Impact of LDLR polymorphisms on lipid levels and atorvastatin's efficacy in a northern Chinese adult Han cohort with dyslipidemia.

BACKGROUND: Dyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia. METHODS: In this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3' untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview. RESULTS: Eleven distinct polymorphisms at LDLR 3' UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin's efficacy. CONCLUSIONS: This research outlined the complex genetic architecture surrounding LDLR 3' UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care. TRIAL REGISTRATION: This multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).

Atorvastatin reduces calcification in valve interstitial cells via the NF-κB signalling pathway by promoting Atg5-mediated autophagy.

Aortic valve calcification (AVC) is a common cardiovascular disease and a risk factor for sudden death. However, the potential mechanisms and effective therapeutic drugs need to be explored. Atorvastatin is a statin that can effectively prevent cardiovascular events by lowering cholesterol levels. However, whether atorvastatin can inhibit AVC by reducing low-density lipoprotein (LDL) and its possible mechanism of action require further exploration. In the current study, we constructed an in vitro AVC model by inducing calcification of the valve interstitial cells. We found that atorvastatin significantly inhibited osteogenic differentiation, reduced the deposition of calcium nodules in valve interstitial cells, and enhanced autophagy in calcified valve interstitial cells, manifested by increased expression levels of the autophagy proteins Atg5 and LC3B-II/I and the formation of smooth autophagic flow. Atorvastatin inhibited the NF-κB signalling pathway and the expression of inflammatory factors mediated by NF-κB in calcified valve interstitial cells. The activation of the NF-κB signalling pathway led to the reversal of atorvastatin's effect on enhancing autophagy and alleviating valve interstitial cell calcification. In conclusion, atorvastatin inhibited the NF-κB signalling pathway by upregulating autophagy, thereby alleviating valve interstitial cell calcification, which was conducive to improving AVC.

Atorvastatin-loaded cubosome: a repurposed targeted delivery systems for enhanced targeting against breast cancer.

Cancer ranks as one of the most challenging illnesses to deal with because progressive phenotypic and genotypic alterations in cancer cells result in resistance and recurrence. Thus, the creation of novel medications or alternative therapy approaches is mandatory. Repurposing of old drugs is an attractive approach over the traditional drug discovery process in terms of shorter drug development duration, low-cost, highly efficient and minimum risk of failure. In this study Atorvastatin, a statin drug used to treat abnormal cholesterol levels and prevent cardiovascular disease in people at high risk, was introduced and encapsulated in cubic liquid crystals as anticancer candidate aiming at sustaining its release and achieving better cellular uptake in cancer cells. The cubic liquid crystals were successfully prepared and optimized with an entrapment effieciency of 73.57% ±1.35 and particle size around 200 nm. The selected formulae were effectively doped with radioactive iodine 131I to enable the noninvasive visualization and trafficking of the new formulae. The in vivo evaluation in solid tumor bearing mice was conducted for comparing131I-Atorvastatin solution,131I-Atorvastatin loaded cubosome and 131I-Atorvastatin chitosan coated cubosome. The in vivo biodistribution study revealed that tumor radioactivity uptake of 131I-Atorvastatin cubosome and chitosan coated cubosome exhibited high accumulation in tumor tissues (target organ) scoring ID%/g of 5.67 ± 0.2 and 5.03 ± 0.1, respectively 1h post injection compared to drug solution which recorded 3.09 ± 0.05% 1h post injection. Concerning the targeting efficiency, the target/non target ratio for 131I-Atorvastatin chitosan coated cubosome was higher than that of 131I-Atorvastatin solution and 131I ATV-loaded cubosome at all time intervals and recorded T/NT ratio of 2.908 2h post injection.

Identification of MGMT promoter methylation as a specific lipid metabolism biomarker, reveals the feasibility of atorvastatin application in glioblastoma.

BACKGROUND: Glioblastoma is one of the deadliest tumors, and limited improvement in managing glioblastoma has been achieved in the past decades. The unmethylated promoter area of 6-O-Methylguanine-DNA Methyltransferase (MGMT) is a significant biomarker for recognizing a subset of glioblastoma that is resistant to chemotherapy. Here we identified MGMT methylation can also work as a specific biomarker to classify the lipid metabolism patterns between methylated and unmethylated glioblastoma and verify the potential novel therapeutic strategy for unmethylated MGMT glioblastoma. METHODS: Liquid Chromatograph Mass Spectrometer has been applied for non-targeted metabolome and targeted lipidomic profiling to explore the metabolism pattern correlated with MGMT promoter methylation. Transcriptome has been performed to explore the biological differences and the potential mechanism of lipid metabolism in glioblastoma samples. In vivo and ex vivo assays were performed to verify the anti-tumor activity of atorvastatin in the administration of glioblastoma. RESULTS: Multi-omics assay has described a significant difference in lipid metabolism between MGMT methylated and unmethylated glioblastoma. Longer and unsaturated fatty acyls were found enriched in MGMT-UM tumors. Lipid droplets have been revealed remarkably decreased in MGMT unmethylated glioblastoma. In vivo and ex vivo assays revealed that atorvastatin and also together with temozolomide showed significant anti-tumor activity, and atorvastatin alone was able to achieve better survival and living conditions for tumor-hosting mice. CONCLUSIONS: MGMT promoter methylation status might be a well-performed biomarker of lipid metabolism in glioblastoma. The current study can be the basis of further mechanism studies and implementation of clinical trials, and the results provide preclinical evidence of atorvastatin administration in glioblastoma, especially for MGMT unmethylated tumors.

Activation of AMPK pathway by low­dose donafenib and atorvastatin combination improves high­fat diet­induced metabolic dysfunction­associated steatotic liver disease.

Metabolic dysfunction­associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high­fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP­activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element­binding protein­1, 3­hydroxy­3­methylglutaryl­CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid ß­oxidation (carnitine palmitoyl­transferase 1C and acyl­CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low­dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.

The value of computed tomography texture analysis in identifying chronic subdural hematoma patients with a good response to polytherapy.

This study aimed to investigate the predictive factors of therapeutic efficacy for chronic subdural hematoma (CSDH) patients receiving atorvastatin combined with dexamethasone therapy by using clinical imaging characteristics in conjunction with computed tomography (CT) texture analysis (CTTA). Clinical imaging characteristics and CT texture parameters at admission were retrospectively investigated in 141 CSDH patients who received atorvastatin combined with dexamethasone therapy from June 2019 to December 2022. The patients were divided into a training set (n = 81) and a validation set (n = 60). Patients in the training data were divided into two groups based on the effectiveness of the treatment. Univariate and multivariate analyses were performed to assess the potential factors that could indicate the prognosis of CSDH patients in the training set. The receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of the significant factors in predicting the prognosis of CSDH patients and was validated using a validation set. The multivariate analysis showed that the hematoma density to brain parenchyma density ratio, singal min (minimum) and singal standard deviation of the pixel distribution histogram, and inhomogeneity were independent predictors for the prognosis of CSDH patients based on atorvastatin and dexamethasone therapy. The area under the ROC curve between the two groups was between 0.716 and 0.806. As determined by significant factors, the validation's accuracy range was 0.816 to 0.952. Clinical imaging characteristics in conjunction with CTTA could aid in distinguishing patients with CSDH who responded well to atorvastatin combined with dexamethasone.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner.

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Hepatic-Accumulated Obeticholic Acid and Atorvastatin Self-Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic-Associated Fatty Liver Disease.

Exploration of medicines for efficient and safe management of metabolic-associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), a selective farnesoid X receptor agonist, has been reported to ameliorate injury and inflammation in various liver diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, and potential side effects. Herein a hepatic-targeted nanodrugs composed of OCA and cholesterol-lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content for orally combined treatment of MAFLD is created. Such carrier-free nanocrystals (OCAHTs) are self-assembled, not only improving the stability in gastroenteric environments but also achieving hepatic accumulation through the bile acid transporter-mediated enterohepatic recycling process. Orally administrated OCAHT outperforms the simple combination of OCA and AHT in ameliorating of liver damage and inflammation in both acetaminophen-challenged mice and high-fat diet-induced MAFLD mice with less systematic toxicity. Importantly, OCAHT exerts profoundly reverse effects on MAFLD-associated molecular pathways, including impairing lipid metabolism, reducing inflammation, and enhancing the antioxidation response. This work not only provides a facile bile acid transporter-based strategy for hepatic-targeting drug delivery but also presents an efficient and safe full-API nanocrystal with which to facilitate the practical translation of nanomedicines against MAFLD.

The association between statin use and depression in diabetes.

BACKGROUND: Depression is a common mental disorder. Some studies have demonstrated that people with diabetes are more likely to suffer from depression. Statins are an everyday use for diabetes. Trials of statin therapy have had conflicting findings on the potential risk of depression. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2005-2018 was used to collect a representative sample. Weighted multivariate logistic regression models were used to evaluate odds ratios (ORs) and 95 % CIs for having depression symptoms. We performed stratified analyses to compare the effects of statins in subsamples with and without diabetes on depression symptoms. RESULTS: Statin use showed a significant and strong decreasing effect on having depression symptoms in participants with diabetes (aOR (adjusted OR) 0.59, p = 0.014) compared with that in non-diabetics (aOR 0.78, p = 0.128). Diabetic individuals with statin use for >5 years had a lower risk of having depression symptoms (aOR 0.42, p = 0.002) than those with shorter-term statin use (1-5 years, aOR 0.69, p = 0.111; <1 year: aOR 0.83, p = 0.646). Atorvastatin was more effective in decreasing depression symptoms either in diabetes (aOR 0.49, p = 0.018) or in non-diabetes (aOR 0.58, p = 0.033). LIMITATIONS: First, the dosage of statins cannot be obtained from NHANES datasets. Second, after being stratified, the number of participants for several statins was insufficient. Third, recall bias may exist in the survey. CONCLUSIONS: Diabetics with depression symptoms may benefit from long-term statin therapy. Atorvastatin and pravastatin should be recommended for diabetic patients with depression.

Taohong Siwu decoction ameliorates atherosclerosis in rats possibly through toll-like receptor 4/myeloid differentiation primary response protein 88/nuclear factor-κB signal pathway.

OBJECTIVE: To investigate the effect of Taohong Siwu decoction (, TSD) on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking. METHODS: Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group: control group, model group, atorvastatin group (AT, 2.0 mg/kg), and TSD groups (20, 10, 5 g/kg) after 7 d of acclimation. The model of atherosclerosis was successfully established except the control group by high fat diet (HFD) and vitamin D2. Biochemical analyzers were used to detect the levels of triglyceride (TG), total cholestero (TC), low density lipoprotein-cholesterol (LDL-C) and high density lipid-cholesterol (HDL-C) in blood lipid. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were determined by enzyme-linked immunosorbent assay. Sudan IV staining and Hematoxylin and eosin staining (HE staining) were performed to observe the pathological changes in aortic tissue. Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins. The expression of target proteins was further detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot analysis. RESULTS: The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma. Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor (TLR4), myeloid differentiation primary response protein 88 (MyD88), and nuclear factor kappa-B (NF-κB). The results of qRT-PCR and Western blot analysis showed that the mRNA and protein expressions of TLR4, MyD88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group. CONCLUSIONS: TSD can ameliorate atherosclerosis in rats, and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/MyD88/NF-κB signal pathway.

Atorvastatin before percutaneous coronary intervention: A systematic review and meta-analysis.

Atorvastatin is widely recommended for long-term secondary prevention in STEMI patients with no contraindication. Although high-dose atorvastatin has been shown to reduce important patient outcomes such as MACE, there is still doubt that high-dose atorvastatin could have the same protective effect in patients undergoing PCI in the short and long term. We searched the following electronic databases: Scopus, Web of Science, MEDLINE, EMBASE, and Cochrane Central considering studies that enrolled adult patients with a confirmed diagnosis of STEMI or NSTEMI undergoing PCI. The intervention must have been atorvastatin alone compared to a placebo, standard care, or a different atorvastatin dose. A total of (n = 11) studies were included in the quantitative analysis. Information on (N = 5,399) patients was available; 2,654 were assigned to receive high-dose atorvastatin therapy, and 2,745 comprised the control group. High-dose atorvastatin pre-loading significantly reduced MACE at one month of follow-up (RR: 0.78; 95% CI: 0.67-0.91; p = 0.014) in both STEMI and NSTEMI. All-cause mortality was reduced in patients with STEMI (RR: 0.28; 95% CI: 0.10-0.81; p = 0.029). The quality of the body of evidence was rated overall as moderate. Patients presenting with STEMI or NSTEMI benefit from high-dose atorvastatin pre-loading before PCI by reducing MACE at 30 days. The use of high-dose atorvastatin in STEMI patients reduced all-cause mortality. The beneficial effects of atorvastatin pre-loading are limited to 30 days post-PCI.

SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia.

This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8-21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0-24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose-exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0-24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients.

Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia.

AIM: In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND: VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE: The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS: The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS: AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION: This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.

Randomized trial to assess the potential role of ascorbic acid and statin for post-contrast acute kidney injury prevention.

PURPOSE: To evaluate the effect of using statins and ascorbic acid for the prevention of post-contrast acute kidney injury (PC-AKI) in patients undergoing urologic diagnostic elective contrast-enhanced computed tomography (CECT). METHODS: This registered trial (NCT03391830) was for statin naïve patients underwent elective CECT. Patients were randomized allocated to two groups: the first group received atorvastatin 80-mg the day before the study and atorvastatin 40-mg two hours before the CECT and for continue on atorvastatin 40-mg two days after CECT; plus ascorbic acid 500 mg with atorvastatin. The other group received two tablets of placebo once/daily before the procedure and for another 3 days. The primary outcome was to assess the incidence PC-AKI. RESULTS: The baseline parameters were comparable between both groups. The final median (interquartile range "IQR") serum creatinine were 0.80 (0.60, 1.00) and 0.80 (0.60, 1.00), respectively, with insignificant p-value (p = 0.8). The median (IQR) final estimated GFR were 95.2 (72.8, 108.1) and 88.6 (71.9, 111.0) mL/min in placebo and statin plus ascorbic acid groups, respectively (p = 0.48). The eGFR difference median (IQR) were - 6.46 (- 11.72, - 4.18) and - 6.57 (- 13.38, - 3.82) ml/min in placebo and statin plus ascorbic acid groups, respectively (p = 0.58). PC-AKI occurred in 11 patients (9.8%) in placebo group and in 3 patients (3%) in statin plus ascorbic acid group (p = 0.04). CONCLUSIONS: Statin and ascorbic acid did not statistically improve neither serum creatinine nor eGFR values in patient underwent CECT. However, it can decrease the incidence of the clinically insignificant PC-AKI.

Comparison of the anticancer effects of various statins on canine oral melanoma cells.

Canine oral melanoma is a highly malignant cancer with a poor prognosis. Statins, commonly used drugs for treating dyslipidemia, exhibit pleiotropic anticancer effects and marked anti-proliferative effects against melanoma cells. The anticancer effects among statins vary; in human cancers, lipophilic statins have shown stronger anticancer effects compared with hydrophilic statins. However, data on the differences in the effects of various statins on canine cancer cells are lacking, hence the optimal statins for treating canine melanoma remain unknown. Therefore, this study aimed to clarify the most effective statin by comparing the anticancer effects of hydrophilic rosuvastatin and lipophilic atorvastatin, simvastatin, fluvastatin and pitavastatin on three canine oral melanoma cell lines. Time-dependent measurement of cell confluence showed that lipophilic statins had a stronger anti-proliferative effect on all cell lines than hydrophilic rosuvastatin. Quantification of lactate dehydrogenase release, an indicator of cytotoxicity, showed that lipophilic statins more effectively induced cell death than hydrophilic rosuvastatin. Lipophilic statins affected both inhibition of cell proliferation and induction of cell death. The anticancer effects of statins on canine oral melanoma cells differed in the following ascending order of IC50 values: pitavastatin < fluvastatin = simvastatin < atorvastatin < rosuvastatin. The required concentration of pitavastatin was approximately 1/20th that of rosuvastatin. Among the statins used in this study, pitavastatin had the highest anticancer effect. Our results suggest lipophilic pitavastatin as the optimal statin for treating canine oral melanoma.

Exploring the Evolution of Statin Pricing in Australia: Observations of Price Disclosure Effects on Pharmaceutical Benefits Scheme Expenditure.

OBJECTIVES: The high cardiovascular disease burden globally and in Australia necessitates attention on statin expenditure, the primary pharmacological intervention for cardiovascular disease risk factors. The Pharmaceutical Benefits Scheme (PBS) subsidies approved statins for Australians. Managing PBS government expenditure occurs through price control strategies of statutory price decreases upon first generic entry and price disclosure. This study investigates the impact price control measures had on statin price evolution and government expenditure between 2010 and 2022. METHODS: Prescription and pricing data were obtained from Services Australia Medicare Statistics, and price reduction strategies from the PBS. Summary statistics compared and described statin price, prescription, number of brands, market share, and government expenditure to atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin price control timelines. RESULTS: Statin prices exposed to price control measures decreased irrespective of dosage and correlated with reductions in government expenditure, with a comparison of 2010 and 2022 showing annual statin expenditure declined by AU$833.5 million (83.25%) whereas prescriptions reduced by 3.0 million (15.7%). Effects of price disclosure on atorvastatin and rosuvastatin market share suggest industry-prompted price reductions may arise from market share loss, whereas reasons external to pricing prompted rosuvastatin to gain market share. CONCLUSIONS: Limited publications on contemporary effects of statin price control measures exist. This investigation found these measures reduced government expenditure for statins by AU$949.1 million, with the price reduction correlating with price control measures. In addition to affirming price control mechanisms remain effective in contemporary times, this investigation provides data for key insights into the Australian statin industry.

A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

Pharmacokinetics of single-dose oral atorvastatin and its metabolites support therapeutic use in orange-winged Amazon parrots (Amazona amazonica).

OBJECTIVE: To evaluate the plasma concentrations and determine pharmacokinetic parameters of atorvastatin and its primary active metabolites (para- and ortho-hydroxyatorvastatin) after administration of a single oral dose in orange-winged Amazon parrots (Amazona amazonica). ANIMALS: 8 adult orange-winged Amazon parrots (4 male, 4 female) of varying ages. METHODS: A compounded oral suspension of atorvastatin 10 mg/mL was administered via oral gavage at 20 mg/kg to each bird. Blood samples were collected at 10 different time points from 0 to 30 hours postadministration to evaluate plasma levels of atorvastatin, para-hydroxyatorvastatin, and ortho-hydroxyatorvastatin. Pharmacokinetic analysis was performed using noncompartmental analysis and commercially available software. RESULTS: Mean ± SD atorvastatin half-life, tmax, and Cmax were 5.96 ± 11.50 hours, 1.60 ± 0.80 hours, and 82.60 ± 58.30 ng/mL, respectively. For para-hydroxyatorvastatin, the half-life, tmax, and Cmax were 6.46 ± 54.20 hours, 5.00 ± 2.51 hours, and 34.10 ± 16.00 ng/mL, respectively, and 5.58 ± 9.92 hours, 3.38 ± 2.10 hours, and 7.35 ± 3.96 ng/mL for ortho-hydroxyatorvastatin. CLINICAL RELEVANCE: The plasma concentrations and pharmacokinetic profile shown support the therapeutic use of atorvastatin at the dose evaluated in this species based on human pharmacokinetic data. While 20 mg/kg PO q24 hours could be used as a starting dosage until further studies evaluating multiple dose administration and efficacy in this species become available, the high interindividual variability results warrant monitoring of the treatment response to make dosing adjustments if needed.

Population Pharmacokinetics of Atorvastatin in High-Altitude and Plain Patients with Hyperlipidemic.

The pharmacokinetic (PK) characteristics of drugs were altered under high-altitude hypoxia. We aim to describe the population PK of atorvastatin (ATV) to identify patient characteristics that are predictive of variability in the PK parameters of the ATV and investigate the effects of high-altitude hypoxia on the blood concentration of ATV in patients with hyperlipidemia. A total of 160 plasma concentrations were collected from 40 patients with hyperlipidemia in plateau areas and 40 in plain areas. The population pharmacokinetic model of patients with hyperlipidemia in plateau and plain areas of China was established by a nonlinear mixed-effects model. The PK of ATV were described by a 1-compartment model with first-order elimination. The main PK parameters of ATV were the first-order absorption rate (0.76 hour-1 fixed); clearance (174.22 L/h) and apparent volume of distribution (1119.62 L). The values of area and age were identified as significant covariates for the clearance, area, age, and urea for the volume of distribution. The steady-state peak concentration in the plateau area was higher than that in the plain area. This study may suggest dose reduction is necessary for patients with hyperlipidemia in high altitudes.

Treatment of Ischemic Stroke by Atorvastatin-Loaded PEGylated Liposome.

There is insufficient evidence on the effect of nanoparticles, particularly liposomes loaded with a statin, on acute ischemic stroke. We investigated the impact of atorvastatin-loaded PEG (polyethylene glycol) conjugated liposomes (LipoStatin) on the outcomes in rats with cerebral ischemia-reperfusion. PEGylated liposome loaded with atorvastatin was developed as a nanoparticle to specifically accumulate in an ischemic region and release the drug to ameliorate the harmful effects of the stroke. LipoStatin was administered to rats with transient middle cerebral artery occlusion through the tail vein immediately after reperfusion (LipoStatin group). LipoStatin efficiently accumulated at the cerebral ischemic injury site of the rat. The LipoStatin group showed a significantly reduced infarct volume (p < 0.01) in brain micro-MR imaging and improved neurological function recovery compared to the control group (p < 0.05). In addition, markedly improved brain metabolism using fluorine-18 fluorodeoxyglucose micro-PET/CT imaging was demonstrated in the LipoStatin group compared with the control group (p < 0.01). Mechanistically, as a result of evaluation through IL-1 beta, TNF-alpha, ICAM-1, and Iba-1 mRNA expression levels at 5 days after cerebral ischemia, LipoStatin showed significant anti-inflammatory effects. Protein expression of occludin, JAM-A, Caveolin-1, and eNOS by western blot at 3 days and fluorescent images at 7 days showed considerable recovery of blood-brain barrier breakdown and endothelial dysfunction. PEGylated LipoStatin can be more effectively delivered to the ischemic brain and may have significant neuroprotective effects. Thus, PEGylated LipoStatin can be further developed as a promising targeted therapy for ischemic stroke and other major vascular diseases.