Search

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD). First, its complexation is shown through Differential Scanning Calorimetry as lyophilization provided distinct thermal properties in comparison to the mixture. The complexation is further proved by utilizing the chemical shift changes in the complexation and T1 values. Furthermore, the reversible favorable complexation was shown by MD calculations. Such physical chemical properties provide evidence that this formulation must be further explored through biological experiments. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

The present study investigated the potential nephro- and pneumoprotective effect of silibinin (Si) after hepatic ischemia–reperfusion (I/R) injury, by measuring pro-inflammatory factors. Sixty-three rats were randomly assigned into three groups, as follows: (a) the sham group (n = 7 rats), subjected to opening and closing the abdomen; (b) the control group (n = 28 rats), subjected to 45-min hepatic ischemia followed by reperfusion; and (c) the silibinin group (n = 28), subjected to 45-min hepatic ischemia followed by intravenous administration of lyophilised SLB-HP-β-CD before reperfusion. Control and silibinin groups were further subdivided into time-point groups, according to the duration of reperfusion. TNF-α, IL-6 and MCP-1 expressions were determined immunohistochemically and by qrT-PCR at each time-point. Kidney TNF-α expression was significantly lower at 180 and 240 min, while lung TNF-α expression was significantly lower at 240 min. Comparison between the control and Si group at the same time-points showed very strong evidence of difference at 240 min, with the levels of IL-6 shifting towards lower values in the Si group. Finally, we found a high MCP-1 expression after 120 min. We conclude that hepatic I/R injury remotely increases pro-inflammatory mediators in the kidney and lung, whereas silibinin shows a time-dependent nephro- and pneumoprotective effect. © 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd

We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.

Purpose: The protective effect of silibinin on kidney and lung parenchyma during hepatic ischemia/ reperfusion injury (IRI) is explored. Methods: Sixty-three Wistar rats were separated into three groups: sham; control (45 min IRI); and silibinin (200 μL silibinin administration after 45 min of ischemia and before reperfusion). Immunohistochemistry and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to evaluate the expression levels of MMP2, MMP3, MMP9, and TIMP2 on kidney and lung. Results: Comparing sham vs. control groups, confirmed that hepatic IRI increased both renal and lung MMP2, MMP3, MMP9 and TIMP2 expressions starting at 180 min (p

Saffron, the dried stigma of Crocus sativus L., is used in traditional medicine for its healing properties and the treatment of various pathological conditions. The present literature review aimed to summarize and evaluate the preclinical and clinical data regarding the protective effects and mechanisms of saffron and its main components (crocin, crocetin, safranal) on cardiovascular risk factors and diseases. Many in vitro and animal studies have been conducted implicating antioxidant, hypolipidemic, anti-diabetic, and antiinflammatory impact of saffron and its constituents. Notably, there is evidence of direct atherosclerosis regression and stabilization in valid atherosclerosis-prone animal models. However, current clinical trials have shown mostly weak effects of saffron and its constituents on cardiovascular risk factors: (a) Modest lowering of fasting blood glucose, without significant reduction of HbA1c in type 2 diabetic patients, (b) moderate/controversial hypolipidemic effects, (c) negligible hypotensive effect, and (d) inconsistent modification of metabolic syndrome parameters. There are important drawbacks in clinical trial design, including the absence of pharmacokinetic/pharmacodynamic tests, the wide variance of doses and cohorts' characteristics, the small number of patients, the short duration. Therefore, large, properly designed, high-quality clinical trials, focusing on specific conditions are required to evaluate the biological/pharmacological activities and firmly establish the clinical efficacy of saffron and its possible therapeutic uses in cardiovascular diseases. © 2021 John Wiley & Sons Ltd.

Quercetin, a flavonoid with possible neuroprotective action has been recently suggested for the early-stage treatment of Alzheimer's disease. The low solubility and extended first pass effect render quercetin unsuitable for oral administration. Alternatively, brain targeting is more feasible with nasal delivery, by-passing, non-invasively, Blood-Brain Barrier and ensuring rapid onset of action. Aiming to increase quercetin's disposition into brain, nasal powders consisting of quercetin-cyclodextrins (methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin) lyophilizates blended with spray-dried microparticles of mannitol/lecithin were prepared. Quercetin's solubility at 37 °C and pH 7.4 was increased 19–35 times when complexed with cyclodextrins. Blending lyophilizates in various ratios with mannitol/lecithin microparticles, results in powders with improved morphological characteristics as observed by X-ray Diffraction and Scanning Electron Microscopy analysis. In vitro characterization of these powders using Franz cells, revealed rapid dissolution and permeation 17 (methyl-β-cyclodextrin) to 48 (hydroxypropyl-β-cyclodextrin) times higher than that of pure quercetin. Ex vivo powders’ transport across rabbit nasal mucosa was found more efficient in comparison with the pure Que. The overall better performance of quercetin-hydroxypropyl-β-cyclodextrin powders is confirmed by ex vivo experiments revealing amount of quercetin permeated ranging from 0.03 ± 0.01 to 0.22 ± 0.05 μg/cm2 for hydroxypropyl-β-cyclodextrin and 0.022 ± 0.01 to 0.17 ± 0.04 μg/cm2 for methyl-β-cyclodextrin powders, while the permeation of pure quercetin was negligible. © 2021 Elsevier B.V.

Bioavailability of active substances is of great importance for the formulation of a drug product, as it actually reflects drug absorption and achievement of the optimum pharmacological effect. A great number of chemical compounds with excellent pharmacological properties possess low solubility and permeability values, ending in low bioavailability in the human body after administration (especially after per os administration). CDs are oligosaccharides that possess biological properties similar to their linear counterparts, but some of their physicochemical properties differ. They are enhancing bioavailability and solving problems of absorption for poorly soluble lipophilic drugs by forming water-soluble inclusion complexes. For this reason, they are widely used in drug delivery systems (Carrier et al. J Control Release 123:78–99, 2007; Kurkov and Loftsson, Int J Pharm 453:167–80, 2013). The main purpose of this chapter is to show a protocol for the preparation of drug:CDcomplex delivery systems. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.

Aims: The population pharmacokinetics (PK) of anidulafungin in critically ill patients hospitalized in intensive care units (ICUs) was explored with the intention of evaluating and optimizing dosing regimens. Methods: A PK study was conducted in a cohort of 13 patients treated with anidulafungin using intensive sampling during multiple periods per patient and the high-performance liquid chromatography method for drug quantification. A population PK model was developed to describe the concentration-time course of anidulafungin and the inter-individual (IIV) and interoccasion variability (IOV) of the PK parameters. Model-based PK simulations have been performed to estimate the probability of target attainment (PTA), given the pharmacokinetic/pharmacodynamic target of free 24-hour area under the free drug concentration-time curve over minimum inhibitory concentration for several dosing regimens. Results: A two-compartment PK model, with first-order elimination, best described the data with population clearance (CL) and central/peripheral volume of distribution (V1/V2) of 0.778 L/h and 10.2/21.1 L, respectively, and a mean ± s.d. AUC0-24 of 119.97 ± 46.23 mg·h/L. Pronounced IIV and IOV variability was found for CL (38% and 31%) and V1 (47% and 30%), respectively. Sequential Organ Failure Assessment (SOFA) and Body Mass Index (BMI) were found to be covariates on CL and V1, respectively. Low PTA values were calculated for borderline Clinical & Laboratory Standards Institute (CLSI)-susceptible Candida strains. Conclusions: Although anidulafungin exposure was found comparable to that in healthy volunteers, elevated interindividual and significant interoccasion variability was found in critically ill ICU patients, which resulted in reduced PTA values in these patients. © 2020 The British Pharmacological Society

Background: Omentin-1 and vaspin are novel adipokines, and their association with atherosclerosis is still under investigation. The present study aimed to assess the relationship of those adipokines with preclinical, non-significant carotid atherosclerosis and the impact of statin therapy on their levels, suggesting a link between adiposity and atherosclerosis. Methods: Eighty-four statin-free subjects with non-significant, preclinical carotid atherosclerosis and elevated LDL- cholesterol levels (>130 mg/dl) were recruited to receive atorvastatin (from 10 to 80 mg per day) (atorvastatin group - AG group). Forty-six age- and gender-matched healthy individuals, without any chronic disease served as controls (control group – CG). Clinical parameters, metabolic profile, serum omentin-1, vaspin concentrations and ultrasound measurements of carotid thickening were obtained at the beginning and after 12 months. Results: At baseline, AG showed lower omentin-1 and vaspin serum levels than CG (p ≤ 0.001). Along the entire study population at baseline, omentin-1 levels were independently related to LDL-cholesterol, while vaspin levels were independently associated with hsCRP and the presence of carotid atherosclerosis (p < 0.05). Within AG, 12-months atorvastatin treatment significantly increased omentin-1 (from 202.79 ± 91.41 ng/ml to 262.56 ± 101 ng/ml, p < 0.001) and vaspin concentrations (from 1.29 ± 0.51 ng/ml to 1.70 ± 0.5 ng/ml, p = 0.002). In standard multiple regression analysis, the presence of carotid atherosclerosis related to baseline vaspin levels (β = −0.232, p < 0.001), while the atorvastatin-induced increase of vaspin was independently associated with hsCRP reduction (β = −0.198, p = 0.045). Conclusion: Low omentin-1 and vaspin serum levels associated with preclinical, non-significant carotid atherosclerosis. Notably, atorvastatin administration significantly increased both adipokines, but the underlying mechanisms and the clinical impact of those changes requires further investigation. © 2020

Neuroinflammation in Alzheimer's disease (AD) revamped the role of a preventive therapeutic action of non steroidal anti-inflammatory drugs; flurbiprofen could delay AD onset, provided its access to brain is enhanced and systemic exposure limited. Nasal administration could enable direct drug access to central nervous system (CNS) via nose-to-brain transport. Here, we investigated the insufflation, deposition, dissolution, transmucosal permeation, and in vivo transport to rat brain of flurbiprofen from nasal powders combined in an active device. Flurbiprofen sodium spray-dried microparticles as such, or soft pellets obtained by agglomeration of drug microparticles with excipients, were intranasally administered to rats by the pre-metered insufflator device. Blood and brain were collected to measure flurbiprofen levels. Excipient presence in soft pellets lowered the metered drug dose to insufflate. Nevertheless, efficiency of powder delivery by the device, measured as emitted fraction, was superior with soft pellets than microparticles, due to their coarse size. Both nasal powders resulted into rapid flurbiprofen absorption. Absolute bioavailability was 33% and 58% for microparticles and pellets, respectively. Compared to intravenous flurbiprofen, the microparticles were more efficient than soft pellets at enhancing direct drug transport to CNS. Direct Transport Percentage index evidenced that more than 60% of the intranasal dose reached the brain via direct nose-to-brain transport for both powders. Moreover, remarkable drug concentrations were measured in the olfactory bulb after microparticle delivery. Bulb connection with the entorhinal cortex, from where AD initiates, makes flurbiprofen sodium administration as nasal powder worth of further investigation in an animal model of neuroinflammation. © 2021 Elsevier B.V.

OBJECTIVES: We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-β-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. METHODS: 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-β-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). KEY FINDINGS: qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. CONCLUSIONS: Silibinin may have a beneficial effect on the protection of the liver. © The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Objectives: To apply therapeutic drug monitoring and dose-individualization of intravenous Busulfan to paediatric patients and evaluate the impact of syringe-pump induced Busulfan infusion lag-time after in vitro estimation. Methods: 76 children and adolescents were administered 2 h intravenous Busulfan infusion every 6 h (16 doses). Busulfan plasma levels, withdrawn by an optimized sampling scheme and measured by a validated HPLC-PDA method, were used to estimate basic PK parameters, AUC, Cmax, kel, t1/2, applying Non-Compartmental Analysis. In vivo infusion lag-time was simulated in vitro and used to evaluate its impact on AUC estimation. Key findings: Mean (%CV) Busulfan AUC, Cmax, clearance and t1/2 for pediatric population were found 962.3 μm × min (33.1), 0.95 mg/L (41.4), 0.27 L/h/kg (33.3), 2.2 h (27.8), respectively. TDM applied to 76 children revealed 6 (7.9%) being above and 25 (32.9%) below therapeutic-range (AUC: 900-1350 μm × min). After dose correction, all patients were measured below toxic levels (AUC < 1500 μm × min), no patient below 900 μm × min. Incorporation of infusion lag-time revealed lower AUCs with 17.1% more patients and 23.1% more younger patients, with body weight

Athlete Biological Passport (ABP) is an indirect approach, implemented by WADA, aimed at detecting blood manipulation based on abnormal changes in haematological markers. Cases report the use of hyperhydration as masking method during anti-doping urine sample collection which could potentially mask suspicious fluctuations on ABP profiles. This study investigated the hyperhydration effect on haemoglobin concentration, reticulocyte percentage and OFF-hr score (an algorithm based on haemoglobin concentration and reticulocyte percentage), with and without recombinant human erythropoietin (rHuEPO) administration. A five-week clinical study performed; Baseline and rHuEPO Phase. Water and a sports drink were used as hyperhydration agents. To examine the hyperhydration effect on the normal ABP profile per volunteer, hyperhydration was implemented at 0, 24 and 48 hours during the baseline. During the rHuEPO phase, volunteers received Epoetin beta (3000 IU) with hyperhydration to be implemented at 0, 24 and 48 hours after drug administration. Blood and urine samples were collected and analysed according to WADA guidelines. No significant effect on ABP markers was observed due to hyperhydration at any time during the study. Pre- and post-hyperhydration data were not statistically different compared to individual baseline data. In conclusion, hyperhydration does not affect the ABP haematological markers under the examined conditions. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Objectives: To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens. Methods: An HPLC–fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens. Key findings: A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains. Conclusions: A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment. © 2020 Royal Pharmaceutical Society

Background: We conducted a prospective study in ICU patients of two tertiary hospitals in order to determine basic pharmacokinetic (PK) parameters, associated variation and target attainment rates for anidulafungin, micafungin and caspofungin. Methods: Serum samples from patients treated for 7 days with the standard doses of anidulafungin (N= 13), micafungin (N= 14) or caspofungin (N= 7) were analysed by validated chromatographic methods. PK parameters determined with non-compartmental analysis were correlated with demographic, laboratory and disease severity characteristics. The percentages of patients attaining drug exposures described in the summary of product characteristics (SmPC) documents and preclinical PK/PD targets for stasis were estimated. Results: The median (range) AUC24 was 101.46 (54.95-274.15)mg-h/L for anidulafungin, 79.35 (28.00- 149.30)mg-h/L for micafungin and 48.46 (19.44-103.69)mg-h/L for caspofungin. The interindividual variability of anidulafungin, micafungin and caspofungin AUC24 was 46%-58%, attributed mainly to variability in volume of distribution (V), clearance (CL) and in both V and CL, respectively. Significant correlations were found between anidulafungin AUC24 and BMI (rs =#0.670, P = 0.012) and liver enzymes (rs = 0.572-0.665, P = 0.013-0.041) and between caspofungin Cmin and transaminase levels (rs =#0.775 to #0.786, P = 0.036-0.041). Less than 50% of our patients attained the corresponding SmPC median AUC24s and none of the patients attained the PK/PD targets for Candida albicans and Candida parapsilosis. Conclusions: Anidulafungin exposure in ICU patients was comparable with that reported in non-ICU patients and in healthy volunteers. Micafungin exposure was comparable to that of other patients but-30% lower than that in healthy volunteers, whereas caspofungin exposure was rather low (-50% lower than in healthy volunteers). Larger interindividual variability (50%-60%) was recorded in ICU patients compared with other groups for all three echinocandins. © 2020 Oxford University Press. All rights reserved.

Background: Ischemia-reperfusion injury (IRI) remains a clinical challenge in liver surgery, trauma and transplantation, contributing to morbidity and mortality worldwide. Thus, its impact, not only on the liver itself but also on remote tissues, has been studied during the last years. Different natural anti-oxidant substances have been researched in animal models, implementing different times of ischemia, aiming to test new therapeutic interventions. Objective: A literature review has been conducted with two goals: (1) to identify different natural anti-oxidants studied in experimental models; and (2) to summarize the various times of ischemia employed. Methods: Scientific papers published in PubMed for the period 2000–2020 were searched and reviewed. Results: More than 30 natural anti-oxidants have been tested. The time of ischemia ranged from 15 to 90 min with 60 min used most frequently, followed by 45 min. No studies were found with time exceeding 90 min. Conclusions: A significant number of research has been conducted on the use and protective effect of natural anti-oxidants in experimental animal models. Based on the published papers, 45–60 min seems to be the optimal duration of ischemia. © 2020

Background: To evaluate the impact of atorvastatin discontinuation on the progression and stability of atherosclerotic plaques in a valid animal model of atherosclerosis. Methods: Seventy ApoE−/− male mice fed with high-fat diet were randomly assigned into: (1) long-term intervention groups: (i) ATL, received atorvastatin for 12 weeks, (ii) CO-12W, control received vehicle for 12 weeks, (iii) ATW-6W, received atorvastatin for 6 weeks which was withdrawn for another 6 weeks. (2) Short-term intervention groups: (i) ATS received atorvastatin for 6 weeks, (ii) CO-6W, control receiving vehicle for 6 weeks, (iii) ATW-3D, ATW-7D, received atorvastatin for 6 weeks which was withdrawn for 3 days and 7 days, respectively. Daily dosage of atorvastatin was 20 mg/kg. Mice were killed and aortic samples were obtained for histological evaluation. Results: Long-term atorvastatin treatment (ATL) induced atherosclerosis regression and stabilization compared to control (P

Low urinary luteinizing hormone (LH) values have been discussed as a marker to detect steroid abuse. However, suppressed LH concentrations related to highly diluted urine samples could be a misleading indication of anabolic steroid abuse. One aim of the present study was to examine the effect of hyperhydration on the interpretation of LH findings during doping control analysis and to investigate different possibilities to correct volume-related changes in urinary LH concentrations. Seven healthy, physically active, nonsmoking White males were examined for a 72-hr period, using water and a commercial sports drink as hyperhydration agents (20 ml/kg body weight). Urine samples were collected and analyzed according to the World Anti-Doping Agency’s technical documents. Baseline urinary LH concentrations, expressed as the mean ± SD for each individual, were within the acceptable physiological range (7.11 ± 5.42 IU/L). A comparison of the measured LH values for both hyperhydration phases (Phase A: 4.24 ± 5.60 IU/L and Phase B: 4.74 ± 4.72 IU/L) with the baseline (“normal”) values showed significant differences (Phase A: p < .001 and Phase B: p < .001), suggesting the clear effect of urine dilution due to hyperhydration. However, an adjustment of urinary LH concentrations by specific gravity based on a reference value of 1.020 seems to adequately correct the hyperhydration-induced decrease on the LH levels. © 2019 Human Kinetics, Inc.

Excessive fluid intake, that is, hyperhydration, may be adopted by athletes as a masking method during antidoping sample collection to influence the excretion patterns of doping agents and, therefore, manipulate their detection. The aim of this exploratory study was to assess the hyperhydration effect on the detection sensitivity of recombinant human erythropoietin (rHuEPO) by sodium N-lauroyl sarcosinate (“sarkosyl”) polyacrylamide gel electrophoresis analysis. The influence of hyperhydration on the serum and urinary pharmacokinetic (PK) profiles of rHuEPO was also investigated. Seven healthy physically active nonsmoking Caucasian males participated in a 31-day clinical study comprising a baseline (days 0, 1-3, and 8-10) and a drug phase (days 15-17, 22-24, and 29-31). Epoetin beta was administered subcutaneously at a single dose of 3000 IU on days 15, 22, and 29. Hyperhydration was applied in the morning on 3 consecutive days (days 1-3, 8-10, 22-24, and 29-31), that is, 0, 24, and 48 h after first fluid ingestion. Water and a commercial sports drink were used as hyperhydration agents (20 mL/kg body weight). Serum and urinary concentration-time profiles were best described by a one-compartment PK model with zero-order absorption. Delayed absorption was observed after hyperhydration and, therefore, lag time was introduced in the PK model. Results showed no significant difference (p > 0.05) on serum or urinary erythropoietin concentrations under hyperhydration conditions. A trend for decreasing volume of distribution and increasing clearance after hyperhydration was observed, mainly after sports drink consumption. However, no significant differences (p > 0.05) due to hyperhydration for any of the serum PK parameters calculated by noncompartmental PK analysis were observed. Renal excretion of endogenous erythropoietin and rHuEPO, as reflected on the urinary cumulative amount, was increased approximately twice after hyperhydration and this supports the nonsignificant difference on the urinary concentrations. Analysis of serum and urine samples was able to detect rHuEPO up to 72 h after drug administration. The detection window of rHuEPO remained unaffected after water or sports drink ingestion. Hyperhydration had no effect on the detection sensitivity of EPO either in serum or urine samples. © 2019 American Pharmacists Association®

Neuroinflammation occurs in the early stages of Alzheimer's disease (AD). Thus, anti-inflammatory drugs in this asymptomatic initial phase could slow down AD progression, provided they enter the brain. Direct nose-to-brain drug transport occurs along olfactory or trigeminal nerves, bypassing the blood-brain barrier. Nasal administration may enable the drug to access the brain. Here, flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were studied. Their target product profile contemplates drug powder deposition in the nasal cavity, prompt dissolution in the mucosal fluid and attainment of saturation concentration to maximise diffusion in the tissue. Aiming to increase drug disposition into brain, poorly soluble flurbiprofen requires the construction of nasal powder microparticles actively deposited in nose for prompt drug release. Two groups of powders were formulated, composed of flurbiprofen acid or flurbiprofen sodium salt. Two spray dryer apparatuses, differing for spray and drying mechanisms, and particle collection, were applied to impact on the characteristics of the microparticulate powders. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast ex vivo transport across rabbit nasal mucosa, superior to the acid form, in particular when the powder was prepared using the Nano B-90 spray dryer at the lowest drying air temperature. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

The aim of the present study was to investigate if hyperhydration could influence the excretion and subsequent detection of budesonide (BDS) and its main metabolites (6β-hydroxy-budesonide and 16α-hydroxy-prednisolone) during doping control analysis by leading to concentrations below the WADA reporting level (30 ng/mL). The influence of hyperhydration on the plasma and urinary pharmacokinetic (PK) profiles of BDS and metabolites was also examined. Seven healthy physically active non-smoking Caucasian males participated in a 15-day clinical study. BDS was administered orally at a single dose of 9 mg on Days 1, 7, and 13. Hyperhydration was applied in the morning on two consecutive days, that is, 0 and 24 hours after first fluid ingestion. Water and a commercial sports drink were used as hyperhydration agents (20 mL/kg body weight). Results showed no significant difference (P > 0.05, 95% CI) on plasma or urinary PK parameters under hyperhydration conditions for all the analytes. However, significant differences (P

Objectives: To prepare a lyophilized saffron aqueous extract (SFE) and determine its chemical profile and serum and tissue pharmacokinetics after intravenous and oral administration to C57/Bl6J mice. Methods: Lyophilized SFE was prepared, characterized using semi-preparative HPLC and NMR analysis, and stability studies at room temperature, and was quantified for crocin content with an HPLC-PDA method. After intravenous and oral administration of SFE (60 mg/kg, reconstituted with water for injection) to C57/Bl6J mice, crocetin (derived from in vivo crocin hydrolysis) serum and tissue levels (unconjugated and total) were measured with an HPLC-PDA method and subjected to compartmental and non-compartmental PK analysis. Key findings: Saffron aqueous extract was rich in all-trans-crocin (27.8 ± 0.1% w/w) and stable for more than 15 months. One-compartment PK model described crocetin's (unconjugated) kinetics after intravenous administration of SFE, while a first-order kinetic parameter described the rate of crocetin biotransformation to crocetin metabolite (conjugated). Α οne-compartment PK model with first-order absorption described crocetin and crocetin's metabolite kinetics after SFE oral administration. Relative oral bioavailability was calculated at 1.17 for total crocetin. Tissue NCA PK analysis revealed extensive crocetin distribution to liver and kidneys. Conclusions: SFE is a stable lyophilized extract rich in all-trans-crocin. The PK study allowed the estimation of basic PK parameters and the bioavailability of SFE’s main bioactive component, crocetin, after peros administration. © 2018 Royal Pharmaceutical Society

Background: Remote kidney damage is a sequel of hepatic ischemia–reperfusion (I/R) injury. Silibinin is the main ingredient of the milk thistle plant seed extract with known antioxidant and hepatoprotective activity. Our study investigates the nephroprotective potential of intravenously administered silibinin, as a lyophilized SLB-hydoxypropyl-beta-cyclodextrin product, in hepatic I/R injury. Material and methods: 63 Wistar rats were divided into three groups: Sham (virtual intervention); Control (45 min ischemia and reperfusion); and Silibinin (200 μL intravenous silibinin administration after 45 min of ischemia). Kidney tissues were collected to determine TNF-α, M30 and histopathological changes at predetermined time intervals. Results: Comparing Sham vs. Control groups, proved that hepatic I/R injury increased renal TNF-α and M30 expression. Deterioration was observed in hyperemia/filtration of renal parenchyma and tubules, cortical filtration, tubular necrosis and edema (tissue swelling index). Intravenous silibinin administration and comparison of the Control vs. Silibinin groups showed a statistically significant decrease in TNF-α levels at 240 min following I/R (p < 0.0001), and in M30 at 180 min (p = 0.03) and 240 min (p < 0.0001). Renal parameters have significantly decreased in: hyperemia/filtration of renal parenchyma at 120 min (p = 0.003), 180 min (p = 0.0001) and 240 min (p = 0.0002); hyperemia/filtration of renal tubules at 120 min (p = 0.02), 180 min (p = 0.0001) and 240 min (p = 0.0005); cortical filtration (240 min - p = 0.005); tubular necrosis (240 min - p = 0.021); and edema (240 min - p = 0.001). Conclusion: Our study confirms that hepatic I/R injury causes remote renal damage while the intravenous administration of silibinin leads to statistically significant nephroprotective action. Copyright © 2017 Taylor & Francis Group, LLC.

The urinary ‘steroid profile’ in doping control analysis is a powerful tool aimed at detecting intra-individual deviations related to the abuse of endogenous steroids. Factors altering the steroid profile include, among others, the excessive fluid intake leading to low endogenous steroids concentrations compared to an individual's normal values. Cases report the use of hyperhydration by athletes as a masking method during anti-doping urine sample collection. Seven healthy physically active non-smoking Caucasian males were examined for a 72-hour period using water and a commercial sports drink as hyperhydration agents (20 mL/kg body weight). Urine samples were collected and analyzed according to World Anti-Doping Agency (WADA) technical documents. Although, significant differences were observed on the endogenous steroid concentrations under the studied hyperhydration conditions, specific gravity adjustment based on a reference value of 1.020 can eliminate the dilution induced effect. Adjustment methods based on creatinine and urinary flow rate were also examined; however, specific gravity was the optimum method in terms of effectiveness to adjust concentrations close to the baseline steroid profile and practicability. No significant effect on the urinary steroid ratios was observed with variability values within 30% of the mean for the majority of data. Furthermore, no masking on the detection ability of endogenous steroids was observed due to hyperhydration. It can be concluded that any deviation on the endogenous steroid concentrations due to excessive fluid intake can be compensated by the specific gravity adjustment and therefore, hyperhydration is not effective as a masking method on the detection of the abuse of endogenous steroids. Copyright © 2018 John Wiley & Sons, Ltd.

Purpose: We investigated the hepatoprotective effect of Silibinin (SLB) to ischemia-reperfusion (I/R) rat model, by evaluating the histological expression of the tissue markers Fas/FasL, HMGB-1 and CD45, and SLB pharmacokinetics. Methods: Seventy-three Wistar-type male rats were randomized in 11 groups: Sham control group (open-close laparotomy); four I/R control groups (laparotomy, 45 min vascular occlusion, reperfusion, euthanasia after 60, 120, 180, and 240 min); four SLB (Si) groups (laparotomy, 45 min vascular occlusion, IV administration of SLB, reperfusion, euthanasia after 60, 120, 180, and 240 min); two SLB pharmacokinetics (PK) groups (IV administration of SLB, euthanasia after 45 and 240 min). Results: Fas/FasL increased with reperfusion time in I/R control groups and decreased in the Si groups, reaching, respectively, the highest and lowest values at 240 min of reperfusion (p

Background and aims We aimed to evaluate a possible atheroprotective effect of saffron aqueous extract (SFE), and its potential anti-inflammatory mechanisms, in apoE knockout (ApoE−/−) mice. Methods Fifty male, ApoE−/− mice, fed a high-fat diet (HFD) for 12 weeks, were randomized into 5 groups: (1) baseline group, euthanatized, without intervention, (2) three saffron groups, receiving HFD and 30,60,90 mg/kg/day of SFE, respectively, for four weeks, per os through gavage, after reconstitution in water for injection (WFI), (3) control group (COG), receiving daily HFD and the same volume of WFI (four weeks). After blood sampling and euthanasia, aortic roots were excised and analyzed for gene expression and/or percentage of aortic stenosis, relative content of macrophages, smooth muscle cells (SMCs), connective tissue, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases-2,-3,-9 (MMP-2,-3,-9) and their inhibitor (TIMP-2) and IL-6. SFE doses were determined by a pilot serum pharmacokinetic study in C57BL/6J wild-type mice. Results SFE did not affect body weight and total cholesterol levels (p > 0.05), while high SFE dose significantly ameliorated glucose and triglycerides profiles compared to other groups (p < 0.05). SFE considerably decreased aortic stenosis in a dose-dependent manner (p < 0.05). Furthermore, increasing SFE doses proportionally reduced macrophages content and increased within plaques content of collagen, elastin, and SMCs, promoting more stable plaque phenotype compared to COG (p < 0.05). Those effects seemed to be associated with a considerable reduction (>30%) in IL-6, TNF-α MCP-1, MMP-2,-3,-9 (p < 0.05) and MMP-2/TIMP-2 ratio. Conclusions SFE exerted dose-dependent anti-atherosclerotic and plaque-stabilizing effects in Apo-E−/− mice, probably mediated by a favorable modification of inflammatory mechanisms, which requires further investigation. © 2017 Elsevier B.V.

The interactions of irbesartan (IRB) and irbesartan–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex with Dipalmitoyl Phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from Differential Scanning Calorimetry (DSC), Small angle X-ray Scattering (SAXS), ESI Mass-Spectrometry (ESI-MS) and solid state Nuclear Magnetic Resonance (ssNMR). Molecular Dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-β-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1 nm from the membrane centre.

Objectives: To test the impact of specific maternal- and neonatal-associated factors on human milk's macronutrients and energy. Methods: This study was conducted with the use of a human milk analyzer (HMA, MIRIS, Uppsala, Sweden). Six hundred and thirty samples of raw milk and 95 samples of donor pasteurized milk were delivered from a total of 305 mothers. Results: A significant inverse correlation of fat, protein and energy content with gestational age and birth weight was established. Fat and energy were lower in colostrum, increased in transitional milk and decreased on the 30th day's mature milk compared to transitional. The rate of protein decline from colostrum to mature milk was lower in premature deliveries compared to that of full-terms, resulting in greater contents of protein in preterm mature milk. The upmost amounts of carbohydrates were found in mature milk of preterm deliveries. A positive correlation was found between maternal age and fat contents. In women with higher post-pregnancy BMI levels greater analogies of fat and energy were presented. In women suffering diet-controlled gestational diabetes (GD), lower protein and higher fat and energy levels were found. Conclusions: Prematurity, maternal age, diet-controlled GD and high post-pregnancy BMI levels were found to impose statistical significant effect on milk's macronutrients and energy. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Background and aims Saffron is an antioxidant herbal derivative; however, its efficacy as a nutritional cardioprotective agent has not been fully elucidated. We investigated the cardioprotective properties of a standardized saffron aqueous extract (SFE) against ischemia/reperfusion (I/R) injury in Wild-Type (WT) and ApoE(−/−) mice and the underlying molecular mechanisms. Methods and results WT and ApoE(−/−) mice were subjected to 30 min I and 2 h R, with the following per os interventions for 4 weeks: 1) WT Control Group, receiving Water for Injection (WFI); 2) WT Crocus Group, receiving SFE at a dose of 60 mg/kg/day; 3) WT Crocus + Wort group, receiving SFE as described above and wortmannin at a dose of 60 μg/kg bolus 15 min before R; 4) ApoE(−/−) Control Group, receiving WFI; 5) ApoE(−/−) Crocus Group, receiving SFE at a dose of 60 mg/kg/day and 6) ApoE(−/−) Crocus + Wort: receiving SFE as described above and wortmannin at a dose of 60 μg/kg bolus, 15 min before R. Ischemic area/area at risk (I/R%) ratio was measured. Blood samples and ischemic myocardial tissue were collected at the 10th min of reperfusion for assessment of troponin I, malondialdehyde (MDA), nitrotyrosine (NT), p-eNOS, eNOS, p-Akt, Akt, p-p42/p-p44, p-GSK3β, GSK3β, IL-6, Nrf2, HO-1 and MnSOD expression. The effect of SFE on Nrf2 expression was also evaluated in vitro. SFE reduced infarct size in WT (16.15 ± 3.7% vs 41.57 ± 2.48%, ***p < 0.001) and in ApoE(−/−) mice (16.14 ± 1.47% vs 45.57 ± 1.73%, ***p < 0.001). The administration of wortmannin resulted in partial inhibition of the infarct size limitation efficacy of SFE (in both WT and Apo-E(−/−) mice). Mice receiving SFE showed increased levels of eNOS, p-Akt, p-ERK1/2, p-44/p-42 and p-GSK3β-Ser9 and reduced expression of IL-6 and iNOS; furthermore, SFE reduced the levels of MDA and NT. SFE induced Nrf2 expression and its downstream targets, HO-1 and MnSOD in the myocardium of the treated animals, and induced Nrf2 expression in vitro in a dose-dependent manner. Conclusions SFE limits myocardial infarction in Wild-Type and ApoE(−/−) mice in a multifaceted manner including activation of Akt/eNOS/ERK1/2/GSK3-β and through Nrf2 pathway, bestowing antioxidant protection against I/R. © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University

The interactions of irbesartan (IRB) and irbesartan–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex with dipalmitoyl phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from differential scanning calorimetry (DSC), small angle X-ray scattering (SAXS), ESI mass spectrometry (ESI-MS) and solid state nuclear magnetic resonance (ssNMR). Molecular dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-β-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1 nm from the membrane centre. © 2017 Elsevier B.V.

Anemia in the elderly is often related to a higher prevalence of chronic diseases such as chronic kidney failure, arthritis, and malignancy. Erythropoiesis-stimulating agents (ESAs) have been used for years to effectively treat anemia and when used appropriately can substantially improve the health status and quality of life of older adults. Following the 2008 recession in Greece, the government introduced ESA price control restrictions, but no prescribing restrictions, in an effort to reduce drug expenditure. Objective: ESA prescribing patterns and treatment costs were analyzed to determine inappropriate or appropriate use of these agents and related health care resources in Greece. Method: A retrospective register-based drug utilization study was carried out using data from prescriptions dispensed at the public pharmacy of the largest social insurance fund (IKAETAM), for patients receiving ESAs over a six-month period. For each patient, demographic data, ESA dosage regimen, treatment indication and cost, prescriber specialty, and prescription origin were recorded. Results: A total of 14,387 prescriptions from 6,074 patients (median age 74 years) were reviewed. A substantial number of patients (13.5%) were treated for off-label indications, for which the average cost per patient per indication was higher. ESA dosage/frequency of administration varied but was in accordance with recommendations. The percentage of patients who received innovator and biosimilar erythropoietin (EPO) was 88% and 12%, respectively. Conclusion: For the optimization of ESA utilization and the reduction of treatment costs, strict ESA prescription monitoring, development of registries, and criteria for off-label indications and biosimilar use in naive patients under the umbrella of risksharing agreements should be proposed. © 2016 American Society of Consultant Pharmacists, Inc. All rights reserved.

Objectives: To investigate the benefits of treating low birth weight infants predominantly with mothers own raw milk and early initiation of breastfeeding (raw human milk/breast-fed infants), in comparison to feeding only with donor banked milk (until the third week of life) and afterwards a preterm formula until hospital discharge (donor banked/formula-fed infants).Methods: One hundred and ninety-two predominantly raw human milk-fed infants (70% of raw and 30% of donor milk) were matched to 192 donor/formula-fed ones (on 1:1 ratio). Aggressive nutrition policy and targeted fortification of human milk were implemented in both groups.Results: The two groups show similar demographic and perinatal characteristics. Predominantly raw milk-fed infants regained earlier their birth weight, suffered less episodes of feeding intolerance and presented a higher body length and head circumference at discharge (p < 0.001). Those treated mainly with their mothers milk were able to initiate breastfeeding almost 2 weeks earlier compared to those fed with donor milk who achieved to be bottle-fed later on post-conceptual age (p < 0.001). Infants being breastfed until the 8th month of life conducted less visits for a viral infection to a pediatrician compared to those in the other group (p < 0.001).Conclusions: Feeding predominantly with mothers raw milk seems to result in optimal neonatal outcomes. © 2015 Informa UK Ltd.

Objective: to compare hospital and health service usage costs of feeding low-birthweight (LBW) infants predominantly with their mother's milk, supplemented with donor milk, with donor milk and preterm formula. Design: prospective matching study. Setting: tertiary public perinatal centre, neonatal intensive care unit (NICU) and donor human milk bank. Participants: 100 LBW infants (Group I) fed predominantly with their mother's milk from the first hour of life, supplemented (mainly for the first week of life) with donor milk, were matched on a 1:1 basis with 100 LBW infants (Group II) who were fed with donor milk for the first 3 weeks of life followed by preterm formula until hospital discharge. Individualised targeted fortification of human milk was implemented in both study groups. Findings: the costs of hospitalisation, doctor visits and prescription drugs for viral infections until 8 months of age were calculated for each infant. Infants fed predominantly with their mother's milk had significantly shorter hospital stays and lower hospitalisation costs. In Group I infants, the duration of enteral gavage feeding was shorter, resulting in significantly lower costs. Up to 8 months of age, Group I infants experienced fewer episodes of viral infections, and the cost of each doctor visit and drug prescription was lower for these infants. Conclusions: feeding LBW infants predominantly with their mother's milk reduces hospital and health service usage costs. Implications for practice: feeding LBW infants predominantly with their mother's milk, supplemented with donor milk, followed by exclusive breast feeding seems to result in potential savings in hospital and health service usage costs. © 2016 Elsevier Ltd.

Voriconazole levels were determined with high-performance liquid chromatography (HPLC) and a microbiological agar diffusion assay using a Candida parapsilosis isolate in 103 serum samples from an HPLC-tested external quality control program (n = 39), 21 patients receiving voriconazole monotherapy (n = 39), and 7 patients receiving combination therapy (n = 25). The results of the bioassay were correlated with the results obtained from the external quality control program samples and with the HPLC results in sera from patients on voriconazole monotherapy and on combination therapy with an echinocandin (Spearman's rank correlation coefficient [rs], > 0.93; mean ± standard error of the mean [SEM] % difference

Silibinin, the main active component of Silybum marianum is a hepatoprotective and antioxidant agent with antitumor effect, exhibiting very low aqueous solubility and oral bioavailability limiting its use in therapeutics. We characterized serum and tissue pharmacokinetics of SLB, calculated its absolute bioavailability and developed an open loop physiologically based pharmacokinetic (PBPK) model, after oral (per os, p.o) and intravenous (i.v.) administration in mice as water-soluble silibinin-hydroxypropyl-beta-cyclodextrin (SLB-HP-β-CD) lyophilized product. 60 C57Bl/6J mice were divided into groups of 5, each group representing one sampling time point. SLB-HP-β-CD lyophilized product was administered orally (50 mg/kg) and i.v. (20 mg/kg) after reconstitution with water for injection. Blood and tissue samples were collected at selected time points after animal sacrificed, properly treated and analyzed with HPLC-PDA for non-metabolized and total SLB. NONMEM pharmacokinetic analysis revealed a 2-compartment PK model to describe serum SLB pharmacokinetics, with zero order absorption after oral administration and was applied as forcing function to an open loop PBPK model incorporating heart, liver, kidneys and lungs. Tissue/plasma Kp values were estimated using i.v. data and can be used to predict tissue SLB distribution after oral administration. Absolute oral bioavailability of SLB from the lyophilized SLB-HP-β-CD product was 10 times higher than after administration of pure SLB. © 2015 Elsevier B.V.

Objectives Recently, a great deal of interest has been developed to isolate and investigate novel bioactive components from natural resources with health beneficial effects. Saffron is the dried stigma of Crocus sativus L. and has been used for centuries in traditional medicine mainly for its healing properties, as well as for the treatment of various pathological conditions. Objectives of the present review are to unravel its therapeutic properties and investigate the potential applications of saffron in contemporary therapy of a wide spectrum of diseases and summarize previous and current evidence regarding the biological/pharmacological activities of saffron and its active ingredients and their possible therapeutic uses. Key findings Recent phytochemistry and pharmacological experiments have indicated that crocin and safranal, the major active ingredients of saffron, exert important actions, such as antioxidant, anti-tumor, anti-diabetic, anti-inflammatory and anti-atherosclerotic. Unfortunately, the vast majority of those data derive from in vitro studies, whereas a limited number of in vivo experiments support the aforementioned effects. In addition to studies with mechanistic implications, very few clinical trials provide preliminary evidence of saffron potentiality to alleviate depression and increase cognitive function in patients with Alzheimer's disease. Summary The history and structural features of saffron constituents are given in the first part of the review, followed by a comprehensive and critical presentation of the published preclinical and clinical studies and review papers on the pharmacology and possible therapeutic uses of saffron and its main active components crocin and safranal. © 2015 Royal Pharmaceutical Society.