Rational Dosage Research Articles

Performance Assessment of a Novel Green Concrete Using Coffee Grounds Biochar Waste

An actual scientific problem in current concrete science is poor knowledge of the problem of modifying concrete with plant waste. At the same time, plant waste benefits from other types of waste because it is a recycled raw material. A promising technological approach to modifying concrete with plant waste is the introduction of components based on the processing of coffee production waste into concrete. This study aims to investigate the use of biochar additives from spent coffee grounds (biochar spent coffee grounds—BSCG) in the technology of cement composites and to identify rational formulations. A biochar-modifying additive was produced from waste coffee grounds by heat treatment of these wastes and additional mechanical grinding after pyrolysis. The phase composition of the manufactured BSCG additive was determined, which is characterized by the presence of phases such as quartz, cristobalite, and amorphous carbon. The results showed that the use of BSCG increases the water demand for cement pastes and reduces the cone slump of concrete mixtures. Rational dosages of BSCG have been determined to improve the properties of cement pastes and concrete. As a result of the tests, it was determined that the ideal situation is for the BSCG ratio to be at a maximum of 8% in the concrete and not to exceed this rate. For cement pastes, the most effective BSCG content was 3% for concrete (3%–4%). The compressive and flexural strengths of the cement pastes were 6.06% and 6.32%, respectively. Concrete’s compressive strength increased by 5.85%, and water absorption decreased by 6.58%. The obtained results prove the feasibility of using BSCG in cement composite technology to reduce cement consumption and solve the environmental problem of recycling plant waste.

Rational quinidine dosage regimen for atrial fibrillation in Thoroughbred racehorses based on population pharmacokinetics.

Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses. Six healthy Thoroughbred horses were treated with 20 mg/kg quinidine sulfate dihydrate (16.58 mg/kg QND base) administered PO or 5 mg/kg quinidine hydrochloride monohydrate (4.28 mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20 mg/kg quinidine sulfate dihydrate administered twice (every 6 h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). The median quinidine concentration for successful sinus rhythm conversion was 2.0 μg/mL (range: 0.5-2.7 μg/mL) in AF horses, while a median concentration of 3.8 μg/mL (range: 1.6-5.1 μg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 μg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 μg/mL in 90, 50, and 10% of horse populations, respectively. Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses.

Clinical Trial Data-Driven Risk Assessment of Drug-Drug Interactions: A Rapid and Accurate Decision-Making Tool.

In clinical practice, the vast array of potential drug combinations necessitates swift and accurate assessments of pharmacokinetic drug-drug interactions (DDIs), along with recommendations for adjustments. Current methodologies for clinical DDI evaluations primarily rely on basic extrapolations from clinical trial data. However, these methods are limited in accuracy owing to their lack of a comprehensive consideration of various critical factors, including the inhibitory potency, dosage, and type of the inhibitor, as well as the metabolic fraction and intestinal availability of the substrate. This study aims to propose an efficient and accurate clinical pharmacokinetic-mediated DDI assessment tool, which comprehensively considers the effects of inhibitory potency and dosage of inhibitors, intestinal availability and fraction metabolized of substrates on DDI outcomes. This study focuses on DDIs caused by cytochrome P450 3A4 enzyme inhibition, utilizing extensive clinical trial data to establish a methodology to calculate the metabolic fraction and intestinal availability for substrates, as well as the concentration and inhibitory potency for inhibitors ( or ). These parameters were then used to predict the outcomes of DDIs involving 33 substrates and 20 inhibitors. We also defined the risk index for substrates and the potency index for inhibitors to establish a clinical DDI risk scale. The training set for parameter calculation consisted of 73 clinical trials. The validation set comprised 89 clinical DDI trials involving 53 drugs. which was used to evaluate the reliability of in vivo values of and , the accuracy of DDI predictions, and the false-negative rate of risk scale. First, the reliability of the in vivo and values calculated in this study was assessed using a basic static model. Compared with values obtained from other methods, this study values showed a lower geometric mean fold error and root mean square error. Additionally, incorporating these values into the physiologically based pharmacokinetic-DDI model facilitated a good fitting of the C-t curves when the substrate's metabolic enzymes are inhibited. Second, area under the curve ratio predictions of studied drugs were within a 1.5× margin of error in 81% of cases compared with clinical observations in the validation set. Last, the clinical DDI risk scale developed in this study predicted the actual risks in the validation set with only a 5.6% incidence of serious false negatives. This study offers a rapid and accurate approach for assessing the risk of pharmacokinetic-mediated DDIs in clinical practice, providing a foundation for rational combination drug use and dosage adjustments.

ОЦЕНКА ВЛИЯНИЯ ПОРОШКА BOLETUS EDULIS НА КАЧЕСТВЕННЫЕ ПОКАЗАТЕЛИ СНЕКОВЫХ МЯСНЫХ ИЗДЕЛИЙ

The aim of the study is to evaluate the possibility of using Boletus edulis (porcini mushroom) powder in meat snack recipes. The objectives of the study were: to establish a rational amount of Boletus edulis powder added to the minced meat of snacks, to determine the quality characteristics of the experimental samples and to compare them with those of the control sample, and to develop preparation stages. A control sample was created as a comparison standard based on the recipe for preparing meat snacks from chicken meat. The experimental samples were prepared based on the recipe of the control sample with the addition of a new ingredient, Boletus edulis powder, which was added to the minced meat in various dosages: sample № 1 – 0.1 %; sample № 2 – 0.5 %; sample № 3 – 1 %. Boletus edulis powder was obtained by grinding dried mushrooms to a powder consistency. An organoleptic and tasting assessment of the samples was carried out, based on which the best experimental sample was selected. According to the obtained results of the quality indicators of meat snacks with the addition of Boletus edulis powder, it was found that the rational dosage of the introduced ingredient is 0.5 %. The stages of obtaining meat snacks from chicken meat with the addition of Boletus edulis powder, which is introduced into the minced meat system during the production of minced meat, were developed. Chilled raw white chicken meat (breast) was ground to a minced meat consistency, while the necessary spices were prepared in accordance with the recipe; the casing was pre-soaked in warm water. The next step is mixing the minced meat with spices and filling the casings with it. The resulting loaves were frozen, after which they were peeled from the ca¬sing and cut into small slices, 0.3 mm thick, on a slicer. This was followed by convection drying at a temperature of 60 °C for 2.5 hours. The introduction of Boletus edulis powder into the recipe for meat snacks will improve the consumer properties of meat products, and will also lead to an expansion of the range with an increased content of physiologically significant substances.

Research Progress on the Efficacy and Safety of Different Basal Insulins in the Treatment of Type 2 Diabetes Mellitus

Objective: To evaluate the efficacy and safety of different basal insulins in the treatment of type 2 diabetes mellitus (T2DM). Methods: The current research progress on different basal insulins was evaluated, with efficacy indicators including fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), and safety indicators focusing mainly on weight change and the incidence of hypoglycemia. Results: Several different basal insulins showed similar metabolic control effects in terms of fasting plasma glucose and glycated hemoglobin. However, the risk of hypoglycemia was lower with insulin glargine 300 (Glar-300), insulin degludec 100 (Deg-100), and insulin degludec 200 (Deg-200) compared to insulin glargine 100 (Glar-100). Additionally, Glar-300 had the least impact on weight. Conclusion: For the treatment of T2DM, different basal insulins have similar therapeutic effects, but there are differences in the incidence of hypoglycemic events and their impact on weight. Rational insulin selection and dosage adjustments should be made based on the different patient groups.

Insecticidal potential and risk assessment of diamide pesticides against Spodoptera frugiperda in maize crops

The effectiveness, tolerance, and safety of pesticides must be established before their scientific or rational. This study evaluates the field control efficacy of broflanilide, tetraniliprole, and chlorantraniliprole in combating Spodoptera frugiperda in maize crops, as well as the resistance of S. frugiperda to these three diamide pesticides after exposure. By assessing field control efficiency, toxicity, effects on development and reproduction, and detoxification enzyme activity of these diamide pesticides on S. frugiperda, highlights broflanilide's significant insecticidal potential. A highly sensitive and efficient method using QuEChERS/HPLCMS/MS was developed to simultaneously detect residues of these three pesticides on maize. Initial concentrations of broflanilide, tetraniliprole, and chlorantraniliprole ranged from 2.13 to 4.02 mg/kg, with their respective half-lives varying between 1.23 and 1.51 days. Following foliar application, by the time of harvest, the terminal residue concentrations of these pesticides were all under 0.01 mg/kg. Chronic dietary intake risk assessments and cumulative chronic dietary exposure for three pesticides indicated that the general population's terminal residue concentration was within acceptable limits. Not only does this research provide valuable insights into field control efficiency, insecticidal effects, resistance, residues, and risk assessment results of broflanilide, tetraniliprole, and chlorantraniliprole on maize, but additionally, it also paves the way for setting suitable Maximum Residue Limits (MRLs) values based on pre-harvest interval values, rational dosage, and application frequency.

Physiologically based pharmacokinetic modelling of cefoperazone in paediatrics.

Cefoperazone is commonly used off-label in the treatment of bacterial meningitis and sepsis in children, and the pharmacokinetic (PK) data are limited in this vulnerable population. The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict pediatric cefoperazone exposure for rational dosing recommendations. A cefoperazone PBPK model for adults was first constructed using Simcyp V22 simulator. Subsequently, the model was extended to children based on the built in age-dependent physiological parameters, while the drug characteristics remained unchanged. The verified pediatric PBPK model was then utilized to assess the rationality of the common dosing regimens for children at different age groups. Cefoperazone PBPK model included elimination via biliary excretion, glomerular filtration, and organic anion transporter 3 (OAT3)-mediated tubular secretion. 95.2% of the observed mean concentrations and 100% of the area under the plasma drug concentration-time curve (AUC) and peak concentration (Cmax) in adults were within a twofold range of model mean predictions. Good predictive accuracy was also observed in children, including neonates. 50 mg/kg q12h cefoperazone demonstrated effective target attainment in virtual term neonates (<1 month) when the MIC was ≤1 mg/L, adhering to the stringent PK/PD target of 75% fT > MIC. 37.5 mg/kg q12h cefoperazone achieved the common 50% fT > MIC target for an MIC ≤ 0. 25 mg/L in virtual pediatric patients ranging from 1 month to 18 years of age. A pediatric PBPK model was developed for cefoperazone, and it could serve as the basis for deriving rational dosing regimens in children.

Construction of warfarin population pharmacokinetics and pharmacodynamics model in Han population based on Bayesian method

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. Dosing regimens of sacituzumab govitecan for the EU (<50 kg: 400 mg, 50-80 kg: 600 mg, and >80 kg: 800 mg) and US population (<40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and >90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively. With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.

A real-world disproportionality analysis of the FDA adverse event reporting system events for ibuprofen

ABSTRACT Introduction Ibuprofen is commonly used as an over-the-counter (OTC) antipyretic and analgesic. As the frequency of its use has increased, there has been a corresponding increase in reports of associated adverse events (AEs). However, these events have not been systematically reported in the literature. Meanwhile, the importance of effective pharmacovigilance in evaluating the benefits and risks of drugs is being recognized. Methods The data was obtained indirectly from FAERS using the OpenVigil 2 database, lexically mapped using software such as MySQL, Microsoft Excel, and the R language, and then subjected to four more rigorous algorithms to detect risk signals associated with ibuprofen AEs. Results By analyzing data from the past 18 years, 878 ibuprofen-related AEs were identified as primary AEs. Notably, unexpected reproductive system and breast diseases, etc., which were unexpected, were observed as important system organ classes (SOCs) associated with ibuprofen. Among the 651 preferred terms (PTs) that simultaneously satisfy the four arithmetic methods, renal tubular acidosis and lip oedema are proposed as new signals for ibuprofen AEs. Conclusion This study explores the important and valuable potential AEs and ADRs of ibuprofen at the SOC and PT levels, respectively. To provide a reference on decision-making for ibuprofen to promote rational clinical dosing.

RESEARCH OF THE TECHNOLOGICAL FEATURES OF THE PAVING TILES MANUFACTURE FOR THE IMPROVEMENT OF INDUSTRIAL AND CIVIL FACILITIES

Purpose. The purpose of the scientific article is to substantiate the parameters of the production of high-quality paving slabs and to determine the basic principles of paving technology of road surfaces using paving slabs. The work is based on the experience gained in the field of paving stone production, specifies the basic principles of its production, as well as methods that allow to increase its strength and resistance to the effects of weather conditions, mechanical influences and loads. Methodology. The research was carried out in accordance with the current regulatory documents that regulate the research of construction composites, raw materials for their manufacture and finished products, which were considered in the submitted work. A number of experimental studies of fine-grained concrete have been conducted from the point of view of their physical and mechanical properties and the parameters of the construction of road surfaces from manufactured elements. Findings. When installing paving slabs, it is necessary to take into account not only the quality of the products themselves, but also observe the technology of laying the soil base for paving. It was established that not only the main composition of fine-grained concrete is important. It is determined from which raw materials and under which manufacturing conditions it is possible to obtain high-quality, durable products. An analysis of the compositions that are most widely used in the conditions of modern production of paving stones is given. The most rational dosage of each component, which affects the properties of the working mixture and the finished construction coating, is also given. Originality. The relationship between the combination of components of fine-grained concrete, which allows obtaining high-quality small-sized products for the installation of a road surface, has been established. The list of the most common paving defects that occur during the manufacturing process has been defined and the technological requirements for the preparation of the soil base for the road surface have been established. Practical value. The obtained research results allow to product high-quality paving slabs, which have the necessary indicators for the installation of a durable road surface. The conditions for the preparation of the ground base for the paving of road surfaces are determined and the importance of their observance is substantiated. This will increase the efficiency of work and ensure the comfort of the population.

Characterizing the Nonlinear Pharmacokinetics and Pharmacodynamics of BI 187004, an 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Humans by a Target-Mediated Drug Disposition Model.

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM-1h-1), and the first-order dissociation rate constant (estimated to be 0.11h-1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials.

Residues of chlorpyrifos in the environment induce resistance in Aedes albopictus by affecting its olfactory system and neurotoxicity

Aedes albopictus, a virus-vector pest, is primarily controlled through the use of insecticides. In this study, we investigated the mechanisms of resistance in Ae. albopictus in terms of chlorpyrifos neurotoxicity to Ae. albopictus and its effects on the olfactory system. We assessed Ca2+-Mg2+-ATP levels, choline acetyltransferase (ChAT), Monoamine oxidase (MAO), odorant-binding proteins (OBPs), and olfactory receptor (OR7) gene expression in Ae. albopictus using various assays including Y-shaped tube experiments and DanioVision analysis to evaluate macromotor behavior. Our findings revealed that cumulative exposure to chlorpyrifos reduced the activity of neurotoxic Ca2+-Mg2+-ATPase and ChAT enzymes in Ae. albopictus to varying degrees, suppressed MAO-B enzyme expression, altered OBPs and OR7 expression patterns, as well as affected evasive response, physical mobility, and cumulative locomotor time under chlorpyrifos stress conditions for Ae. albopictus individuals. Consequently, these changes led to decreased feeding ability, reproductive capacity, and avoidance behavior towards natural enemies in Ae. albopictus populations exposed to chlorpyrifos stressors over time. To adapt to unfavorable living environments, Ae. albopictus may develop certain tolerance mechanisms against organophosphorus pesticides. This study provides valuable insights for guiding rational insecticide usage or dosage adjustments targeting the nervous system of Ae. albopictus.

Population pharmacokinetics of lumefantrine and its metabolite, desbutyl-lumefantrine, in children under five years of age with malaria

We developed a population pharmacokinetic model to characterize the Pharmacokinetics (PK) of lumefantrine and its active metabolite, desbutyl-lumefantrine, in children under 5 years. Data were available from 55 children treated for uncomplicated falciparum malaria with standard 3-day Artemether- Lumefantrine (AL) regimen. Combined sparse and intense PK sampling strategy was used to obtain venous samples for 28 days. Using NONMEM, a two-compartment linear pharmacokinetic model incorporating lag time with first order absorption characterized the PK of lumefantrine. Desbutyl-lumefantrine PK was also characterized with a two compartment model. Inter-subject variability in apparent Clearance (CL/F) was explained by Body Mass Index (BMI) and age, while weight partially explained variability in apparent volume of distribution of the central compartment (V2/F). Ontogeny in CYP3A4, the isozyme metabolizing lumefantrine, was incorporated into the age component of lumefantrine CL/F model. Incorporation of BMI into CL/F model explained variability due to weight and stunting. For lumefantrine typical inter-compartment clearance (Q/F), CL/F, V2/F for a typical subject weighing 13.0 kg and BMI 16.62 kg/m2 , and apparent volume of distribution of peripheral compartment (V3/F) were 0.176 L/hr, 3.19 L/hr, 28.1 L, and 58.4 L, respectively. Lumefantrine CL/F was higher in children ≤2 year compared to those &gt;2 years, notably decreased with increasing BMI (-1.10) and age from two to just less than five years (CL/FAGE: -0.423 (-0.648, -0.198)). Results indicate lumefantrine CL/F is a function of age and BMI. Our findings provide structural basis for future evaluation of rational AL dosing guidelines among under five year olds.

THE USE OF LECITHIN OF ORGANIC ORIGIN IN THE TECHNOLOGY OF BAKERY PRODUCTS

The production of bakery products of organic origin has limitations in the use of various ingredients, first of all, 95% of the recipe composition should be of organic production. Organic low-fat sunflower lecithin LECICO SUN P 400 from the German company Lecico has appeared on the market of organic products, which makes it possible to expand the possibilities of improving the quality of bakery products labelled as organic. The purpose of the research is to develop a recipe for an organic loaf with an extended shelf life by using organic low-fat sunflower lecithin LECICO SUN P 400 from the German company Lecico and to study its effect on the consumer characteristics of an organic loaf with an extended shelf life. Based on trial laboratory baking and the calculation of a comprehensive quality indicator, a rational dosage of organic low-fat sunflower lecithin LECICO SUN P 400 in the amount of 0.6 % by weight of flour was established to improve the consumer properties of bakery products. Thus, in the case of adding 0.6 % by weight of flour, the specific volume increased by 9.1 % compared to the control due to an increase in the specific volume of the dough and a weakening of the gluten framework with the introduction of organic low-fat sunflower lecithin LECICO SUN P 400. It was found that the shape stability and porosity of the products are improved. It was found that the use of organic low-fat sunflower lecithin LECICO SUN P 400 prolongs the freshness of bakery products, namely, the degree of preservation of freshness of the products increases by 1.5 times, which is confirmed by a lower degree of crumbling and the formed sub-crust layer during 72 hours of storage. Taking into account the rational dosage of organic low-fat sunflower lecithin LECICO SUN P 400, a recipe for the organic loaf ‘Soniachnyi’ was developed using 100 kg of organic high-grade wheat flour, pressed bakery yeast - 3 kg, table salt - 1.3 kg, organic sugar - 2 kg, organic peasant sweet cream butter - 2.5 kg, organic low-fat sunflower lecithin LECICO SUN P 400 - 0.6 kg

Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development.

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. Although there is much promise in this initiative, there are several challenges that need to be addressed, including multidimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long-term tolerability beyond dose-limiting toxicities, and the lack of reliable biomarkers for long-term efficacy. Through the lens of Totality of Evidence and with the mindset of model-informed drug development, we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.

ВОЗМОЖНОСТЬ ИСПОЛЬЗОВАНИЯ ПОРТУЛАКА ОГОРОДНОГО (PORTULACA OLERACEA L.) ДЛЯ ОБОГАЩЕНИЯ МЯСНЫХ РУБЛЕНЫХ ИЗДЕЛИЙ

The purpose of the study is to identify the possibility of using the aerial part of purslane in cutlet recipes. Objectives: to determine the dosage of purslane in ground turkey meat, ensuring the best quality indicators of the product; to conduct a tasting assessment of the product; to develop a schematic diagram for the production of semi-finished meat and vegetable products. The components for the production of chopped semi-finished meat products complied with the regulatory documentation: turkey meat – in accordance with GOST R 55365-2012 “Mince meat. Technical conditions" and GOST 32951-2014 "Semi-finished meat and meat-containing products. General technical conditions"; chicken eggs – according to GOST 31654-2012 “Chicken eggs for food. Technical conditions"; onions – according to GOST 34306-2017 “Fresh onions. Technical conditions"; black pepper – according to GOST 29050-91 “Spices. Black and white pepper. Technical conditions"; table salt – according to GOST R 51574-2018; vegetable oil – according to GOST 1129-2013; breadcrumbs – according to GOST 28402-89. Organoleptic and tasting assessment of finished products was carried out in accordance with GOST 31986-2012 (GOST 7269-2015 and GOST 9959-2015) on a 5-point scale. A recipe was developed for turkey meat cutlets with the addition of a plant component – purslane. Purslane was collected in the vicinity of Krasnoyarsk and was added crushed to minced meat in dosages from 3 to 9 % in increments of 3 instead of raw meat. The study of the organoleptic characteristics of the finished minced meat product showed that the rational dosage introduced into the meat cutlet mass of the vegetable ingredient is 6 % of the mass of the minced meat. The test sample with the introduction of 6 % plant component received the highest rating from tasters. Stages for the production of cutlets have been developed with the addition of chopped aerial parts of purslane to the recipe. The use of purslane in the recipe for chopped semi-finished meat products will help expand the range of this type of product, improve the consumer properties of meat products, increase the content of essential components in the composition, and reduce costs.

ПЕРСПЕКТИВЫ ИСПОЛЬЗОВАНИЯ ЯГОДНОГО СЫРЬЯ В РЕЦЕПТУРАХ ТУШЕНОГО МЯСА ИЗ ОЛЕНИНЫ

The purpose of the study is to determine the possibility of using berry raw materials - cowberries and Siberian juniper in the recipe for venison stew and to assess the quality characteristics of the product and safety. Objectives: to develop a recipe for venison stew using cowberries and junipers as ingredients; to evaluate the quality and safety of the resulting product. Developed recipes for venison stew with the addition of various amounts of berry raw materials such as cowberries and Siberian juniper are presented. A rational dosage for adding berry raw materials were established, ensuring the best organoleptic characteristics of the product: when adding cowberry to the recipe for venison stew, the amount of cowberries chosen is 3 %, when adding juniper berries – 0.15 %. The study of physicochemical, microbiological indicators and safety was carried out in a test sample containing 3 % cowberries and 0.15 % dried juniper berries, which received the best organoleptic and tasting assessment. The developed product from deer meat with cowberries and juniper berries meets the requirements of GOST 32125-2013 in terms of physical and chemical parameters. In terms of microbiological indicators and safety, venison stew with berry components complies with TR CU 034/2013 “On the safety of meat and meat products” and TR CU 021/2011 “On the safety of food products”. From the results obtained it follows that stewed deer meat with the addition of cowberries and Siberian juniper meets the regulatory standards in terms of quality characteristics and safety and is recommended for production.

Therapeutic drug monitoring in pregnancy: Levetiracetam.

Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Effects of (-)-epicatechin on hepatic triglyceride metabolism.

(-)-Epicatechin (EC) consumption is associated with an improvement of hyperlipemia and other metabolic changes linked to obesity and western-style diets. This work investigated the effects of EC on triglyceride (TG) metabolism both in vivo, where mice were supplemented with EC (2 and 20 mg EC per kg body weight), and in vitro, when human HepG2 hepatocytes were incubated in the presence of EC and the main EC metabolites found in human plasma. Increased hepatic TG levels were only observed after 24 weeks supplementation with EC (20 mg per kg body weight), with a preserved liver structure and absence of inflammation or oxidative stress. EC caused increased expression of diacylglycerol acyltransferases (DGAT2), key enzymes in TG synthesis, and the upregulation of PPARα, which promotes free fatty acid (FFA) oxidation. On the other hand, incubation of HepG2 cells in the presence of high concentrations of EC (1-10 μM) did not affect TG deposition nor DGAT2 expression. In summary, in mouse liver, EC upregulated mechanisms that can neutralize the potential toxicity of FFA, i.e. TG synthesis and FFA β-oxidation. Results in mouse liver and HepG2 cells stress the safety of EC in terms of TG metabolism and development of hepatopathies in doses within the limits given by a rational time and dose for human consumption.