Cholesterol (Blood lipid) lowering potential of Rosuvastatin chitosan nanoparticles for atherosclerosis: Preclinical study in rabbit model.

Atherosclerosis is the condition of narrowing of arteries due to plaque buildup on the artery walls. Aortic valve calcification (AVC) is one of the reasons of atherosclerosis which leads to narrowing at the opening of the aortic valve which is commonly referred as Aortic valve stenosis (AS). The Rosuvastatin-chitosan (ROS-chitosan) nanoparticles were prepared using ionotropic gelation method. Nanoparticulate formulation was optimized by 3 factor, 2 level full factorial design to find the effect of independent variables on particle size and percentage encapsulation efficiency. Particle size, encapsulation efficiency, scanning electron microscopy, in vitro drug release of nanoparticles was determined. The adult male rabbit of 4-5 months old were chosen for the study. Hypercholesterolemia was induced in experimental animals by administering diet with Cholesterol and Cholic acid (1.25 % and 0.5% respectively.) Blood lipid profile, interleukin 6 levels and histopathological study was performed. Rosuvastatin was found to be significantly effective in lowering the blood lipid levels. It helps to attenuate atherosclerosis as well as calcification of various valve tissues in experimental animals.

Evinacumab for Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).

Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin.

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

Sensitive fluorescence detection of atorvastatin by doped carbon dots synthesized in deep eutectic media.

Fluorescence properties of nanoparticles can be influenced by solvent. In this work, carbon dots (CDs) were synthesized in deep eutectic solvent by microwave assisted method. Quantum yield (QY) and size of the synthesized CDs were 41.3% and 2 nm, respectively. N/Cl -doped CDs had excellent sensitivity and selectivity for atorvastatin and detection limit was 0.8 nM. Simple and low-cost synthesis method and excellent sensitivity are advantages of this detection method for atorvastatin. The as-synthesized N/Cl-doped CDs were successfully used to determine atorvastatin in blood serum.

A Drug-Drug Interaction Study to Evaluate the Effect of TAS-303 on CYP3A Activity in the Small Intestine and Liver.

TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.

High molecular weight oat ß-glucan enhances lipid-lowering effects of phytosterols. A randomised controlled trial.

BACKGROUND & AIMS: Oat ß-glucan (OBG) and phytosterols (PS) are known to lower blood cholesterol levels via different mechanisms. Combination of high molecular weight (MW) OBG and PS in a single functional food could have complementary and/or synergistic effects for optimising heart health. The aim of this study was to investigate the effects of dietary supplementation with high-MW OBG with or without PS on plasma lipids in hypercholesterolaemic individuals. METHODS: In a double-blinded, placebo-controlled, 2 × 2 factorial trial, participants were randomised to receive biscuits fortified with either no PS or OBG (PL, n = 18) or 2 g PS (PS, n = 18), 3 g OBG (OBG, n = 18), or combination of 2 g PS and 3 g OBG (PS-OBG, n = 18) per day for 6 weeks. Primary outcome was fasting plasma total cholesterol (TC) and secondary outcomes were LDL-cholesterol, LDL-C; HDL-cholesterol, HDL-C; triglycerides, TG and TC to HDL-cholesterol (TC:HDL) ratio. RESULTS: TC and LDL-C were significantly lowered following PS (-4.6% and -7.6% respectively; p < 0.05), OBG (-5.7% and -8.6%; p < 0.01) and PS-OBG (-11.5% and -13.9%; p < 0.0001) administration. The reduction in TC in the PS-OBG group was significantly greater compared to PL (p < 0.001) and PS (p < 0.05). PS-OBG group had a significantly greater reduction in LDL-C compared to PL (p < 0.01) but not in comparison to PS or OBG groups. TC:HDL ratio was significantly reduced following PS-OBG (-8.9%; p < 0.01) only, and there was no significant difference found between groups. Plasma TG reduced by 8.4% following PS-OBG, however, this was statistically non-significant. Plasma HDL-C remained unchanged across all groups. CONCLUSIONS: Dietary supplementation with high-MW OBG and PS in a single functional food enhances their lipid-lowering potential. Blood cholesterol lowering by PS and OBG is additive. Delivery of these two bioactive nutrients in a single food allows optimisation of their lipid-lowering effects and may provide added heart health benefits with enhanced compliance. The trial was registered with the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au/(ACTRN12618001455257).

Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies.

The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open-label, and 2-period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10-mg dose of rosuvastatin with a 7-day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high-fat and high-calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.

A novel direct method to determine adherence to atorvastatin therapy in patients with coronary heart disease.

AIMS: Objective methods to monitor statin adherence are needed. We have established a liquid chromatography-tandem mass spectrometry assay for quantification of atorvastatin and its metabolites in blood. This study aimed to develop an objective drug exposure variable with cut-off values to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease. METHODS: Twenty-five patients treated with atorvastatin 10 mg (n = 5), 20 mg (n = 6), 40 mg (n = 7) and 80 mg (n = 7) participated in a directly observed atorvastatin therapy study to confirm baseline adherence. After the directly observed therapy, half of the patients (test group) were instructed to stop taking atorvastatin and return for blood sample collection the subsequent 3 days. Levels of atorvastatin and metabolites were compared between the test group and the adherent control group. RESULTS: The sum of parent drug and all measured primary metabolites correlated well with the atorvastatin dose administered (Spearman's rho = 0.71, 95% CI 0.44-0.87). The dose-normalized atorvastatin plus metabolites concentrations completely separated the partially adherent test group from the controls at 0.18 nM/mg after 3 days without atorvastatin. To reduce the risk of misinterpreting adherent patients as partially adherent, a corresponding cut-off at 0.10 nM/mg is proposed. A metabolite level of 2-OH atorvastatin acid <0.014 nmol/L provided the optimal cut-off for nonadherence. CONCLUSION: A direct method to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease has been developed. This tool may be important for novel studies on adherence and potentially useful in clinical practice.

Association between individual cholesterol and proteinuria response and exposure to atorvastatin or rosuvastatin.

AIM: The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response. MATERIALS AND METHODS: The PLANET trials randomized patients with a UPCR of 500-5000 mg/g and fasting LDL-cholesterol >2.33 mmol/L to a 52-week treatment with atorvastatin 80 mg, rosuvastatin 10 mg or 40 mg. For the current analysis, patients with available samples at week 52 and treatment compliance >80% by pill count were included (N = 295). The main outcome measurements were percentage change in UPCR and absolute change in LDL-cholesterol (delta LDL) from baseline to week 52. RESULTS: Median (interquartile range) plasma concentration at week 52 for atorvastatin 80 mg was 3.9 ng/mL (IQR: 2.1 to 8.7), for rosuvastatin 10 mg 1.0 ng/mL (IQR: 0.7 to 2.0) and for rosuvastatin 40 mg 3.5 ng/mL (IQR: 2.0 to 6.8). Higher plasma concentration of statin was associated with larger LDL-cholesterol reductions at week 52 [rosuvastatin r = -0.40 (P < .001); atorvastatin r = -0.28 (P = .006)]. The plasma concentration of both statins did not correlate with UPCR change [rosuvastatin r = 0.07 (P = .30); atorvastatin r = 0.16 (P = .13)]. CONCLUSIONS: Individual variation in plasma concentrations of rosuvastatin and atorvastatin was associated with LDL-cholesterol changes in patients. The individual variation in UPCR change was not associated with the plasma concentration of both statins.

Access and concentrations of atorvastatin in the prostate in men with prostate cancer.

BACKGROUND: Statins have anticancer effects on prostate cancer both in vitro and in vivo. It is unclear whether this is due to systemic cholesterol-lowering or direct local growth inhibition in the prostate. It is also unclear whether statins can access the prostate; lipophilic statins could, in theory, pass lipid-enriched cell membranes by passive diffusion. However, statin concentrations in the human prostate have not been measured before. METHODS: The study population was based on a randomized clinical trial where 158 men with prostate cancer were randomized to use 80 mg atorvastatin (ATV) or placebo daily for a median of 27 days before radical prostatectomy. ATV and atorvastatin lactone (ATV-Lactone) concentrations in the plasma and in the prostate were measured with mass spectrometry in men randomized to the ATV arm. Linear trends between intraprostatic concentration and plasma concentration, body mass index, age, and duration of intervention were examined. The relative tissue concentrations of ATV and ATV-Lactone were calculated in prostatic tissue and plasma to evaluate drug homeostasis. Subgroup analyses were stratified by tumor and population characteristics. RESULTS: The analysis involved a total of 55 men. When limited to men whose tissue concentrations of ATV was measurable (n = 28, 50%), median ATV concentration was 212% higher in the tissue (median concentration 17.6 ng/g) compared to the plasma (median concentration 3.6 ng/mL). Also, ATV-L concentration was 590% higher in the tissue as compared to the plasma concentration. No statistically significant linear trends between the plasma and tissue concentrations were observed. When comparing the relative concentration of atorvastatin lactone over ATV, the concentrations were in balance in the plasma, In the prostate, however, the relative concentration of atorvastatin lactone was 57% lower compared to ATV (P = .009 for the difference between prostate tissue and plasma). No effect modification by tumor or population characteristics was observed. CONCLUSIONS: Measurable ATV concentrations in the prostate support ATV's ability to access the prostate from the circulation. ATV may accumulate in the prostate as intraprostatic concentrations are elevated compared to the plasma concentration.

A Method for Direct Monitoring of Atorvastatin Adherence in Cardiovascular Disease Prevention: Quantification of the Total Exposure to Parent Drug and Major Metabolites Using 2-Channel Chromatography and Tandem Mass Spectrometry.

BACKGROUND: Low adherence to statin therapy remains a public health concern associated with poor prognosis in cardiovascular disease patients. A feasible method for statin adherence monitoring in clinical practice has yet to be developed. In this article, we describe a novel method designed for the direct monitoring of atorvastatin adherence based on the sum of parent drug and major metabolites in blood samples. METHODS: Acid and lactone forms of atorvastatin, 2-OH-atorvastatin, and 4-OH-atorvastatin were assayed. Plasma proteins were precipitated with an acidified mixture of methanol, acetonitrile, and aqueous zinc sulfate, and the supernatant was analyzed with 2-channel reversed-phase chromatography coupled to tandem mass spectrometry. Assay validation was performed according to the guidelines provided by the European Medicines Agency and the US Food and Drug Administration. RESULTS: The effective run time was 1 minute and 45 seconds per sample. Mean accuracy ranged from 92% to 110%, and coefficients of variation were ≤8.1% over the measurement ranges for individual compounds. The sum of acids and corresponding lactones was stable in clinical plasma samples kept at ambient temperature for up to 6 days after blood sampling (mean sum within 96.6%-101% of baseline). CONCLUSIONS: A fast and reliable assay for the quantification of atorvastatin and its 5 major metabolites in clinical blood samples is reported. Limitations of preanalytical stability were solved using the sum of the acid and lactone forms. The assay is feasible for implementation in clinical practice, and the sum of parent drug and metabolites may be used for direct monitoring of atorvastatin adherence.

Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices.

The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150-mg subcutaneous dose administered to healthy subjects (n = 156-158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (Cmax ) ranged between 11.0 and 11.3 µg/mL, and area under the plasma concentration-time curve (AUCinf ) ranged between 177.6 and 185.0 µg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for Cmax and AUCinf fell within the 80%-125% range for both DS and delivery device comparisons. Comparable low-density lipoprotein cholesterol profiles were observed, with nadir values of 54.3-56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection-site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150-mg subcutaneous injection regardless of site of DS manufacture or delivery device used.

Atorvastatin: A Review of Analytical Methods for Pharmaceutical Quality Control and Monitoring.

Background: Atorvastatin, a lipid-regulating drug, was the best-selling drug in the world in the early 2000s. Thus, monitoring of this drug is important because it is accessible to a large portion of the population. In addition, its quality control is fundamental to provide quality medicines. Method of analysis can be the first step in the rational use of pharmaceuticals. Objective/Methods: In this context, a critical review of analytical methods present in the literature and official compendia for the pharmaceutical quality control of atorvastatin was made. Results: Among the analytical methods most used in the evaluation of atorvastatin, HPLC is highlighted, followed by HPLC coupled to MS, and spectrophotometry in UV. Tablets are the most studied pharmaceutical samples, and plasma is the most studied biological matrix. In the literature, studies with atorvastatin-based pharmaceutical products are more common than biological materials. Acetonitrile is the organic solvent most commonly used in the methods surveyed to evaluate atorvastatin. Conclusions: Currently, awareness of the impact that the analytical choice has on the health of the operator and the environment is growing. Therefore, the suitability of existing methods for the determination of atorvastatin can be made to adhere to the current analytical chemistry. In this way, the analytical, environmental, and human consciousness will remain united. Highlights: Although the literature shows interesting methods from an economic and environmental point of view, such as UV, Vis miniaturized, and TLC, they can still be improved to meet the requirements of the current sustainable analytical chemistry.

Development, validation and application of a novel HPLC-MS/MS method for the quantification of atorvastatin, bisoprolol and clopidogrel in a large cardiovascular patient cohort.

Cardiovascular disease is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Importantly, there is interindividual variation in response to cardiovascular medications, leading to variable efficacy and adverse events. Therefore a rapid, selective, sensitive and reproducible multi-analyte HPLC-MS/MS assay for the quantification in human plasma of atorvastatin, its major metabolites 2-hydroxyatorvastatin, atorvastatin lactone and 2-hydroxyatorvastatin lactone, plus bisoprolol and clopidogrel-carboxylic acid has been developed, fully validated, and applied to a large patient study. Fifty microliter plasma samples were extracted with a simple protein precipitation procedure involving acetonitrile with acetic acid (0.1%, v/v). Chromatographic separation was via a 2.7 µm Halo C18 (50 × 2.1 mm ID, 90 Å) column and gradient elution at a flow rate of 500 µL/min consisting of a mobile phase of water (A) and acetonitrile (B), each containing 0.1% formic acid (v/v), over a 6.0 min run time. The six analytes and their corresponding six deuterated internal standards underwent positive ion electrospray ionisation and were detected with multiple reaction monitoring. The developed method was fully validated with acceptable selectivity, carryover, dilution integrity, and within-run and between-run accuracy and precision. Mean extraction recovery for the analytes was 92.7-108.5%, and internal standard-normalised matrix effects had acceptable precision (coefficients of variation 2.2-12.3%). Moreover, all analytes were stable under the tested conditions. Atorvastatin lactone to acid interconversion was assessed and recommendations for its minimisation are made. The validated assay was successfully applied to analyse 1279 samples from 1024 patients recruited to a cardiovascular secondary prevention prospective study.

Pharmacokinetics and Pharmacodynamics of Anacetrapib in Black and White Healthy Subjects.

Anacetrapib is a cholesteryl ester transfer protein inhibitor intended for the treatment of dyslipidemia. A phase 1 study was conducted to examine the pharmacokinetics and pharmacodynamics of multiple doses of anacetrapib in black compared to white healthy subjects. Although there was no apparent race-related pharmacokinetic effect, attenuation of the lipid response was observed in black subjects. Specifically, high-density lipoprotein cholesterol percentage increased 18.1% (absolute percentage points) less in black subjects (89.9%) when compared to increases in white subjects (108.0%). Similarly, the decrease in low-density lipoprotein cholesterol was 17.8% (absolute percentage points) less in blacks (-21.2%) relative to whites (-39.0%). In contrast, there were no apparent race-related differences in cholesteryl ester transfer protein mass or activity. Anacetrapib was generally well tolerated in this study. The results of this study suggest that there may be race-related differences in pharmacodynamics of anacetrapib independent of pharmacokinetics.

A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women.

An open-label, 3-period study was conducted in 30 healthy postmenopausal women (mean age, 58.4 years) who received a single oral dose of atorvastatin 20 mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40 mg on days 4-11 (period 2), and coadministration of atorvastatin 20 mg + bazedoxifene 40 mg on day 12 (period 3). Serial blood samples were collected (24 hours after bazedoxifene and 72 hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho-hydroxy and para-hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20 mg (Cmax and AUCss were within bioequivalence limits). Similarly, atorvastatin and ortho-hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para-hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. Cmax for atorvastatin and ortho-hydroxyatorvastatin was 14% and 18% lower, respectively, and Tmax was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.

Potencies of vitamin D analogs, 1α-hydroxyvitamin D3 , 1α-hydroxyvitamin D2 and 25-hydroxyvitamin D3 , in lowering cholesterol in hypercholesterolemic mice in vivo.

Vitamin D3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D3 [1α(OH)D3 ], 1α-hydroxyvitamin D2 [1α(OH)D2 ] and 25-hydroxyvitamin D3 [25(OH)D3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D3 and 1α(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] and 1α,25-dihydroxyvitamin D2 [1,25(OH)2 D2 ], respectively. 1α(OH)D2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D2 [1,24(OH)2 D2 ], another active VDR ligand. 25(OH)D3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D3 , is activated by CYP27B1 in the kidney to 1,25(OH)2 D3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D3  > 1248 nmol/kg 25(OH)D3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D3 . Except for 1.21 nmol/kg 1α(OH)D2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH)2 D3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D3 and 25(OH)D3 exhibit cholesterol lowering properties upon activation to 1,25(OH)2 D3 : 1α(OH)D3 is rapidly activated by liver enzymes and 25(OH)D3 is slowly activated by renal Cyp27b1 in mouse.

CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

OBJECTIVE: CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers. APPROACH AND RESULTS: Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre-ß1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1-mediated CEC at baseline (P<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P≤0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre-ß1-HDL (P=0.5) or CEC (P=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I-normalized CEC; P=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure. CONCLUSIONS: CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events.

Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability.

Cyclodextrins play an important role in supramolecular chemistry acting as building blocks than can be cross-linked by various linker molecules forming nano-porous structures called nanosponges (NS). NS have the ability to enhance the stability, solubility and bioavailability of various actives. This work aimed at elaborating rosuvastatin (ROS) loaded NS to improve its oral bioavailability. Carboxylate-linked NS were synthesized by reacting ß-CD with pyromellitic dianhydride (PDA) at different molar ratios under specific conditions. ROS-loaded NS were prepared by lyophilisation technique and characterized for particle size, zeta potential, entrapment efficiency and drug release. Occurrence of cross-linking and ROS incorporation within the NS were assessed by DSC, FT-IR and SEM micrographs. NS prepared at a molar ratio of 1:6 of ß-CD: PDA demonstrated the highest entrapment efficiency (88.76%), an optimum particle size of 275nm, a narrow size distribution (PDI of 0.392), and zeta potential of -61.9 indicating good colloidal stability. In vivo oral pharmacokinetics study in male Sprague Dawley rats showed that ROS-NS provided an outstanding enhancement in oral bioavailability compared to drug suspension and marketed tablets besides their physicochemical stability for 3month. Accordingly, ROS-NS represent a superior alternative to the conventional marketed formulation for effective ROS delivery.

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.