State Institute for Drug Control

Abstract Objective To develop a headspace capillary gas chromatography (HS-GC) method for the determination of residual solvents in Siponimod active pharmaceutical ingredient (API), including methanol, ethanol, acetone, isopropanol, acetonitrile, methylene chloride, ethyl acetate,tetrahydrofuran, n-heptane, toluene, N,N-dimethylformamide, and dimethyl sulfoxide. Methods The analysis was performed using HS-GC with an Agilent DB-624 capillary column (60 m × 0.32 mm, 1.80 µm). The temperature program was set as follows: initial temperature of 45°C held for 17 minutes, then increased to 240°C at a rate of 15°C per minute and held for 10 minutes. Helium was used as the carrier gas at a flow rate of 1.0 mL/min. The injector temperature was set at 210°C, and the FID detector temperature was 260°C. The headspace equilibrium temperature was 105°C, and the equilibrium time was 35 minutes. Results All 12 residual solvents were completely separated. Each solvent showed a good linear relationship between concentration and peak area within the tested range, with correlation coefficients (r) no less than 0.999. The average recovery rates ranged from 95.3% to 100.9%, and the relative standard deviations (RSD) were between 0.8% and 2.7% (n=9). Conclusion This validated analytical approach demonstrates exceptional accuracy, reproducibility, and high sensitivity, enabling robust quantification of 12 residual solvents in siponimod API through a harmonized protocol compliant with ICH Q3C and pharmacopeial standards. Its optimized efficiency and scalability render it a pivotal solution for pharmaceutical quality assurance systems.

Despite EU-wide risk minimisation measures in March 2019 to prevent inappropriate prescribing of systemic and inhaled fluoroquinolones, pharmacovigilance evidence suggests that decreases in prescribing have been of limited magnitude. We renew the call to adhere to guidelines on appropriate prescribing of fluoroquinolones. We also advocate for proper patient counselling on the risks of serious adverse reactions to these antibiotics, including how to recognise the symptoms, to facilitate shared-decision making with patients.

In the current landscape, regulatory agencies face the challenge of reconciling timely authorizations for novel medicines addressing life-threatening conditions with thorough evaluations of their benefits and risks. This challenge is pronounced with advanced therapy medicinal products (ATMPs), where expedited approval mechanisms and orphan drug designations are often applied, making post-authorization measures a crucial mechanism to address uncertainties. We compared post-authorization measures imposed by the U.S. Food and Drug Administration and the European Medicines Agency on ATMPs approvals, from 2009 to 2023. A systematic extraction of FDA postmarketing requirements (PMRs) and EMA-imposed post-authorization measures (PAMs) from publicly available regulatory documents was conducted. Descriptive analysis focused on post-authorization measure categories, objectives, study designs, and their status and registration rates. A total of 15 ATMPs were approved in both jurisdictions over the study period. For these products, the EMA imposed 53 PAMs (34 Annex II conditions and 19 Specific Obligations), whereas the FDA imposed 27 PMRs. As of December 2023, 15 EMA-imposed PAMs were fulfilled, with no explicit fulfilments indicated for FDA PMRs. Both agencies promoted real-world data use in around half of the imposed PAMs (23 by EMA vs. 15 by FDA), marking regulators' growing recognition of Real-World Evidence for decision-making. This study highlights disparities between imposed PAMs: EMA imposed more PAMs, covering efficacy, safety, and quality aspects, while the FDA required fewer measures focusing on specific safety concerns. These discrepancies primarily reflect distinct regulatory structures and approaches to further post-authorization data collection between the EMA and FDA, rather than disparities in initial benefit/risk assessments.

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer's disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aβ, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aβ in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aβ and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.

La période romaine dans la région du Moyen-Danube constitue un contexte géopolitique spécifique au sein du large éventail d’interactions entre Romains et Barbares découlant de leur coexistence directe et du voisinage de ces deux mondes distincts. Les basses terres situées au nord du limes du Moyen-Danube étaient occupées par les populations germaniques (vraisemblablement par les « tribus » des Marcomanni et Quadi), comme l’attestent de nombreux témoignages archéologiques. La plupart des recherches archéologiques dans la région ont été traditionnellement ancrées dans le paradigme culturel-historique, accordant, jusqu’à récemment, une attention plutôt limitée aux aspects quantitatifs et spatio-temporels. Le projet en cours (Czech Science Foundation) vise, dans une certaine limite, à combler cette lacune. Entre autres objectifs, il se focalise sur la collecte de toutes les données spatiales et attributaires pertinentes qui devraient permettre d’obtenir des proxies représentatifs et significatifs pour faire des estimations démographiques à différentes échelles (régions – « zones clés », zones résidentielles, foyers, etc.) dans le contexte des chefferies germaniques. En outre, l’étude des relations structurelles et des corrélations potentielles entre les variables sociales, économiques ou climatiques est nécessaire pour identifier les trajectoires générales du développement de la région. À l’aide de diverses techniques de calcul (par exemple, les analyses spatiales, la statistique multivariée, la modélisation à base d’agents, les techniques de la science des réseaux), il s’agit d’évaluer le potentiel d’interprétation des données disponibles, de valider certains modèles théoriques et hypothèses existants et d’identifier les éventuelles régularités dans les données disponibles.

UAVs, used for professional purposes, often intervene in unfamiliar terrain and challenging conditions. Unlike recreational UAVs, such professional and specialised UAVs are very expensive to develop and operate, and their value is not negligible. Due to the nature of operations in an unknown or dangerous environment, there are also situations with forced interruption and termination of the flight mission or a collision with the environment. Locating a lost vehicle presents a new challenge for UAV operators. The possibilities of today’s localised commercial aircraft in distress (COSPASS/SARSAT systems) are undesirable for selective special-purpose drones. The optimisation of the location in the event of an emergency or catastrophic landing may be justified by a social or other condition, where the user wants to search for the device by a system other than the one experienced for rescuing people, ideally on their reserved frequencies. The article proposes a new approach to solving the problem based on the design of a terrestrial localisation system based on the methods of processing and correlation of the obtained data by the physical principle of the Doppler effect and its own system adaptation. This creates an innovative concept of a targeting system based on the broadcasting of distress (VHF) signal by crashed UAV. This signal is captured and evaluated by the IDVOR system, making it possible to determine the direction in which the searched UAV is placed. In order to determine the difference between standard targeting systems of the UAV, which use information about position (exact coordinates (x,y,z)), the IDVOR system is able to determine direction, independent of other systems in every “enemy” or “inhospitable” territory.

Background Breast cancer is the most frequently diagnosed and leading cause of death amongst cancers in women. Understanding its burden is important in healthcare management. We assessed direct medical and indirect costs of advanced breast cancer (ABC) in selected countries: Bulgaria, Croatia, Czech Republic, Estonia, Greece, Israel, Latvia, Poland, Romania, and Slovak Republic. Methods The data were collected in individual countries with a unified questionnaire (covering epidemiology, mortality, treatment patterns, and economic aspects) based on databases/registries, published studies, or experts’ opinions in the absence of published data. International scope allowed for consistency checks and missing data imputing. Results The total annual costs of ABC per 100,000 women varied from 1 million EUR in Romania to 3.4 million EUR in Slovak Republic with the differences partially related to data availability. The direct costs resulted mainly from the costs of treatment (covering surgery, breast reconstruction, external breast prosthesis, chemotherapy, radiation, hormonal and targeted therapy). The indirect costs (lost productivity due to premature mortality and reduced employment rate) constitute a large part (>50%) of the total costs. The average (for all countries) total annual costs per 100,000 women amounts to 1.8 million EUR. Conclusion ABC is associated with substantial healthcare costs and imposes a significant societal burden, as indicated by high indirect costs. Early detection, timely intervention, and effective treatment of early stage BC hold potential to decrease burden of ABC. Our findings may be used in informing decisions on resource allocation, improving cancer policies and supporting national cancer plans. Highlights · Advanced breast cancer costs between 1 and 3.4 million euro per 100,000 women in studied countries; lost productivity (from societal perspective) accounts for most of the cost. · The data availability is still limited; comparisons between countries reveal some gaps, but collecting more information, e.g. in registries, is crucial for improved decision making. · The results of our study may be used in cost-effectiveness modelling of diagnostic or treatment technologies.

Abstract Background Evidence shows that sexual minorities are more vulnerable to substance use and psychological distress as a result of minority stress compared with heterosexuals. So far, research conducted outside North America or Western Europe has been underrepresented. This research compares for the first time the substance use, quality of mental health and life satisfaction between the sexual minority people and heterosexuals using a nationally representative probability sample in the Czech population. Methods Sample of the general population aged 15+ years surveyed within the National Survey on Substance Use in 2016 in randomly selected households (N = 3,601, F2F interviews). Prevalence of licit and illicit substance use, psychological distress (MHI-5 scale) and life satisfaction (SWLS scale) were analyzed by respondents' self-reported sexual identity and behaviors. Logistic regressions were applied to evaluate the differences between groups. Adjustment for basic sociodemographic characteristics was performed. Results 2.8% of adults identified as sexual minorities, including 0.5% lesbians or gays and 2.3% bisexuals. Sexual minorities were more likely to experiment with (illicit) substance use in the last 12 months (OR = 1.74, 95% CI: 1.03-2.94), more often experience psychological distress (OR = 2.56, 95% CI: 1.50-4.38), and were slightly less often satisfied with their lives (OR = 0.79, 95% CI: 0.46-1.37) compared to heterosexuals. Sexual minority status was not found as a significant predictor for daily tobacco smoking nor for frequent excessive/binge alcohol consumption. Conclusions In accordance with international evidence, sexual minorities represent a vulnerable group from the perspective of substance use and psychological distress. Factors influencing life satisfaction of sexual minority people living in geographically underrepresented regions need to be further investigated using measures more sensitive to local cultural circumstances.

With the aim to develop a novel multifunctional gene delivery system that may overcome the common barriers of gene transfection, near-infrared fluorescent triphenylamine-pyrazine was modified with a DNA condensing triazole-[12]aneN3 moiety through different length alkyl ester linkages to afford three new non-viral gene vectors, TDM-A/B/C. All compounds showed prominent solvatochromic fluorescence (Stokes shift of up to 383 nm) and two-photon absorption properties (σ2P to 101 GM), and exhibited strong aggregation-induced emission (AIE). Gel electrophoresis demonstrated that plasmid DNA was completely condensed at a concentration of 10 μM (TDM-A), 14 μM (TDM-B) and 16 μM (TDM-C), and released in esterase and acidic environment. SEM demonstrated that the three compounds were able to self-assemble and co-aggregate with DNA to form regular nanoparticles. Experiments demonstrated that TDM-A/B/C was able to integrate with DNA through electrostatic interactions and supramolecular stacking, and the short alkyl linkage favored the strong interaction with DNA. Among the three compounds, TDM-B showed the best luciferase and GFP transfection activities in the presence of DOPE, which were 156% and 310% higher than those of Lipo2000, respectively. The transfection process of DNA was clearly traced through one- and two-photon fluorescence microscopy imaging. Cellular uptake inhibition assay indicated that the DNA complex entered the cell mainly via clathrin-independent endocytosis. Furthermore, the in vivo transfection experiments of TDM-B/DOPE were successfully implemented in zebra fish embryos, and the GFP gene expression level was superior to that of Lipo2000 (200%). Finally, this study clearly unraveled that the length of the alkyl linkage affected the DNA condensation and transfection activity, which can serve as a base for the future rational design of non-viral gene vectors.