В районах падения первой ступени ракеты-носителя в зоне Ю-4 и на сопредельной территории (Улытауский район Улытауской области и частично в Амангельдинском районе Костанайской области) проведено систематическое исследование речной воды для оценки гидрохимических процессов, источников загрязнения и качества воды с использованием комплексного подхода, необходимого для контроля загрязнения компонентами ракетного топлива. В статье представлены наиболее широко используемые модели индекса качества воды (ИКВ): метод взвешенных арифметических показателей (Weighted Arithmetic Index Method developed by Brown et al., 1972), индекс качества воды Канадского Совета министров по окружающей среде (Canadian Council of Ministers of the Environment Water Quality Index). Модель ИКВ позволяет преобразовывать обширные данные о качестве воды в одно значение или индекс. Во всем мире модель ИКВ применяется для оценки качества воды (поверхностных и подземных вод) на основе местных критериев качества воды. В этом исследовании подчеркивается, что необходима надлежащая очистка речных вод перед их использованием для различных целей. Рассчитанные коэффициенты корреляции Пирсона показывают, что между определенными параметрами существует положительная и отрицательная корреляция.

Introduction. About a quarter of the world's population suffers from helminthic invasion. Praziquantel is a drug for the treatment of helminthiasis caused by cestodes and trematodes. The development of generic drugs for the fight against helminthiasis in Russia seems to be relevant.The aim of the study was to compare the pharmacokinetics profiles of generic Praziquantel and Biltricid® (reference drug), to assess their safety during their bioequivalence study.Materials and methods. An open, randomized, crossover, four-period, replicative design study was conducted on 32 male healthy volunteers.Results. Similar pharmacokinetic profiles of praziquantel were found when volunteers took Praziquantel and Biltricid®. According to the analysis of variance, the main factors that make a significant contribution to the observed variability of the data were interindividual differences in volunteers and the sequence of taking drugs. 90% CI of the ratios of AUC0-t, AUC0-∞, and Cmax of the tested drug to the reference one were in the range of 80-125%. Praziquantel preparations have been found to have a satisfactory safety profile.

Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics.The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions.Materials and methods: the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto®, 10 mg filmcoated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once; blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS).Results: no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto®, respectively: Cmax of 134.6 ± 58.0 ng/mL and 139.9 ± 49.3 ng/mL, AUC0–48 of 949.7 ± 354.5 ng×h/mL and 967.6 ± 319.9 ng×h/mL, AUC 0–∞ of 986.9 ± 379.7 ng×h/mL and 1003.6 ± 320.4 ng×h/mL, T1/2 of 8.2 ± 3.2 h and 7.8 ± 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0–48, and AUC0–∞ geometric means were 88.04–108.67%, 89.42–104.92% and 89.44–104.81%, respectively.Conclusions: the test product Rivaroxaban and the reference product Xarelto® were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products.

The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism’s level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer.

Introduction. Gestobutanoil is a synthetic pregnane steroid with gestagenic activity. Gestobutanoil has two pharmacologically active metabolites (AMOL and megestrol acetate). This implies the need for a detailed study of the kinetics of metabolites. It is rational to combine the study of the pharmacokinetics of gestobutanoil and its metabolites (AMOL and megestrol acetate). The simultaneous determination of several analytes in the rats’ serum can be carried out using chromatography-mass-spectrometry.Aim. Development of an analytical method for the simultaneous determination of gestobutanoil and two its metabolites in a biomatrix (rat serum).Materials and methods. The following methods were used to determine gestobutanoyl and two its metabolites in a biological matrix: GC-MS, HPLCESI-MS, HPLC-ESI-MS with derivatization, HPLC-APCI-MS.Results and discussion. When working with GC-MS, the chromatographic peaks of gestobutanoyl, AMOL, and megestrol acetate were strongly blurred and superimposed on each other, which is apparently due to the thermolability of the substances. The GC-MS method was abandoned in favor of HPLC. Analytes were separated by HPLC gradient elution on a C18 column. ESI ionization did not give typical protonated ions of gestobutanoyl and AMOL, and the intense signals of their cationized ions and fragment ions, which were observed in the spectra of AMOL and gestobutanoyl, could not ensure the reproducibility of the spectra, since the conditions of their formation are not suitable for routine analysis. Derivatization of analytes to form oximes and substituted hydrazones did not give the expected reaction products for HPLC-ESI-MS. APCI made it possible to remove intense cationized ions from the spectra of gestobutanoyl and AMOL and to increase the reliability of the method. The HPLCAPCI-MS technique was reproduced on model rat blood serum.Conclusion. An HPLC-MS method was developed for the simultaneous determination of gestobutanoyl, megestrol acetate, and AMOL. The technique was tested on a model rat blood serum containing all three analytes.

Background. Anagrelide is used for the treatment of essential thrombocythemia. This drug selectively affects thrombocytes without inducing pronounced myelosuppression, which provides a satisfactory safety profile. Aim. To compare pharmacokinetics and to assess bioequivalence of two anagrelide drugs for oral administration in healthy volunteers. Materials & Methods. Open, randomized, two-period, twosequence, crossover study comparing pharmacokinetics and bioequivalence of anagrelide included 30 volunteers. The participants received a single dose of either test or reference drug, depending on the study period. Serial blood samples for pharmacokinetic analysis were collected within 12 hours after drug administration. Plasma anagrelide concentration was measured by high-performance liquid chromatography/mass spectrometry. Pharmacokinetic parameters were analyzed by non-compart-mental method. ANOVA analysis of variance was used for assessing the difference between the mean values of the AUC0-t, AUC0_ and Cmax pharmacokinetic parameters at 5 % significance level. Results. The mean values of maximum concentration (С ) after a single dose of anagrelide were 12.68 ± 2.99 ng/mL and 12.46 ± 3.15 ng/mL for test and reference drugs, respectively. Relative bioavailability was 1.16 ± 0.18. The AUC0-12 mean values calculated by anagrelide concentrations after a single dose of test and reference drugs were 30.38 ± 7.0 ng • h/mL and 28.78 ± 7.50 ng • h/mL, respectively, and the AUC0_ mean values were 31.13 ± 7.15 ng • h/mL and 29.55 ± 7.61 ng • h/mL, respectively. The assessment of main vital functions and laboratory parameters did not reveal any effect of the drugs on the health status of trial participants. Conclusion. Pharmacokinetic profile of the test drug (generic anagrelide) did not considerably differ from that of reference drug, which indicates in vivo bioequivalence of it. The assessment of drug safety yielded satisfactory tolerance; no serious adverse events have been reported.

Представлены результаты разработки ВЭЖХ-методики количественного определения меропенема в плазме крови человека для терапевтического лекарственного мониторинга в условиях стационара. Детектирование осуществляли спектрофотометрически при 298 нм, время хроматографирования составило 12 мин. Методика валидирована по основным параметрам, при этом линейность наблюдалась в широком диапазоне концентраций (от 0,2 до 150 мкг/мл), а нижний предел количественного определения составил 0,2 мкг/мл. Коэффициент корреляции градуировочной кривой составил 0,9998. Нижний предел количественного определения на уровне 0,2 мкг/мл обеспечивает необходимую чувствительность методики. Показана применимость разработанной методики для оперативного контроля содержания меропенема в плазме крови пациентов, что позволяет индивидуализировать дозы препарата и повысить эффективность и рациональность антибактериальной терапии.

The development of an HPLC method for quantitative determination of meropenem in human blood plasma for therapeutic drug monitoring in clinics is reported. Spectrophotometric detection was made at 298 nm. The chromatography time was 12 min. The method was validated for the basic parameters and was linear over a wide concentration range (from 0.2 to 150 ìg/mL). The lower limit of quantitation was 0.2 ìg/mL, which provided the required method sensitivity. The correlation coefficient of the calibration curve was 0.9998. The developed method was shown to be applicable for real-time monitoring of the meropenem content in patient blood plasma, which allowed the dose to be personalized and the efficacy and rationality of the antibacterial therapy to be increased.

Для сравнительного анализа содержания дабигатрана в крови были взяты 2 разные методики из литературы для сопоставления результатов экспериментов по эффективности и точности. Исследование проведено на 30 пациентах, которые перенесли операцию на коленном суставе. Плазму крови отбирали у больных, которые проходят антикоагулянтную терапию и принимали препарат в дозе 220 мг. Остаточные и пиковые концентрации дабигатрана определяли методом ВЭЖХ-МС и ВЭЖХ-МС/МС.

Разработана и валидирована ВЭЖХ-МС методика одновременного количественного определения нового гестагенного фармакологического средства и 2 его метаболитов в сыворотке крови крыс и кроликов. Метод селективен и специфичен. Предел обнаружения для всех аналитов составил 5 нг/мл, нижний предел количественного определения — 10 нг/мл. Для всех аналитов калибровочные кривые имели вид: y = ax + b. Коэффициенты корреляции > 0,99. Изучены эффект влияния матрицы и степень извлечения, а также стабильность аналитов в стандартных растворах, готовых пробах и биоматрице при многократном замораживании и размораживании.

The aim of the study is to evaluate the metabolism of progestin drug Gestobutanoil in the experiment with administration of tablet dosage form containing Gestobutanoil (2 mg), to experimental animals (rats and rabbits). Materials and Methods. There was performed analysis of biomatrix obtained from different species of animals: female rats weighing 200.0 +/- 60.0 g and female rabbits weighing 3.0 +/- 0.2 kg, which were administered different doses of the drug, single or multiple. Metabolites were identified using high performance liquid chromatography-mass spectrometry (HPLC-MS). Results. The analysis shows that Gestobutanoil is rapidly metabolized into 17 alpha-acetoxy-3 beta-hydroxy-6-methylpregna-4,6-dien-20-one (AMP-17) and 17-hydroxy-6-methylpregna-1,4-diene-3,20-dione in the form of acetate (MA). The steroid core of Gestobutanoil has the butyric acid radical in the 3 beta position. This radical cleavage underlies biotransformation of Gestobutanoil. The obtained pharmacokinetic parameters for metabolites have demonstrated that Gestobutanoil has a stepwise nature of metabolism: the time to reach the maximum concentration of AMP-17 is 1.5 h, MA - 3 h. Also AMP-17 proves to penetrate into the peripheral tissues better than MA. Conclusion. The data obtained speak of a unique, different from other gestagens, metabolism of Gestobutanoil. Unlike the known progestogen medroxyprogesterone acetate whose main route of transformation is hydroxylation of the steroid nucleus of the molecule with rather high bioavailability in an unchanged state, Gestobutanoil shows rapid biotransformation into metabolites AMP-17 and MA manifesting their own gestagenic activity with release of butyric acid, which, in turn, may produce a calming effect on the central nervous system.

Several issues with pharmacokinetic studies of new drugs, in particular, experiment planning, development of study protocols, dose selection, and administration routes, are reviewed. The number of used animals is justified statistically with respect to bioethics. The pharmacokinetic study protocol is discussed in more detail according to domestic regulatory requirements. Modern approaches to combining bioanalytical methods with pharmacokinetic studies are described.

An HPLC-MS method for simultaneous quantitative determination of a novel gestagenic pharmaceutical and two of its metabolites in rat and rabbit blood sera was developed and validated. The method was selective and specific. The detection limit for all analytes was 5 ng/mL; lower limit of quantitation, 10 ng/mL. Calibration curves for all analytes had the form y = ax + b. The correlation coefficients were >0.99. Matrix effects, degree of extraction, and stability of analytes in standard solutions, analytical samples, and the biomatrix with multiple freeze—thaw cycles were studied.

A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 x 4.6 mm, 5 mu m)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was < 5.6% and the between-run precision was < 3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.

Рассмотрены некоторые вопросы изучения фармакокинетики новых лекарственных средств, в частности, планирование эксперимента, разработка протокола исследования, выбор доз, путей введения. Приведено статистическое обоснование количества используемых животных с точки зрения биоэтики. Процедура исследования фармакокинетики рассмотрена более подробно в соответствии с требованиями отечественных нормативных документов. Описаны современные подходы применения биоаналитических методов при сопровождении фармакокинетических исследований.

Two different literature methods were used to compare the experimental efficacy and accuracy of dabigatran assays in blood of 30 patients with knee replacements. Blood plasma was collected from patients who underwent anticoagulant therapy and were administered the medicine at a dose of 220 mg. Residual and peak dabigatran concentrations were determined by HPLC-MS and HPLC-MS/MS.

Представлен анализ данных литературы, отечественных и зарубежных методических документов по доклиническим исследованиям безопасности и токсикокинетики лекарственных средств. Согласно Правилам регистрации и экспертизы лекарственных средств для медицинского применения ЕАЭС в общий технический документ разработчик обязан включать сведения о токсикокинетических исследованиях, которые подлежат оценке при проведении экспертизы результатов доклинических исследований. Сформулированы основные подходы к экспертной оценке результатов токсикокинетических исследований лекарственных средств. Определено основное содержание экспертного анализа, включающего методологическую базу исследований, результаты исследований, характеристику профиля безопасности, экстраполяцию доклинических данных, характеристику факторов риска и прогнозируемого профиля клинической безопасности для пациентов. Включение токсикокинетических исследований в программу доклинического токсикологического изучения имеет принципиальное значение для адекватной экстраполяции экспериментальных данных и прогноза безопасности применения лекарственных средств у человека. Экспертный анализ токсикокинетических данных позволяет оценить корректность интерпретации результатов токсикологических исследований, характеристики профиля токсичности лекарственного средства и риска развития токсических эффектов.

Разработан и валидирован метод ВЭЖХ-МС/МС количественного определения нового противотуберкулезного лекарственного средства PBTZ169 в сыворотке крови, моче и фекалиях с использованием внутреннего стандарта — периндоприла. Метод селективный и специфичный, правильный и прецизионный. Калибровочные кривые линейны в диапазоне 2 – 2000, 5 – 3000 и 100 – 10000 нг/мл для сыворотки крови, мочи и фекалий, соответственно. Коэффициенты корреляции > 0,99. Пределы обнаружения PBTZ169 составили 1, 2,5 и 50 нг/мл для сыворотки, мочи и фекалий, соответственно. Предел количественного определения в сыворотке — 2 нг/мл, в моче — 5 нг/мл, в фекалиях — 100 нг/мл.

Literature data and domestic and foreign methodological documentation for preclinical studies of the safety and toxicokinetics of pharmaceuticals are analyzed. According to Marketing Authorization and Assessment Rules for Medicinal Products in the EAEU, a developer must include in a General Technical Document information on toxicokinetic studies that is evaluated during a review of preclinical test results. The main approaches to expert evaluation of drug toxicokinetic studies are formulated. The main content of the expert analysis includes the methodological basis and results of the research, safety profile characteristics, extrapolation of preclinical data, risk factor characteristics, and predicted clinical patient safety profile. The inclusion of toxicokinetic studies in a program of preclinical toxicological studies is important in principle for an adequate extrapolation of experimental data and prediction of the safety of pharmaceuticals in humans. Expert analysis of toxicokinetic data allows toxicology study results, drug toxicity profile characteristics, and the risk of toxic side effects to be interpreted correctly.

An HPLC-MS/MS method for quantitative determination of the new antituberculosis drug PBTZ169 in blood serum, urine, and feces using perindopril as an internal standard was developed and validated. The method was selective, specific, accurate, and precise. Calibration curves were linear in the ranges 2 – 2,000, 5 – 3,000, and 100 – 10,000 ng/mL for blood serum, urine, and feces, respectively, with correlation coefficients >0.99. The detection limits of PBTZ169 were 1, 2.5, and 50 ng/mL for serum, urine, and feces, respectively. The limits of quantitation were 2 ng/mL in serum; 5, urine; and 100, feces.