A comprehensive assessment of machine learning algorithms for enhanced characterization and prediction in orodispersible film development.

Orodispersible films (ODFs) have emerged as innovative pharmaceutical dosage forms, offering patient-specific treatment through adjustable dosing and the combination of diverse active ingredients. This expanding field generates vast datasets, requiring advanced analytical techniques for deeper understanding of data itself. Machine learning is becoming an important tool in the rapidly changing field of pharmaceutical research, particularly in drug preformulation studies. This work aims to explore into the application of machine learning methods for the analysis of experimental data obtained by ODF characterization in order to obtain an insight into the factors governing ODF performance and use it as guidance in pharmaceutical development. Using a dataset derived from extensive experimental studies, various machine learning algorithms were employed to cluster and predict critical properties of ODFs. Our results demonstrate that machine learning models, including Support vector machine, Random forest and Deep learning, exhibit high accuracy in predicting the mechanical properties of ODFs, such as flexibility and rigidity. The predictive models offered insights into the complex interaction of formulation variables. This research is a pilot study that highlights the potential of machine learning as a transformative approach in the pharmaceutical field, paving the way for more efficient and informed drug development processes.

Application of Machine-Learning Algorithms for Better Understanding the Properties of Liquisolid Systems Prepared with Three Mesoporous Silica Based Carriers.

The processing of liquisolid systems (LSS), which are considered a promising approach to improving the oral bioavailability of poorly soluble drugs, has proven challenging due to the relatively high amount of liquid phase incorporated within them. The objective of this study was to apply machine-learning tools to better understand the effects of formulation factors and/or tableting process parameters on the flowability and compaction properties of LSS with silica-based mesoporous excipients as carriers. In addition, the results of the flowability testing and dynamic compaction analysis of liquisolid admixtures were used to build data sets and develop predictive multivariate models. In the regression analysis, six different algorithms were used to model the relationship between tensile strength (TS), the target variable, and eight other input variables. The AdaBoost algorithm provided the best-fit model for predicting TS (coefficient of determination = 0.94), with ejection stress (ES), compaction pressure, and carrier type being the parameters that influenced its performance the most. The same algorithm was best for classification (precision = 0.90), depending on the type of carrier used, with detachment stress, ES, and TS as variables affecting the performance of the model. Furthermore, the formulations with Neusilin® US2 were able to maintain good flowability and satisfactory values of TS despite having a higher liquid load compared to the other two carriers.

Cadmium, lead, mercury and arsenic in fresh vegetables and vegetable products intended for human consumption in the Republic of Serbia, 2015-2017.

The concentrations of cadmium (Cd), lead (Pb), mercury (Hg) and arsenic (As) were determined in 455 samples of 27 species of vegetables and 28 different processed vegetables collected during the period from January 2015 to December 2017. Vegetables (n = 387) and vegetable products (n = 68) originated from 31 countries, including Serbia. The samples were analysed by inductively coupled plasma - optical emission spectrometry (ICP-OES). The concentrations of Cd, Pb, Hg and As in the vegetables and vegetable products were compared to the maximum levels set by the European Union and the Serbian legislation. The concentration of mercury was less than the limit of detection in each analysed sample. One or multiple measurable toxic metals (Cd, Pb and/or As) were found in 250 samples (54.9%; n = 455). According to the Regulations which were valid until the end of August 2021, the maximum levels of Cd, Pb and As were exceeded in 19 samples (4.2% of the samples of vegetable and vegetable products; n = 455), i.e. in 13 samples of vegetables: Cd in three, Pb in nine and As in one sample and in 6 samples of vegetables products: Cd in three, Pb in one and As in two samples. Regarding the new EU and Serbian legislation which is valid since September 2021 the maximum levels of Cd and Pb for vegetables and vegetable products were exceeded in 118 samples (25.9% of the samples of vegetable and vegetable products; n = 455), i.e. in 95 samples of vegetables: Cd in 67 and Pb in 28 samples and in 23 samples of vegetable products: Cd in 20 and Pb in 3 samples.

Post-COVID-19 Status and Its Physical, Nutritional, Psychological, and Social Effects in Working-Age Adults-A Prospective Questionnaire Study.

BACKGROUND: The main objective of this study was to evaluate the evolution of physical and daily routine, dietary habits, and mental and social health in individuals with recent COVID-19 infection. METHODS: A qualitative prospective cross-sectional study was conducted from 01 October 2021 to 01 March 2022, which included 80 working-age adults from the territory of Central Serbia who had PCR-confirmed SARS-CoV-2 infection in the previous six months. Two structured pre-coded closed-ended questionnaires were submitted to the participants: a questionnaire about post-COVID-19 status (pCOVq) and a shortened version of the World Health Organization's Quality of Life Scale (WHOQOL-BREF). RESULTS: The presence of the COVID-19 disease in the previous period of 6 months among the working-age participants significantly affected the duration of aerobic, anaerobic, and high-intensity physical activities, but also the possibility of performing certain activities such as walking, which represents basic aerobic activity and a measure of general health among middle-aged participants. In the majority of cases (78%), in the post-COVID-19 period, participants indicated a decline in educational and productive activities. CONCLUSION: Post-COVID status in working-aged participants consists of reduced physical activity, lower quality of life, and similar nutritional habits. Health policies should be more focused on these findings.

Processability evaluation of multiparticulate units prepared by selective laser sintering using the SeDeM Expert System approach.

3D printing in dosage forms fabrication is in the focus of researchers, however, the attempts in multiparticulate units (MPUs) preparation are scarce. The aim of this study was to fabricate different size MPUs by selective laser sintering (SLS), using different polymers, and investigate their processability based on the SeDeM Expert System approach. MPUs (1- or 2-mm size) were prepared with model drug (ibuprofen or caffeine), polymer (poly(ethylene)oxide (PEO), ethyl cellulose (EC) or methacrylic acid-ethyl acrylate copolymer (MA-EA)) and printing aid. Comprehensive sample characterization was performed and experimentally obtained parameters were mathematically transformed and evaluated using the SeDeM Expert System framework. The obtained samples exhibited irregular shape, despite the spherical printing object design. Polymer incorporated notably affected MPUs properties. The obtained samples exhibited low bulk density, good flowability-, as well as stability-related parameters, which indicated their suitability for filling into capsules or sachets. Low density values implied that compressibility enhancing excipients may be required for MPUs incorporation in tablets. Samples containing EC and MA-EA were found suitable for compression, due to high compacts tensile strength. The obtained results indicate that SeDeM Expert System may extended from powder compressibility evaluation tool to framework facilitating powders/multiparticulate units processing.

Cadmium, lead, mercury, and arsenic in fresh fruits and fruit products intended for human consumption in the Republic of Serbia, 2015-2017.

The European Commission has established legislation for toxic metals in certain foodstuffs in order to protect public health already in 1993. After several amendments, new maximum levels for cadmium and lead in certain foods were set as per 30 and 31 August 2021 for lead and cadmium, respectively. The new Serbian Regulation on "maximum levels of certain contaminants in food" is fully harmonised with this European legislation. The concentrations of cadmium (Cd), lead (Pb), mercury (Hg), and arsenic (As) were determined in 832 samples of 39 species of fruits and processed fruits, collected during the period January 2015 to December 2017. Fruits and fruit products originated from 45 countries, including Serbia. Samples were analysed by inductively coupled plasma - optical emission spectrometry (ICP-OES). Concentrations of cadmium, lead, mercury, and arsenic in fruits and fruit products were compared to these maximum levels (MLs). Overall, measurable Cd, Pb, Hg, and As were found in 377 samples (45.3%). According to the former regulations, the maximum levels of Cd and Pb for analysed fruits and fruit products were exceeded in only 10 samples (1.20%; n = 832): Cd in 6 and Pb in 4 samples, but according to the latest regulations, the maximum levels of Cd and Pb for fruits were exceeded in 196 of the samples (23.9%; n = 820): Cd in 191 and Pb in 5 samples. The increase of ML exceedances shows that attention needs to be paid for compliance of food to the recent MLs for these metals.

Generation of a dual optical frequency comb by large signal modulation of a semiconductor laser.

In this paper, we present and theoretically investigate a simple and power efficient scheme for dual optical frequency comb generation residing on a single directly modulated semiconductor laser driven by two superimposed current waveforms. Our detailed model estimates dual combs comprising teeth pairs within 20 dB margin spanning up to 116 GHz with power per teeth pair up to 8.8 µW. In addition, we report dual combs with 40 GHz span comprising ultraflat teeth pairs, with flatness of the order of 1 dB.

Investigation into liquisolid system processability based on the SeDeM Expert System approach.

Liquisolid systems are emerging formulation approach for poorly soluble drugs, based on adsorption/absorption of drug dispersion and obtaining free-flowing powder with good compressibility. SeDeM Expert System represents a powder processability evaluation method. It may provide additional insight into liquisolid systems critical quality attributes, but the contribution of this approach remains to be explored. The aims of this study were: pellet preparation by combination of liquisolid technology and water granulation/extrusion, evaluation of liquisolid based systems (pellets/admixtures) and investigation into the applicability of SeDeM Expert System in liquisolid systems characterization. Pellets/admixtures were prepared with microcrystalline cellulose as carrier and crospovidone/silicon dioxide as coating agent. Ibuprofen solution in polyethylene glycol 400 was used as liquid phase. After comprehensive sample characterization, experimentally obtained parameters were mathematically transformed and evaluated in the SeDeM Expert System framework. Pellets exhibited low aspect ratio and excellent flowability, despite liquid load up to 52.2%. The investigated liquisolid admixtures exhibited good flowability and faster drug dissolution than pellets. Single pellet crushing test results exhibited strong correlation with compact indentation hardness and may be used as indentation hardness predictor. SeDeM Expert System provides useful insight into liquisolid system processability and comparative evaluation and it may facilitate final solid dosage form development.

An Investigation into Mechanical Properties and Printability of Potential Substrates for Inkjet Printing of Orodispersible Films.

Inkjet printing is novel approach in drug manufacturing that enables dispensing precise volumes of ink onto substrates. Optimal substrate properties including suitable mechanical characteristic are recognized as crucial to achieve desired dosage form performance upon administration. Identification of relevant quality attributes and their quantification is subject of intensive scientific research. The aim of this work was to explore applicability of different materials as printing substrates and explore contribution of the investigated substrate properties to its printability. Substrates were characterized with regards to uniformity, porosity, disintegration time, mechanical properties and drug dissolution. Experimentally obtained values were mathematically transformed and the obtained results were presented as relevant radar charts. It was shown that structurally different substrates may be employed for orodispersible films inkjet printing. Main disadvantage of single-polymer films was low drug load, and their printability was dependent on film flexibility and mechanical strength. Structured orodispersible film templates exhibited favorable mechanical properties and drug load capacity. Wafer edible sheets were characterized with high mechanical resistance and brittleness which somewhat diminished printability, but did not hinder high drug load. Obtained results provide insight into application of different materials as printing substrates and contribute to understanding of substrate properties which can affect printability.

Influence of selenium yeast on the growth, selenium uptake and mineral composition of Coriolus versicolor mushroom.

The ability of Coriolus versicolor medicinal mushroom to grow and accumulate selenium during submerged cultivation in a selenium-fortified medium is examined in this paper. For selenium supplementation, commercial selenium yeast was used. Control, nonenriched sample and reference cultures cultivated in the medium enriched with commercial yeast Saccharomyces cerevisiae were also prepared. The mushroom demonstrated a high ability to accumulate selenium from the added source (around 970 and 1,300 µg/g of dry mycelium weight for samples enriched with selenium in a concentration of 10 and 20 mg Se/L, respectively). The addition of selenium significantly (p ≤ .05) increased the biomass yield, whereas the addition of nonenriched yeast had no significant (p ≤ .05) impact. Furthermore, regression analysis showed statistically significant (p ≤ .05) and positive correlations between the content of Se and Fe (r = .92), Se and Cu (r = .92), Se and Mn (r = .98), and Se and Sr (r = .96), suggesting that selenium incorporation was followed by incorporation of these elements, and led to mineral enrichment of the obtained mycelium. Methanol extracts prepared from mycelium biomass demonstrated a better inhibitory effect on Gram-positive bacterial strains with minimal inhibitory concentrations between <0.3125 and 40 mg/ml. The obtained results showed that selenium yeast could be used for obtaining a potential novel food supplement: mushroom biomass with high selenium content and enhanced mineral composition.

Toward identification of the risk group of food products: Chemometric assessment of heavy metals content in confectionery products.

The main raw material for cookies production is wheat flour (white or wholemeal/integral) as a nutritionally highly valuable component. In addition to the benefits it brings, this raw material is also a potential source of contamination with residues of heavy metals originating from soil and plant protection agents. Therefore, it is necessary to analyze their concentrations in both wheat flour and final products, since the wheat flour is often present in cookies and related confectionery products in a proportion >60 or 70%. The aim of this paper was to determine the content of heavy metals, including highly toxic ones (As, Cd, Hg and Pb) and essential metals with potential toxic effects (Fe, Cu, Cr, Co, Mn, Ni, Zn) in cookies, waffles and crackers available in local markets in the Autonomous Province of Vojvodina, Republic of Serbia. The present study is focused on chemometric estimation of the risk group of confectionery products containing wheat flour in an easy and efficient way. Hierarchical cluster analysis, principal component analysis, linear discriminant analysis and the sum of ranking differences analysis were applied for this purpose as chemometric tools with substantially different theoretical bases. The obtained results indicated that there is a specific group of cookies with a relatively high content of heavy metals. The group of crackers contained lower concentrations of heavy metals than the other groups of studied products. The results of the sum of ranking differences analysis indicate that there is no strict separation between the samples regarding the ratio among heavy metals contents.

Artificial neural network approach to modelling of metal contents in different types of chocolates.

The relationships between the contents of various metals in different types of chocolates were studied using chemometric approach. Chemometric analysis was based on the application of artificial neural networks (ANN). ANN was performed in order to select the significant models for predicting the metal contents. ANN equations, that represent the content of one metal as a function of the contents of other metals were established. The statistical quality of the generated mathematical models was determined by standard statistical measures and cross-validation parameters. High agreement between experimental and predicted values, obtained in the validation procedure, indicated the good quality of the models. The obtained results indicate the possibility of predicting the metal contents in different types of chocolate.

Detection of genetically modified soybean in crude soybean oil.

In order to detect presence and quantity of Roundup Ready (RR) soybean in crude oil extracted from soybean seed with a different percentage of GMO seed two extraction methods were used, CTAB and DNeasy Plant Mini Kit. The amplifications of lectin gene, used to check the presence of soybean DNA, were not achieved in all CTAB extracts of DNA, while commercial kit gave satisfactory results. Comparing actual and estimated GMO content between two extraction methods, root mean square deviation for kit is 0.208 and for CTAB is 2.127, clearly demonstrated superiority of kit over CTAB extraction. The results of quantification evidently showed that if the oil samples originate from soybean seed with varying percentage of RR, it is possible to monitor the GMO content at the first stage of processing crude oil.

Design space approach in optimization of fluid bed granulation and tablets compression process.

The aim of this study was to optimize fluid bed granulation and tablets compression processes using design space approach. Type of diluent, binder concentration, temperature during mixing, granulation and drying, spray rate, and atomization pressure were recognized as critical formulation and process parameters. They were varied in the first set of experiments in order to estimate their influences on critical quality attributes, that is, granules characteristics (size distribution, flowability, bulk density, tapped density, Carr's index, Hausner's ratio, and moisture content) using Plackett-Burman experimental design. Type of diluent and atomization pressure were selected as the most important parameters. In the second set of experiments, design space for process parameters (atomization pressure and compression force) and its influence on tablets characteristics was developed. Percent of paracetamol released and tablets hardness were determined as critical quality attributes. Artificial neural networks (ANNs) were applied in order to determine design space. ANNs models showed that atomization pressure influences mostly on the dissolution profile, whereas compression force affects mainly the tablets hardness. Based on the obtained ANNs models, it is possible to predict tablet hardness and paracetamol release profile for any combination of analyzed factors.

Oxidative stress in rat kidneys due to 3,4-methylenedioxymetamphetamine (ecstasy) toxicity.

AIM: The mechanism of MDMA (3,4-methylenedioxymethamphetamine)-induced toxicity is believed to be, in part, due to enhanced oxidative stress. As MDMA is eliminated via the kidney, the aim of this study was to investigate whether MDMA created conditions of oxidative stress within rat kidney. METHODS: Adult male Wistar rats were divided into three groups, control treatment (water), acute MDMA administration (single oral dose: 5, 10, 20 or 40 mg/kg body weight) and subacute MDMA administration (5, 10, or 20 mg/kg body weight per day during 14 days). Animals were sacrificed 8 h after the single oral MDMA administration in the acute MDMA administration group and after the last MDMA administration in the subacute MDMA administration group. Rectal temperature measurements, oxidative stress status parameters and histological examinations were performed. RESULTS: In all MDMA-administered rats, rectal temperature markedly increased peaking approximately 1 h after MDMA ingestion. Superoxide dismutase activity and thiobarbituric acid reactive substances increased after MDMA administration. Histological examinations of the kidney revealed dose-dependent disruption of tissue structure in subacute MDMA-administered rats. The latter was not observed in acute MDMA-administered rats.

The role of nitric oxide in paraquat-induced oxidative stress in rat striatum.

The role of nitric oxide (NO) in paraquat (PQ)-induced neurotoxicity is still not fully understood. In this study we used NG-nitro-L-arginine methyl ester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, in order to examine the effects of NO, reactive oxygen species (ROS) generation and lipid peroxidation (LPO) development during PQ-mediated neurotoxicity. Oxidative stress development in the striatum of Wistar rats intrastriatally (i.s.) poisoned with PQ (and in some cases pre-treated with L-NAME) was investigated by measuring superoxide anion (O2.-), malondialdehyde (MDA) and nitrate (NO3-), 30 min, 24 hours and 7 days after treatment. L-NAME pre-treatment provided the possibility to distinguish the role of ROS from reactive nitrogen species (RNS) in oxidative stress development induced by PQ. Our results confirm the involvement of NO in PQ-mediated neurotoxicity and reduced LPO by L-NAME pre-treatment implying that the latter has a protective role.

The effects of exposure to extremely low-frequency magnetic field and amphetamine on the reduced glutathione in the brain.

Continuous exposure to extremely low-frequency magnetic field (ELF-MF, 50 Hz, 0.5 mT) alone and combined with D-amphetamine (1.5 mg/kg) affected the reduced glutathione content in brain regions of rats. Compared to sham-exposed rats, the glutathione content in the forebrain cortex of the ELF-MF-exposed rats decreased (P < 0.001), but this reverted after giving amphetamine upon ELF-MF exposure. In this group, the glutathione content was increased in the brain stem and cerebellum (P < 0.05 compared to the sham-exposed, ELM-MF-exposed, and amphetamine-treated groups). It is suggested that biogenic monoamines are involved in the reduced glutathione changes observed. The changes are not uniform in the brain regions examined.

N-methyl-3,4-methylenedioxyamphetamine-induced hepatotoxicity in rats: oxidative stress after acute and chronic administration.

BACKGROUND: The underlying mechanisms of N-methyl-3,4-methylenedioxyamphetamine--MDMA--induced hepatotoxicity are still unknown. The aim of this study was to evaluate hepatic oxido-reductive status in the rats liver after the single and repeated administration of MDMA. METHODS: MDMA was dissolved in distilled water and administered in the doses of 5 mg, 10 mg, 20 mg, and 40 mg/kg. The animals from the acute experiment were treated per os with the single dose of the appropriate solution, through the orogastric tube. The animals from the chronic experiment were treated per os, with the doses of 5, 10, or 20 mg/kg of MDMA every day during 14 days. The control groups were treated with water only. Eight hours after the last dose, the animals were sacrificed, dissected, their livers were rapidly removed, frozen and stored at -70 degrees C until the moment of analysis. The parameters of oxidative stress in the crude mitochondrial fractions of the livers were analyzed. RESULTS: Superoxide dismutase (SOD) activity increased in the livers of the animals that were treated with single doses of MDMA. Chronically treated animals showed the increased SOD activity only after the highest dose (20 mg/kg). The content of reduced glutathione decreased in both groups, but the depletion was much more expressed after the single administration. Lipid peroxidation index increased in dose-dependent manner in both groups, being much higher after the single administration. CONCLUSION: The increased index of lipid peroxidation and the decreased reduced glutathione levels suggested that MDMA application induced the state of oxidative stress in the liver. These changes were much more expressed after the single administration of MDMA.

7-nitroindazole reduces nitrite concentration in rat brain after intrahippocampal kainate-induced seizure.

Kainic acid is an endogenous excitotoxin acting on glutamate receptors, that leads to neurotoxic damage resembling the alterations observed in some neurological disorders. Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. NO may be a key mediator of excitotoxic neuronal injury in the central nervous system. We investigated the effects of 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor in vivo, on nitrite concentration after kainic acid injection (0.6 mg/ml, pH 7.2) unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 h and 7 days) following kainate injection in the ipsilateral and contralateral hippocampus, forebrain cortex, striatum and cerebellum homogenates. 7-Nitroindazole (100 microM) can effectively inhibit NO synthesis in rat brain after kainate-induced intrahippocampal neurotoxicity and suppressed nitrite accumulation. The present results suggest that neuronal NO synthase inhibitors may be useful in the treatment of neurological diseases where excitotoxic mechanisms play a role.