Efficiency and Toxicity of Imatinib Mesylate Combined with Atorvastatin Calcium in the Treatment of Steroid-Refractory Chronic Graft-versus-Host Disease: A Single-Center, Prospective, Single-Arm, Open-Label Study.

INTRODUCTION: Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported that imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS: Sixty SR-cGVHD patients were entered into this trial to investigate the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets, and adverse events. RESULTS: At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes, and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, p < 0.0001). The overall survival in patients with ORR was improved (p = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (p = 0.021, HR = 0.335, 95% CI: 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (p = 0.0117) and Th17 cells (p = 0.0171) decreased, while the number of Treg cells (p = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia, which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION: Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.

Improved Dissolution Properties of Co-amorphous Probucol with Atorvastatin Calcium Trihydrate Prepared by Spray-Drying.

A co-amorphous model drug was prepared by the spray-drying (SD) of probucol (PC) and atorvastatin calcium trihydrate salt (ATO) as low water solubility and co-former components, respectively. The physicochemical properties of the prepared samples were characterized by powder X-ray diffraction (PXRD) analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and dissolution tests. Stability tests were also conducted under a stress environment of 40 °C and 75% relative humidity. The results of PXRD measurements and thermal analysis suggested that PC and ATO form a co-amorphous system by SD. Thermal analysis also indicated an endothermic peak that followed an exotherm in amorphous PC and a physical mixture (PM) of amorphous PC and ATO; however, no endothermic peak was detected in the co-amorphous system. The dissolution profiles for PC in the co-amorphous sample composed of PC and ATO were improved compared to those for raw PC crystals or the PM. Stability tests indicated that the co-amorphous material formed by PC and ATO can be stored for 35 d without crystallization, whereas amorphous PC became crystallized within a day. Therefore, co-amorphization of PC and ATO prepared by SD is considered to be a useful method to improve the solubility of PC in water.

Effect of atorvastatin calcium plus clopidogrel in the treatment of patients with transient ischemic attacks and its effect on blood lipids and platelets.

OBJECTIVE: To explore the clinical effect of atorvastatin calcium combined with clopidogrel in the treatment of patients with transient ischemic attacks (TIAs) and its effect on blood lipids and platelets. METHODS: Low-density lipoprotein cholesterol (LDL-C)], platelet-related parameters [prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count (PLT)], incidence of cerebral infarction, and adverse reactions. RESULTS: The clinical outcomes of the experimental group patients were significantly better than those of the control group patients (p < 0.05). The experimental group exhibited notably lower levels of TG, TC, and LDL-C compared to the control group (p < 0.05). Platelet-related indices-PT, APTT, and PLT-showed no significant differences between groups before and after treatment (p > 0.05). The incidence of cerebral infarction was notably lower in the experimental group (p < 0.005), while the occurrence of adverse reactions showed no significant difference between groups (p > 0.05). CONCLUSION: Atorvastatin calcium combined with clopidogrel demonstrates a positive impact on individuals with TIAs by significantly lowering levels of LDL, total cholesterol, and triglycerides. However, it is noteworthy that platelet-related indices did not exhibit significant differences between the experimental and control groups. While the observed improvements in blood lipids are attributed to the effects of atorvastatin, the combination with clopidogrel did not show a substantial influence on platelet-related parameters. Thus, the overall therapeutic impact, particularly on platelet-related indices, may require further investigation and clarification. Despite these nuances, our findings suggest potential benefits in reducing the risk of adverse reactions and cerebral infarction, supporting the consideration of this approach for wider clinical use.

Optimization of a solidified micelle formulation for enhanced oral bioavailability of atorvastatin calcium using statistical experimental design.

To enhance the oral bioavailability of atorvastatin calcium (ATV), a novel solidified micelle (S-micelle) was developed. Two surfactants, Gelucire 48/16 (G48) and Tween 20 (T20), were employed for micelle formation, and two solid carriers (SC), Florite PS-10 (FLO) and Vivapur 105 (VP105), were selected as solid carriers. The S-micelle was optimized using a Box-Behnken design with three independent variables, including G48:T20 (X1, 1.8:1), SC:G48 + T20 (X2, 0.65:1), and FLO:VP105 (X3, 1.4:0.6), resulting in a droplet size (Y1) of 198.4 nm, dissolution efficiency at 15 min in the pH 1.2 medium (Y2) of 47.6%, Carr's index (Y3) of 16.9, and total quantity (Y4) of 562.5 mg. The optimized S-micelle resulted in good correlation showing percentage prediction values less than 10%. The optimized S-micelle formed a nanosized dispersion in the aqueous phase, with a higher dissolution rate than raw ATV and crushed Lipitor®. The optimized S-micelle improved the relative bioavailability of oral ATV (25 mg equivalent/kg) in rats by approximately 509 and 271% compared to raw ATV and crushed Lipitor®, respectively. In conclusion, the optimized S-micelle possesses great potential for the development of solidified formulations for improved oral absorption of poorly water-soluble drugs.

Effect of nimodipine combined with atorvastatin calcium on microinflammation and oxidative stress levels in patients with cerebral vasospasm after subarachnoid hemorrhage.

Objective: To evaluate the effect of nimodipine combined with atorvastatin calcium on the micro inflammation and oxidative stress levels in patients with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) and its clinical implications. Methods: A total of 80 patients with CVS caused by SAH who had been admitted to Baoding First Central Hospital from August 2021 to August 2022 were selected and randomly divided into two groups. The control group underwent conventional symptomatic treatment, while the experimental group was administered nimodipine combined with atorvastatin calcium on the basis of conventional treatment. The changes in the micro inflammatory cytokines and oxidative stress factors in the two groups were compared, as well as the differences in clinical efficacy and incidence of adverse drug reactions. Result: After treatment, the levels of inflammatory cytokines in the experimental group decreased more significantly than those in the control group (p=0.00). After treatment, the serum levels of oxidative stress factors were obviously higher in the experimental group than in the control group (p=0.00). After treatment, the total efficacy was 77.5% in the experimental group and 55% in the control group, and the difference was statistically significant (p=0.04). Conclusions: Nimodipine combined with atorvastatin calcium could significantly improve the clinical symptoms in patients with CVS after SAH, which would be beneficial, safe, and effective for the patient's recovery.

Analysis on efficacy of compound dextran combined with atorvastatin calcium in patients with CVS caused by SAH based on TCD blood flow indexes.

Objectives: To analyze the effects of compound dextran combined with atorvastatin calcium on blood flow indexes, peroxidase 2 (Prx2) and endothelin-1 (ET-1) in patients with cerebral vasospasm (CVS) caused by subarachnoid hemorrhage (SAH). Methods: One hundred patients with CVS caused by SAH treated in Baoding No.1 Central Hospital from January 2019 to December 2020 were divided into observation group and control group. The control group was treated with atorvastatin calcium tablets, while the observation group was additionally treated with compound dextran. The hospital stays, Glasgow Outcome Scale (GOS), hemoglobin (Hb) and hematocrit (Hct) levels before and five days after treatment were recorded. The hemodynamic parameters of the middle cerebral artery (MCA) and the serum levels of Prx2 and ET-1 were detected. Results: After treatment, GOS and Hct levels in the observation group were both higher than those in the control group (P < 0.05). After treatment, the mean and peak velocities of the MCA in the observation group were significantly lower than those in the control group (P < 0.05). After treatment, the serum levels of Prx2 and ET-1 in the observation group were significantly lower compared with those in the control group (P < 0.05). However, no significant differences were found in the incidences of adverse reactions between the two groups (P > 0.05). Conclusions: Compound dextran combined with atorvastatin calcium can effectively enhance clinical efficacy, improve cerebral blood flow and reduce serum Prx2 and ET-1 levels in patients with CVS caused by SAH.

High-resolution 13 C and 43 Ca solid-state NMR and computational studies of the ethylene glycol solvate of atorvastatin calcium.

We report 43 Ca and 13 C solid-state nuclear magnetic resonance (NMR) spectroscopic studies of the ethylene glycol solvate of atorvastatin calcium. The 13 C and 43 Ca chemical shift and 43 Ca quadrupolar coupling tensor parameters are reported. The results are interpreted in terms of the reported X-ray diffraction crystal structure of the solvate and are compared with the NMR parameters of atorvastatin calcium trihydrate, the active pharmaceutical ingredient in Lipitor®. Hartree-Fock and density functional theory calculations of the NMR parameters based on a cluster model derived from the optimized X-ray diffraction crystal structure of the ethylene glycol solvate of atorvastatin calcium are in reasonable agreement with the experimental 43 Ca and 13 C NMR measurables.

BCS class II drug loaded protein nanoparticles with enhanced oral bioavailability: in vitro evaluation and in vivo pharmacokinetic study in rats.

The aim of the study was to improve the bioavailability of atorvastatin calcium (ATC) by formulating polymeric nanoparticles (NPs) with an easy and cost-effective approach. ATC entrapped gelatin nanoparticles (AEGNPs) were prepared by using a simple one-step desolvation method. The formed NPs were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. Morphological study exhibited a homogenous spherical shape of formulated NPs. FTIR studies revealed the chemical compatibility of the drug with gelatin. The improvement in drug delivery kinetics of AEGNPs could be attributed to amorphization along with the reduction in particle size of ATC. The pharmacokinetic study in Sprague-Dawley rats revealed that the Cmax and AUC0-24 of AEGNPs in rats were ∼4-fold and ∼11-fold higher than that of pure ATC suspension. The research presented successfully shows that AEGNPs preparation by one-step desolvation, using minimum excipients is a quick, easy and reproducible method. These results suggest that the ATC encapsulated gelatin NP is a promising approach for the oral delivery of ATC, improving the bioavailability of the drug.

Gastroretentive bilayer film for sustained release of atorvastatin calcium and immediate release of amlodipine besylate: pharmaceutical, pharmacokinetic evaluation, and IVIVC.

The present study was aimed to optimize capsulated unfolding type gastroretentive bilayer film constituting immediate release (IR) layer of amlodipine besylate and sustained release (SR) layer of atorvastatin calcium. A three-factor, three-level Box-Behnken-design was used to optimize bilayer film with dual-release characteristics. The selected independent variables were HPMC-K3, Eudragit RSPO, and Carbopol 934P and the responses were floating duration, swelling index, and in vitro release from SR layer in 8 h. The films were also assessed for pharmacotechnical characteristics, release kinetics, DSC, FTIR, and SEM. The pharmacokinetics of the drugs from the optimized formulation was compared with the marketed formulation in rabbits. The capsulated accordion film unfolded and provided SR of atorvastatin for 8 h (96.76% ± 0.71) and IR of amlodipine within 25 min (98.07% ± 0.62) for the optimized formulation (F14). The swelling index and floating duration for the optimized formulation were 140.48 ± 0.57 and 8.53 ± 0.10 h, respectively. Results of pharmacokinetics showed that faster absorption of amlodipine and improved bioavailability (2.16-fold) of atorvastatin in blood was made available through bilayer film. In vitro-in vivo correlation was established using numerical deconvolution method. It can be concluded that the capsulated gastroretentive system provided site specific simultaneous SR of antihyperlidemic drug and IR of antihypertensive drug as single pill that has therapeutic potential to manage cardiovascular risk.

[Effects of Atorvastatin Calcium on the Survival of Ultra-long Dorsal Random Skin Flaps in Rats].

OBJECTIVE: To investigate the effects of atorvastatin calcium (ATR) on the survival of ultra-long dorsal random skin flaps in rats. METHODS: Thirty SD rats were divided into five groups ( n=6) according to the random number table: normal saline control group (CON group), ATR 10 mg/kg group (P10 group), ATR 20 mg/kg group (P20 group), ATR 30 mg/kg group (P30 group), and ATR 40 mg/kg group (P40 group). After pretreatment with ATR or 0.9% saline for 3 days, an ultra-long dorsal random skin flaps with size of 8 cm×2 cm was made on the back of each rat and replanted in situ. After the operation, the ATR or saline treatment lasted for 3 d. Seven days after operation, the appearance of skin flaps was observed with naked eyes, the survival rate of skin flaps was calculated. The pathological changes in the surviving areas of skin flaps were observed by HE staining, the number of microvessels in skin flaps was observed by immunohistochemistry staining, the mRNA expressions of vascular endothelial growth factor ( VEGF) and basic fibroblast growth factor ( bFGF) were tested by quantitative real-time PCR, and the contents of superoxide dismutase, nitrogen monoxide and malonaldehyde were tested by enzyme linked immunosorbent assays (ELISA). RESULTS: On the 7 thday after operation, the skin flap of the CON group showed a large area of necrosis, and the necrotic part formed crusts. Crusts were hard and inelastic, and a large amount of tissue fluid exudated. The fascial layer showed dark purple. No exudation of tissue fluid was observed in the flaps of P10, P20, P30 and P40 groups. The scab shell fell off naturally and the fur grew normally. HE staining of CON group showed that a large number of inflammatory cell infiltration, epidermal loss and necrosis in skin flaps, but the pathological changes in skin flaps were significantly improved after treatment with ATR. Compared with the CON group, the survival rate of skin flaps, the number of microvessels in skin flaps and the levels of VEGF mRNA, bFGF mRNA, SOD, NO in skin flaps also increased with the dose of ATR, which reached a peak at 30 mg/kg ATR ( P<0.05). However, the level of MDA in skin flaps decreased with the dose of ATR, which reached the lowest at 30 mg/kg ATR ( P<0.05). CONCLUSION: ATR can enhance the survival of ultra-long dorsal random skin flaps in rats, which may be related to promoting microangiogenesis and inhibiting inflammatory and oxidative stress.

Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.

BACKGROUND: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression. RESULTS: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008). CONCLUSIONS: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

Safety and tolerability of high-intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus.

BACKGROUND: Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins; however, little data exist using high-intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus. METHODS: This single-center, retrospective analysis included adult HT recipients from January 1, 2005, to December 31, 2015, who received HI statin therapy during posttransplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol. RESULTS: Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; P > 0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (P = 0.02) and 19 mg/dL (P = 0.10), respectively. CONCLUSIONS: High-intensity statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for the treatment of refractory hyperlipidemia.

Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism.

BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. METHODS: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)-apolipoprotein B-100 (apoB), intermediate-density lipoprotein-apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. RESULTS: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (P<0.001 and P.032, respectively), intermediate-density lipoprotein-apoB (P=0.021 and P=.002, respectively), and LDL-apoB (P<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein-apoB (P=0.043) and LDL-apoB (P<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (P<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. CONCLUSIONS: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.

Efficacy and Safety Profiles of Oral Atorvastatin-Loaded Nanoparticles: Effect of Size Modulation on Biodistribution.

Atorvastatin calcium (AC)-loaded nanoparticles (NPs) of mean particle diameter <100 nm and narrow distribution were prepared and characterized. Their in vivo PK as well as PD measures following oral administration in different dosage regimens in hyperlipidemic rats were evaluated. The results revealed that the oral bioavailability of two selected AC-NPs formulations was 235% and 169% relative to Lipitor. However, the treatment regimens were not superior in reducing serum total cholesterol (TC), low-density lipoproteins (LDL), and triglycerides (TG) levels compared to Lipitor. Moreover, the AC-NPs treatments were associated with significant adverse effects observed biochemically and histologically. These results were contradictory with those obtained from a previous study in which similarly formulated AC-NPs of mean particle diameter >200 nm were found to be more safe and effective in reducing TC, LDL, and TG levels when administered to hyperlipiemic rats at reduced dosing frequency compared to daily dose of Lipitor despite their lower oral bioavailability. The discrepant correlation between pharmacokinetics (PK) and pharmacodynamics (PD) results was suggested to pertain to the different biodistribution profiles of AC-NPs depending on their sizes. Hereby, we provide a simple approach of particle size modulation to enhance the efficacy and safety of atorvastatin.

In vitro and in vivo evaluation of cyclodextrin-based nanosponges for enhancing oral bioavailability of atorvastatin calcium.

The aim of this study was to explore the feasibility of complexing the poorly water-soluble drug atorvastatin calcium (AC) with ß-cyclodextrin (ß-CD) based nanosponges (NS), which offer advantages of improving dissolution rate and eventually oral bioavailability. Blank NS were fabricated at first by reacting ß-CD with the cross-linker carbonyldiimidazole at different molar ratios (1:2, 1:4, and 1:8), then NS of highest solubilization extent for AC were complexed with AC. AC loaded NS (AC-NS) were characterized for various physicochemical properties. Pharmacokinetic, pharmacodynamics and histological finding of AC-NS were performed in rats. The prepared AC-NS showed particles size ranged from 408.7 ± 12.9 to 423 ± 15.9 nm while zeta potential values varied from -21.7 ± 0.90 to -22.7 ± 0.85 mV. The loading capacity varied from 17.9 ± 1.21 to 34.1 ± 1.16%. DSC, FT-IR, and PXRD studies confirmed the complexation of AC with NS and amorphous state of the drug in the complex. AC-NS displayed a biphasic release pattern with increase in the dissolution rate of AC as compared to plain AC. Oral administration of AC-NS (1:4 w/w, drug: NS) to rats led to 2.13-folds increase in the bioavailability as compared to AC suspension. Pharmacodynamics studies in rats with fatty liver revealed significant reduction (p < .05) in total cholesterol, triglyceride, LDL-C and increased level of beneficial HDL-C along with improvement in the associated liver steatosis as confirmed through photomicrographs of liver sections. In this study, we confirmed that complexation of AC with NS would be a viable approach for improving oral bioavailability and in vivo performance of AC.

Atorvastatin Calcium Inhibits PDGF-ßß-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRß-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-ßß, 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-ßß-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-ßß-treated VSMCs. We demonstrated that atorvastatin calcium induced cell cycle arrest in the G0/G1 phase in response to PDGF-ßß 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-ßß-treated VSMCs. Moreover, pretreatment with atorvastatin calcium inhibited the PDGF-ßß-treated phosphorylation of PDGFRß 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 PDGFRß-Akt signaling cascade.

Effect of two lipid-lowering strategies on high-density lipoprotein function and some HDL-related proteins: a randomized clinical trial.

BACKGROUND: The influence of lipid-lowering therapy on high-density lipoprotein (HDL) is incompletely understood. We compared the effect of two lipid-lowering strategies on HDL functions and identified some HDL-related proteins. METHODS: Thirty two patients were initially screened and HDLs of 21 patients were finally analyzed. Patients were randomized to receive atorvastatin 20 mg (n = 11) or atorvastatin 5 mg/ezetimibe 10 mg combination (n = 10) for 8 weeks. The cholesterol efflux capacity and other anti-inflammatory functions were assessed based on HDLs of the participants before and after treatment. Pre-specified HDL proteins of the same HDL samples were measured. RESULTS: The post-treatment increase in cholesterol efflux capacities was similar between the groups (35.6% and 34.6% for mono-therapy and combination, respectively, p = 0.60). Changes in nitric oxide (NO) production, vascular cell adhesion molecule-1 (VCAM-1) expression, and reactive oxygen species (ROS) production were similar between the groups. The baseline cholesterol efflux capacity correlated positively with apolipoprotein (apo)A1 and C3, whereas apoA1 and apoC1 showed inverse associations with VCAM-1 expression. The changes in the cholesterol efflux capacity were positively correlated with multiple HDL proteins, especially apoA2. CONCLUSIONS: Two regimens increased the cholesterol efflux capacity of HDL comparably. Multiple HDL proteins, not limited to apoA1, showed a correlation with HDL functions. These results indicate that conventional lipid therapy may have additional effects on HDL functions with changes in HDL proteins. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02942602 .

Development and optimisation of atorvastatin calcium loaded self-nanoemulsifying drug delivery system (SNEDDS) for enhancing oral bioavailability: in vitro and in vivo evaluation.

The objective of this study was to develop and optimise self-nanoemulsifying drug delivery system (SNEDDS) of atorvastatin calcium (ATC) for improving dissolution rate and eventually oral bioavailability. Ternary phase diagrams were constructed on basis of solubility and emulsification studies. The composition of ATC-SNEDDS was optimised using the Box-Behnken optimisation design. Optimised ATC-SNEDDS was characterised for various physicochemical properties. Pharmacokinetic, pharmacodynamic and histological findings were performed in rats. Optimised ATC-SNEDDS resulted in droplets size of 5.66 nm, zeta potential of -19.52 mV, t90 of 5.43 min and completely released ATC within 30 min irrespective of pH of the medium. Area under the curve of optimised ATC-SNEDDS in rats was 2.34-folds higher than ATC suspension. Pharmacodynamic studies revealed significant reduction in serum lipids of rats with fatty liver. Photomicrographs showed improvement in hepatocytes structure. In this study, we confirmed that ATC-SNEDDS would be a promising approach for improving oral bioavailability of ATC.

Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

Formulation of solid self-nanoemulsifying drug delivery systems using N-methyl pyrrolidone as cosolvent.

Atorvastatin calcium (ATRC) is a poor water soluble drug used for treatment of hypercholesterolemia. This research is aimed to improve solubility and dissolution rate of ATRC by formulating into solid self-nanoemulsifying drug delivery system (S-SNEDDS) using N-methyl pyrrolidone (NMP) as cosolvent. Solubility of ATRC was determined in various vehicles. Ternary phase diagrams were constructed to identify stable nanoemulsion region. SNEDDS formulations were evaluated for robustness to dilution, thermodynamic stability study, % transmittance, self-emulsification time, globule size and transmission electron microscopy. The optimized liquid SNEDDS showed robust to all dilutions exhibiting no signs of phase separation or precipitation for 24 h. Liquid SNEDDS was transformed into S-SNEDDS using different adsorbents. Differential scanning calorimetry and scanning electron microscopy studies unravel the transformation of native crystalline state to amorphous state/solubilized state. In vitro dissolution study of S-SNEDDS was found to be significantly higher in comparison to that from plain drug, irrespective of pH (p < 0.001). Furthermore, ex vivo permeation studies showed a 4.45-fold improvement in apparent permeability coefficient (Papp) from S-SNEDDS compared to plain drug. In conclusion, S-SNEDDS prepared using NMP as cosolvent provides an effective approach for improved oral delivery of ATRC.