; Mice, Inbred C57BL
PubMed: 36092168
DOI: 10.1155/2022/7957255