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 key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. We have selected magnetic resonance imaging (MRI) as the method of choice for visualizing the dynamic processes occurring during the swelling of xanthan tablets in a variety of media. The aims were (i) to develop a new method using MRI for accurate determination of penetration, swelling and erosion fronts, (ii) to investigate the effects of pH and ionic strength on swelling, and (iii) to study the influence of structural changes in xanthan gel on drug release. Two dimensional (2D) MRI and one dimensional single point imaging (SPI) of swollen xanthan tablets were recorded, together with T2 mapping. The border between dry and hydrated glassy xanthan-the penetration front-was determined from 1D SPI signal intensity profiles. The erosion front was obtained from signal intensity profiles of 2D MR images. The swelling front, where xanthan is transformed from a glassy to a rubbery state (gel formation), was determined from T2 profiles. Further, the new combination of MRI methods for swelling front determination enables to explain the appearance of the unusual Ćbright frontĆ observed on 2D MR images in tablets swollen in HCl pH 1.2 media, which represents the position of swelling front. All six media studied, differing in pH and ionic strength, penetrate through the whole tablet in 4 h 0.3 h, but formation of the gel layer is significantly delayed. Unexpectedly, the position of the swelling front was the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers. The latter are seen to be the consequence of the different hydrodynamic radii of the xanthan molecules, which affect the drug release kinetics. The slowest release of pentoxifylline was observed in water where the thickest gel was formed, whereas the fastest release was observed in HCl pH 1.2, in which the gel layer was thinnest. Moreover, experiments simulating physiological conditions showed that changes of pH and ionic strength influence the xanthan gel structure relatively quickly, and consequently the drug release kinetics. It is therefore concluded that drug release is greatly influenced by changes in the xanthan molecular conformation, as reflected in changed thickness of the gel layer. A new method utilizing combination of SPI, multi-echo MRI and T2 mapping eliminates the limitations of standard methods used in previous studies for determining moving fronts and improves current understanding of the dynamic processes involved in polymer swelling.
COBISS.SI-ID: 2780273
BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be usedas standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosal-to-mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetrywas abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.
COBISS.SI-ID: 3232881
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
Background: The objective of the present study is to evaluate the cost-effectiveness of human papillomavirus (HPV) vaccination alongside cervical cancer screening programme in Slovenia. Methods: A previously published Markov model representing natural history of HPV infection was adapted to Slovenian context. The model followed a cohort of 12-year-old girls to 85-year-old women. Two strategies were compared: HPV vaccination alongside conventional cytological screening versus screening alone. Analysis was performed from the health care payer perspective. Results: Vaccination with screening compared with screening alone was associated with an incremental cost-effectiveness ratio (ICER) of 23 178 EUR per quality adjustedlife-year (QALY) gained and 54 536 EUR per life-year gained (LYG) at the discounting rate of 5%. Sensitivity analyses demonstrated that the ICER was most sensitive to the need for booster dose and to different values of discount rates. In case the booster dose was assumed 10 years after initial vaccination, the ICER value was increased to 58 690 EUR per QALY. On the otherhand, using lower values of discount rates than the base case 5% significantly reduced the ICER value. Conclusion: According to the cost-effectiveness thresholds of 30 000 EUR per QALY which was adopted by the Health Council in Slovenia, HPV vaccination alongside screening programme can be regarded as cost-effective. However, cost-effectiveness of HPV vaccination would become questionable in case a booster dose was needed to provide lifetime protection.
COBISS.SI-ID: 2834033