Body wasting and cachexia change body composition and organ function, with effects on drug pharmacokinetics. The aim of this study was to investigate how cancer and cancer cachexia modify liver metabolism and renal drug elimination in rats. Nine male Wistar-Han rats received a single oral dose of midazolam and propranolol (markers of hepatic metabolism), and 10 rats received single intravenous dose of iohexol, a marker of glomerular filtration rate. After drug delivery, multiple dried blood samples were obtained within 2 h post-dose to evaluate drug pharmacokinetic profiles. After baseline sampling (D0), rats were injected with tumour cells. Drug application and blood sampling were repeated when rats developed tumours (Day 5-D5), and when rats were severely cachectic (Day 10-D10). Clearance (CL) and volume of distribution (Vd) of drugs were assessed with non-linear mixed effects modelling. Weight and body composition were measured on D0 and D10 and were related to pharmacokinetic parameters. All three drugs showed non-significant trend towards increased CL and Vd on D5. On D10, midazolam andpropranolol CL and midazolam Vd significantly decreased from baseline (80.5%, 79.8%, and 72.0%, respectively, P(0.05 for all). Iohexol CL decreased by 29.8% from baseline value on D10, which was related to body weight loss (Pearson's r=0.837, P=0.019). Hepatic metabolism and renal drug elimination are significantly reduced in cachexia, which could increase risk of dose-related adverse events.
COBISS.SI-ID: 3843185
To explore the association between use of sedative drugs and frailty. Cross-sectional study. First wave of The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of the community-dwelling population aged 50 years or older in Ireland. Participants were 1642 men and 1804 women aged 65 years or older. Regular use of sedative drugs determined according to the sedative load (SL) model, frailty phenotype status, and frailty deficit index (FI) score assessed using validated, established protocols. Overall, 19% of the participants took sedative drugs, most frequently hypnotics and antidepressants. Sedative drug use was at 46% for frail, 23% forprefrail, and 9% for nonfrail participants. After adjustment for covariates, SL was positively associated with being prefrail (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.11-1.46) and frail (OR 1.30; 95% CI 1.02-1.64). Advancing age but not sex remained significant (P ( .001). After adjustment for covariates, the association between SL and the FI was also significant at P )-.001 (ß = 1.77; 95% CI 1.13-2.42). Higher SL was positively associated with phenotype frailty and the FI. This suggests that careful consideration must be given when prescribing sedatives to frail older adults, who are most vulnerable to adverse drug reactions and adverse health outcomes.
COBISS.SI-ID: 3800689
In recent years, a great deal of interest has been focused on the development of novel atomic force microscopy (AFM)-based methods. From first being an unstable method, AFM has emerged as the perfect tool for the study of phenomena at the nanoscale, which includes quantitative single molecule studies. Numerous novel AFM methods play a crucial role in the invention of novel drugs, their delivery systems, based on either polymers or inorganic/metallic matrices, and in the examination of disease-related tissue changes. Such contemporary progressive studies are a perfect example of interdisciplinary research, which results in exemplary findings and discoveries. This review focuses especially on the literature published in the last decade; however the most important earlier discoveries are also included.
COBISS.SI-ID: 19422230
A Markov decision model was developed to estimate the cost-effectiveness of dabigatran, rivaroxaban, apixaban and edoxaban compared to different levels of treatment control with warfarin. The analysis from the Slovenian healthcare payer perspective showed that novel oral anticoagulants (NOACs) are cost effective at average anticoagulation control in Slovenia of 60 %. At higher level of anticoagulation control, the cost effectiveness of NOACs is reduced.
COBISS.SI-ID: 3791729
The aim of the present study is to evaluate the influence of factors such as biopharmaceutical properties and study protocol on the emptying of pellets from the human stomach in a fed state. A systematic literature search for data on human gastric emptying of pellets from a fed stomach state investigated by g-scintigraphy was carried out. After selection of comparable data, a joint statistical analysis on the basis of multiple linear regression with 132 individual t50 values (time for 50% of the pellets to be emptied from the stomach) was performed. Parameters such as a second meal administration that can influence t50 values were also examined and included into the interpretation of the results. The results showed that an increase in the caloric value of the meal in the interval between 1200 and 3600 kJ increased the mean t50 value. Pellets with a density of 2.8 g/cm3 remained in the stomach longer than pellets of usual density with the same caloric value of the meal. Pellets incorporated in a tablet are emptied faster from the stomach than encapsulated pellets. A 45-min delay in the application of pellets after the start of the meal significantly diminished the mean t50 value, compared with application immediately after consuming the meal. Thus, in the development of non-disintegrating pellets intended for fed-state application, all of these cited factors should be considered because of their potential influence on the gastric residence time.
COBISS.SI-ID: 3846769
The aim of our work was to produce a modern nanomaterial with incorporated blood-derived growth factors, produced by electrospinning, applicable in treatment of chronic wounds. Platelet-rich plasma was chosen as a natural source of growth factors. Results showed that platelet-rich plasma stimulates keratinocyte and fibroblast cell growth in vitro. Its optimal concentration in growth medium was 2% (v/v) for both types of skin cells, while higher concentrations caused alterations in cell morphology, with reduced cell mobility and proliferation. In the next step hydrophilic nanofibers loaded with platelet-rich plasma were produced from chitosan and poly(ethylene oxide), using electrospinning. The morphology of nanofibers was stable in aqueous conditions for 72 h. It was shown that electrospinning does not adversely affect the biological activity of platelet-rich plasma. The effects of nanofibers with incorporated platelet-rich plasma on cell proliferation, survival, morphology and mobility were examined. Nanofibers limited cell mobility, changed morphology and stimulated cell proliferation. Despite of the small amount of blood-derived growth factors introduced in cell culture via platelet-rich plasma-loaded nanofibers, such nanofibrillar support significantly induced cell proliferation, indicating synergistic effect of nanotopography and incorporated growth factors. The overall results confirm favorable in vitro properties of produced nanofibers, indicating their high potential as a nanomaterial suitable for delivery of platelet-rich plasma in wound healing applications.
COBISS.SI-ID: 3673201
As of November/December 2016, this highly cited paper received enough citations to place it in the top 1% of the academic field of Pharmacology & Toxicology based on a highly cited threshold for the field and publication year. Data from Essential Science Indicators?. Nanofibers represent an attractive novel drug delivery system for prolonged release. However, sustained release of hydrophilic drugs, like ciprofloxacin hydrochloride (CIP), from polymeric nanofibers is not an easy task. The present study investigates the effect of different hydrophobic polymers (PCL and PMMA) alone in monolithic nanofibers, or with hydrophilic polymers (PVA, PEO, and chitosan) in blended nanofibers aiming to achieve sustained CIP release. CIP release from PCL nanofibers was 46% and from PMMA just 1.5% over 40 day period. Thus, PMMA holds great promise for modification of CIP release from blended nanofibers. PMMA blends with 10% PEO, PVA or chitosan were used to electrospin nanofibers from solution in the mixture of acetic and formic acid. These nanofibers exhibited different drug-release profiles: PEO containing nanofiber mats demonstrated high burst effect, chitosan containing mats revealed very slow gradual release, and PVA containing mats yielded smaller burst effect with favorable sustained release. We have also shown that gradual sustain release of antibiotic like CIP can be additionally tuned over 18 days with various blend ratios of PMMA with PVA or chitosan reaching almost 100%. Mathematical model in agreement with the experimental observation revealed that the sustained CIP release from the blended nanofiber corresponded to the two-stage desorption process.
COBISS.SI-ID: 3989361
Mini-tablets represent a new trend in solid dosage form design, with the main goal of overcoming some therapeutic obstacles such as impaired swallowing and polypharmacy therapy, and also offering some therapeutic benefits such as dose flexibility and combined release patterns. Mini-tablets are a promising patient-friendly drug delivery system. Mini-tablets are tablets with a diameter (3 mm produced on conventional tablet presses equipped with multiple tooling. Mini-tablet production is similar to the production of standard tablets but requires excellent powder flow due to the small dies, exact control of process parameters and special caution during tablet press assembly in order to avoid tool damage. Mini-tablets (coated or uncoated and single- or multiple-unit systems) are mainly developed as patient-friendly systems for pediatric and geriatric patients and also for personalized medicine because they offer improved swallowing and flexible dosing, combining various release kinetics, doses and active compounds in only one system. Mini-tablets may also be successfully used as multiple-unit modified release systems (extended release, delayed-colon release, pulsatile and bi-modal release and gastroretentive systems) providing improved drug bioavailability compared with single-unit systems. Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing and a combination of different release patterns and/or different active compounds (decreasing dosing frequency and/or polypharmacy therapy problems). In terms of complete expression of the benefits of mini-tablets over other oral dosage forms on the market, further investigation in formulation possibilities and development of suitable dosing devices is of essential importance.
COBISS.SI-ID: 3724401
Sunscreens containing ZnO and TiO2 nanoparticles (NPs) are increasingly applied to skin over long time periods to reduce the risk of skin cancer. However, long-term toxicological studies of NPs are very sparse. The in vitro toxicity of ZnO and TiO2 NPs on keratinocytes over short- and long-term applications is reported. The effects studied are intracellular formation of radicals, alterations in cell morphology, mitochondrial activity, and cell-cycle distribution. Cellular response depends on the type of NP, concentration, and exposure time. ZnO NPs have more pronounced adverse effectson keratinocytes than TiO2. TiO2 has no effect on cell viability up to 100 ?g mL-1, whereas ZnO reduces viability above 15 ?g mL-1 after short-term exposure. Prolonged exposure to ZnO NPs at 10 ?g mL-1 results in decreased mitochondrial activity, loss of normal cell morphology, and disturbances in cell-cycle distribution. From this point of view TiO2 has no harmful effect. More nanotubular intercellular structures are observed in keratinocytes exposed to either type of NP than in untreated cells. This observation may indicate cellular transformation from normal to tumor cells due to NP treatment. Transmission electron microscopy images show NPs in vesicles withinthe cell cytoplasm, particularly in early and late endosomes and amphisomes. Contrary to insoluble TiO2, partially soluble ZnO stimulates generation of reactive oxygen species to swamp the cell redox defense system thus initiating the death processes, seen also in cell-cycle distribution and fluorescence imaging. Long-term exposure to NPs has adverse effects on human keratinocytes 'in vitro', which indicates a potential health risk.
COBISS.SI-ID: 2842481
The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution / absorption profiles resulting from fasted administration of a diclofenac extended release pellet formulation. For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract. Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies. Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying. The comparison of predicted individual in vivo release profiles and individual in vivo absorption profilesshowed a high degree of similarity, thus confirming the suitability ofa set of different gastric residence times used in in vitro drug release testing. Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellets gastric emptying kinetics.
COBISS.SI-ID: 3370609