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Lapatinib is a small molecule, a heterocyclic quinazoline derivative. The drug is used for targeted therapy of patients with breast cancer, in which there is overexpression of the human epidermal growth factor receptors (HER/ErbB). This review is devoted to studying modern instrumental methods of qualitative and quantitative analysis of lapatinib, which can be used both for quality control and standardization (of bulk pharmaceuticals and dosage forms) and pharmacokinetics studies of a drug. Reverse-phase high-performance liquid chromatography (RP-HPLC) is mainly used to identify lapatinib in tablets. Depending on the purpose of the study, various detectors are used (ultraviolet or diode-matrix detector), which makes it possible to determine not only the native compound but also the products of its degradation. Definition of lapatinib in the presence of degraded products is necessary for forced degradation studies to determine drug stability. When a drug is being developed, it is important to define and understand its pharmacokinetics. For such studies, high-performance liquid chromatography (HPLC) coupled with the mass selective detector is often used. It allows determining lapatinib in biological fluids. However, these methods are not applicable for identifying the drug directly in dosage forms and require further development and validation.

The safety of the new anti-tuberculosis drug Tiozonide was studied by bioinformatics and preclinical methods using laboratory animals and with the participation of healthy volunteers. The absence of toxic effects on the main life support systems of mammals predicted by QSAR models was confi rmed by the results of acute, subchronic and chronic toxicity tests in various laboratory animals. Monitoring of the vital indicators of volunteers and a comparative analysis of the generalized results of these indicators before (screening), during and after the study showed the absence of reliable and clinically signifi cant changes that threaten the life and health of people.

A pharmacokinetic study of the absorption into the bloodstream, bioavailability and excretion of Gamavit from the body after intramuscular administration to laboratory mini-pigs was conducted. Quantitative determination was carried out by HPLC using a fluorimetric detector, for which Gamavit was labeled with Cy5 dye, which was then used for mini-pigs inoculation. The developed methods for determining Gamavit in the blood and feces were validated according to the following validation parameters: selectivity, calibration curve, accuracy, precision, limit of quantitative determination, sample transfer, and sample stability. The confirmed analytical range of the method for Gamavit detection in blood plasma and feces was 1.00…50.0 mcg/ml. Maximum concentration of Gamavit in the blood of mini-pigs after a single intramuscular injection was 30.97 mcg/ml and was reached on average 15 minutes after administration. 24 hours following administration, Gamavit was still detected in the blood in insignificant amounts. The average half-life of Gamavit in the blood is 8.64±3.50 hours. After administration at a dose of 0.1 ml/kg, the clearance of the drug is 1.27 l/kg * h, the excretion rate at an effective concentration of 30 mg/l is 38 mg/kg*h, and the maintenance dose when using the drug 1 time a day is 0.9…1.0 ml. The detection of the label in the feces of the studied animals indicates that one of the ways Gamavit removal is excretion with the help of bile acids, as well as partial excretion with feces.

A bioequivalence (BE) study is one of the key stages of investigations required for the registration of oral generic drugs. The planning of this type of study is determined by many factors, including the linearity of the pharmacokinetics of the active substance. The choice of the drug dose for a BE study will depend on this property in registering several drug strengths. Regulatory requirements for planning BE studies of drugs with non-linear pharmacokinetics are considered using atazanavir and valaciclovir as examples. An analysis of protocols and reports of BE studies received by the SCEEMP according to the State Drug Registry and open published data on BE revealed differences in both the tested drug dosages and the number of tests performed. All characteristics of the given active substance, available literature data, international experience, and current regulatory requirements should be taken into account in planning and evaluating BE studies of drugs with non-linear pharmacokinetics.

The aim of the study was to evaluate the subchronic and chronic toxicity of the substance – thiosonide - in experiments on rabbits and rats. The animals received doses ranging from therapeutic to 75 times higher. The drug in studied doses did not cause any significant changes in body weight increase of animals, behavioral reactions, food and water consumption. There were no changes in the biochemical and cellular composition of peripheral blood, the protein-synthesizing function of the liver, carbohydrate metabolism, and the functional state of the cardiovascular system. In the work of the central nervous system, a slight decrease in motor activity was observed in male rats that were long-term treated with a drug substance in a dose of 100 mg/kg (more than 10 times higher than the therapeutic dose). A local irritant effect in the gastrointestinal tract of experimental rats was noted according to the results of histological studies, most pronounced under the influence of the drug at a dose of 100 mg/kg. According to the results of histological studies, minor dystrophic changes in the liver, kidneys and myocardium were found in some animals under the influence of a drug substance at a dose of 100 mg/kg. Thus, the active substance of the anti-tuberculosis drug does not have toxic properties that limit its long-term use, which allows us to consider it as a promising tool for inclusion in the basic long-term courses of treatment of the disease.

Veratrum poisonings are described in the toxicology literature as multiple Veratrum species grow in different parts of the Northern Hemisphere and are occasionally ingested by mistake. Veratrum toxicity is attributed to the steroidal alkaloids contained in all parts of the plant. In Russia, Veratrum poisonings are more common since there is an over-the-counter Veratrum lobelianum-based tincture, Veratrum Aqua (VA), which is topically used for the treatment of lice infestation. Despite its toxicity, VA is misused in traditional medicine as a remedy for alcohol use disorder. We describe four cases of VA poisoning that occurred in Moscow, Russia. Three main V. lobelianum alkaloids (jervine, protoveratrine A (proA) and protoveratrine B) were determined in patient plasma and urine samples using liquid chromatography–tandem mass spectrometry (LC–MS-MS). Here, we describe a novel validated LC–MS-MS method for jervine and proA quantification. A simple and rapid liquid–liquid extraction with methyl tert-butyl ether was utilized for analyte extraction. Chromatographic separation was achieved using a Poroshell 120 EC-C18 column, and the total run time was 14 min. The lower limit of quantification was 0.1 ng/mL for jervine and proA in both plasma and urine. Biological samples were obtained upon hospital admission and during treatment, thus enabling to get a better understanding of the alkaloid elimination profile. Upon admission, plasma concentrations of jervine (concentration range: 0.10–5.01 ng/mL) prevailed over proA (concentration range: 0–0.67 ng/mL). At this time, proA already reached maximum concentrations in urine (concentration range: 0.15–37.70 ng/mL). Maximum concentrations of jervine in urine were observed 24 h after admission (concentration range: 0.10–9.55 ng/mL). In all cases, plasma concentrations of Veratrum alkaloids correlated with condition severity. Since none of the patients confirmed VA intake, instrumental analysis was the basis for the definitive diagnosis of VA poisoning.

Acute hellebore poisoning is characteristic for the Russian Federation because of the use of this plant for the treatment of alcoholism at home. The varying severity of clinical symptoms, which sometimes become lifethreatening, the lack of anamnestic reliable information about the use of hellebore and the difficulties of chemical and toxicological confirmation of its use complicate the diagnosis of acute poisoning, and do not allow timely medical care. In addition, there is no classification of hellebore poisoning in ICD-10, block (T51-T65), which also affects the assessment of the actual frequency of this acute intoxication. The purpose of this work is to clarify the number of acute hellebore poisoning in the Russian Federation. The analysis of medical records of patients hospitalized with acute hellebore poisoning in toxicological departments of a number of subjects of the Russian Federation for 2014 - 2018 was carried out. The dynamics of such acute poisoning over the specified period, the gender and age composition of victims, and the circumstances of poisoning were revealed. The relevance of developing methods of chemical and toxicological analysis for the determination of hellebore alkaloids is confirmed, which will increase the reliability of diagnosis and detection of cases of hellebore poisoning.

This article analyzes the application of the method for determining the activity of CYP3A4 by determining the concentration of endogenous cholesterol and its metabolite/4-hydroxycholine in blood plasma. It also provides information on the convergence assessment of data obtained using alternative methods for determining the activity of the same CYP450 isoenzyme (CYP3A4) using different substrates: cholesterol and cortisol.

Issues with planning bioequivalence studies of lopinavir/ritonavir (LPV/RTV) preparations are discussed. LPV is an antiviral (HIV) medicine and HIV protease inhibitor that was developed in a fixed-dose combination with RTV. According to existing RF legislation, results from bioequivalence studies with a reference drug must be submitted to register generics. Protocols and reports of bioequivalence studies of LPV/RTV film-coated tablet dosage forms that were submitted for review to the SCEEMP, MHRF, are analyzed. The number of administered tablets and duration of sample collection differed slightly in the study designs. The number of volunteers included in the study differed more substantially and was calculated based on the intra-subject coefficient of variation of LPV/RTV. A search of the internet for data on the variability of LPV/RTV found several results indicating that LPV/RTV was highly variable (30%). Recommendations for planning bioequivalence studies of LPV/RTV preparations are formulated based on the analysis.

Methods for determining the genotoxic impurity N-nitrosodimethylamine (NDMA) in valsartan drug substance by gas chromatography (GC) with mass-spectrometric detection in SIM and MRM modes using direct introduction and vapor-phase analysis are compared. The obtained LOQ and DL differed insignificantly. The test results led to the conclusion that use of a method corresponding to the capabilities and equipment of the laboratory was advisable.

US FDA requirements published in the new 2018 guidance for bioanalytical method validation and the necessity to confirm their reliability for determining analyte concentrations are reviewed. The history of regulations for bioanalytical method validation is briefly described. The key changes and additions to the FDA guidance for bioanalytical method validation that include unified requirements for chromatographic and ligand-binding method validation, instructions for biomarker validation, a separate section focused on new technologies (e.g., dry blood-spot method), and introduction of the fit-for-purpose concept are discussed. FDA and EAEU requirements for validation of chromatographic assay parameters are compared. In general, the requirements of the new FDA guidance and the EAEU agree despite several differences in the number of parameters and their acceptance criteria.

The flavonoid profile of the lyophilized aqueous extract of Caragana jubata shoots was established based on previous studies. The antimicrobial activity of the lyophilizate was studied in vitro using a screening method for determining the antimicrobial activity of herbal preparations because the flavonoids were potential microorganism inhibitors according to the literature. The bacteriostatic and fungistatic activity was studied in vitro using double serial dilutions of the preparations in liquid growth media. The results revealed moderate antimicrobial activity of the lyophilized aqueous extract of C. jubata against all tested strains of pathogenic Gram-positive and Gram-negative bacteria (S. aureus, E. coli, P. vulgaris, P. aeruginosa) and yeast-like and mycelial fungi (C. albicans, M. canis). The results allowed the lyophilized aqueous extract to be recommended for treating skin and mucous membrane diseases associated with bacterial inflammatory processes.

Aim. Investigation of comparative dissolution kinetics of generic medicinal products containing moxonidine versus reference drug. Material and methods. Objects of the research were film-coated tablets containing moxonidine (INN) in a dose 0.4 mg: a reference drug Physiotens® and 4 generic drugs. In vitro dissolution test of moxonidine from the study drugs was performed using comparative dissolution kinetics test (CDKT). The CDKT was performed in the media with the following pH: 1.2 (1:9 mixture of 0.1 M hydrochloric acid and water), 4.5 (acetate buffer solution, prepared as per State Pharmacopoeia, XIII), and 6.8 (phosphate buffer solution, prepared as per State Pharmacopoeia, XIII). The sampling for dissolved moxonidine was performed 5, 10, 15, 20, and 30 min after the test was started. An high performance liquid chromatography method with ultraviolet detection at 220 nm was used to assay. Results. Within 15 min more that 85% of moxonidine dissolved from the reference drug and all study drugs at pH 1.2; dissolution profiles were similar without calculation of similarity factor f2. Similarly, at pH 4.5 dissolution profiles of study drugs #2 and #3 were similar to that of the reference drug, and the similarity factor f2 was not calculated. However, in case of study drugs #1 and #4 significant differences were observed at a single time point (15 min), which suggests that their dissolution profiles are non-similar to that of the reference drug. Similarity factors f2 were calculated 17.52 and 35.30, respectively (less than 50). At pH 6.8 similarity factors f2 for all study generic drugs were also less than 50 (23.8, 49.8, 38.6, and 35.9), so their dissolution curves were non-similar to that of reference drug. Conclusion. In our study we observed difference in release in vitro of medicinal products containing moxonidines: none of the study drugs was fully similar to the reference drug in all media. The differences observed at pH 6.8 were noteworthy, where the samples had or faster kinetics (study drugs #2 and #3), or slower dissolution kinetics (test drugs #1 and #4). Observed differences in moxonidine release rate may impact absorption of active pharmaceutical ingredient into the blood following drug administration.

The development of peptide-based drugs, which are usually synthetic analogues of endogenous peptides, is currently one of the most topical directions in drug development. Among them, antitumor peptide-based drugs are of great interest. Anticancer peptides can be classified into three main groups based on their mechanism of action: inhibitory, necrosis-inducing and pro-apoptotic peptides. As an antitumor therapy, peptides are considered to have at least the same efficacy as chemotherapy or surgical treatment, but offer advantages in terms of safety and tolerability, given that chemotherapy is usually characterized by severe adverse effects, and surgery carries additional risks for patients. Short peptides have a number of benefits over other molecules. First, compared with full-length proteins and antibodies, short peptides are less immunogenic, more stable ex-vivo (prolonged storage at room temperature), and have better tumor or organ permeability. Moreover, the production of such short peptide-based drugs is more cost effective. Second, in comparison with small organic molecules, peptides have higher efficacy and specificity. Finally, due to the fact that the main products of peptide metabolism are amino acids, these drugs are usually characterized by lower toxicity. Short peptides have a highly selective mechanism of action, thereby demonstrating low toxicity. Furthermore, with the addition of different stabilizing structural modifications, as well as novel drug delivery systems, the peptide-based drugs are proving to be promising therapeutics for cancer mono- or polytherapy. However, challenges remain including that endogenous and synthetic peptide molecules can be oncogenic. Therefore, it is important to investigate whether peptides contribute to tumor growth. In order to answer such questions, numerous preclinical and clinical studies of peptide-based therapeutics are currently being conducted.

Planning issues for darunavir (DRV) bioequivalence studies are considered. DRV is an antiviral (HIV) agent classified as an HIV protease inhibitor. Bioequivalence test results must be submitted for registration of generic drugs in the RF according to Federal Law 61-FZ. Bioequivalence study protocols and reports for DRV preparations that were submitted for review to the SCEEMP were analyzed. Differences in study designs including administration after fasting or meals, with or without a low dose of ritonavir, numbers of volunteers included in the study, and intra-subject variability were found. The internet was also searched for data on DRV variability. Recommendations for planning bioequivalence studies of DRV preparations were formulated based on the analysis.

The aim of this study was to evaluate marine algae extracts in terms of their anti-inflammatory activity using a combination of chromatographic separation and chemical detection with subsequent infrared vibrational spectroscopy identification. Extraction parameters, chemical fingerprint, and the activity levels were considered for the method optimization. High-performance thin-layer chromatography (HPTLC) combined with microchemical derivatization, was used to separate and detect bioactive compounds with antioxidant activity and anti-inflammatory activities, and to detect different classes of terpenoids. Infrared attenuated total reflectance (ATR) spectral analysis of the bands with bioactive compounds, identified sulfated polysaccharides to be responsible for the anti-inflammatory activity in extracts of brown algae Carpoglossum confluens and Phyllospora comosa. Steroids as unique antioxidants with significant free radical scavenging activities were observed in extracts of brown algae Cystophora platylobium, Cystophora retorta, Carpoglossum confluens and Phyllospora comosa. HPTLC combined with biochemical assays and FTIR-ATR spectrometry was demonstrated to be a straightforward strategy for bioprofiling marine algae extracts.

Mathematical modeling of pharmacokinetic (PK) and pharmacodynamic (PD) parameters essential for establishing correct dosing regimens is an alternative to pharmacokinetic studies (PKS) adopted in the clinical setting. The aim of this work was to compare the values of PK parameters for vancomycin obtained in an actual PKS and through MM in postoperative patients with kidney injury. Our prospective study included 61 patients (47 males and 14 females aged 60.59 ± 12.23 years). During PKS, drug concentrations at steady state Сtrough and Cpeak were measured by high-performance liquid chromatography followed by the calculation of the area under the plasma concentration-time curve AUC24. For mathematical modeling, a single-compartment model was employed; PK parameters were estimated using R 3.4.0. The values of Ctrough measured 48 h after the onset of antibiotic therapy during PKS were significantly lower than those predicted by MM (р = 0.004). In a group of patients with acute kidney injury (AKI), AUC24 measured at the end of treatment was significantly higher than its value predicted by MM (р = 0.011). The probability of achieving the target AUC24 to MIC ratio of over 400 μg•h /ml is higher in the group of patients with Ctrough = 10–15 μg /ml. Our findings confirm that the use of MM in postoperative patients with renal dysfunction is limited and therapeutic drug monitoring should be used instead.

Literature data on the chemical composition and biological activity of Caragana jubata (Pall.)Poir. (Fabaceae, bean), a new potential source of medicinal raw material that is widely used in Russian folk medicine, were reviewed. Preliminary experiments on the composition of biologically active compounds and the pharmacological activity of the aqueous extract of the aerial part of C. jubata were performed by us. An analysis of the literature data and our results led to the conclusion that polyphenolic compounds (flavonoids), primarily mono- and diglycoside derivatives of O-hydroxylated flavonols, were the dominant fraction of biologically active compounds from C. jubata. According to the literature, C. jubata could possess hepatoprotective and antiviral activity. In vitro antioxidant activity of the aqueous extract of the aerial part of C. jubata, anti-inflammatory and wound-healing activity, and a lack of antibacterial activity against several pharmacopeial strains were found in our research. C. jubata could be recommended for further preclinical and clinical trials for efficacy and safety as a potential medicinal plant based on the information analysis and experiments.

An HPLC-MS/MS method for determination of rivaroxaban in human blood serum was developed. Sample preparation included protein precipitation by MeOH followed by centrifugation and dilution with deionized H2O. The developed procedure had simple sample preparation, a short analysis time, and a wide analytical range (1.00 to 1,000.00 ng/mL). The procedure was convenient for routine bioanalytical studies, in particular, for therapeutic drug monitoring.

Results from experiments conducted for the parameter Residual Organic Solvents during the course of developing a draft regulation for the drug substance of the innovative pharmacological agent thrombaptanib are reported. The structure of the compound is given. Its pharmacological action is described. A list of potential residual organic solvents was compiled by analyzing the synthetic scheme and manufacturing technology. A separate part of the work describes in detail a developed GC-MS procedure for determining residual organic solvents. Validation results of the procedure for Specificity, Linearity, Accuracy, Precision, and Reproducibility are presented. The validation protocol for the procedure at the time of the studies followed domestic guides for validation that were written based on existing international documents because there was no existing GPM for validation in the current edition of the SP RF. A test sample of thrombaptanib was analyzed using the developed procedure for Residual Organic Solvents. The developed procedure was included in the Residual Organic Solvents section of the draft regulation.

Background Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods A total of 60 patients, aged 37-81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p

An HPLC-MS/MS method for determining dabigatran in human blood serum was developed. Samples were prepared by precipitation of proteins using MeOH followed by centrifugation and dilution with deionized H2O. The developed method had a simple sample-preparation procedure, short analysis time, and wide analytical range (from 1 to 1,000 ng/mL). This method was suitable for routine bioanalytical studies, in particular, therapeutic drug monitoring.

Polyphenolic compounds (flavonoids) of lyophilized aqueous extracts from Caragana jubata (Pall.) Poir. raw material from 2010 and 2015 were studied using modern HPLC-DAD-MS. Primarily mono- and diglycosides of O-hydroxylated (myricetin, quercetin, kaempferol) and O-methylated flavonols (isorhamnetin, laricitrin, syringetin) were identified. Long-term storage of dried raw material under standard conditions had little effect on the quantitative content of polyphenolic compounds. Acute toxicity studies of C. jubata extract showed no toxicity.

The aim of the study was to investigate the hepatoprotective activity of an aqueous extract of Caragana jubata (Pall.) Poir. Acute experimental hepatitis was induced by acetaminophen administration of 1000 mg/kg. Studies were conducted in white Wistar rats. The aqueous extract of C. jubata demonstrated the hepatoprotective effect, comparable to that of the reference preparation "Carcil". This was manifested by the normalization of biochemical blood parameters (ALT, AST, alkaline phosphatase, cholesterol, total bilirubin) and antioxidant activity of liver homogenates, determined by the method based on oxidation of luminol induced by 2,2¢-azo-bis-2-amidinopropane. Normalization of morphofunctional indices was also shown in a histological study of liver of rats that received aqueous extract from C. jubata.Tsel'iu issledovaniia bylo izuchenie gepatoprotektornoĭ aktivnosti rasteniia Caragana jubata (Pall.) Poir. (karagana grivastaia) na modeli ostrogo gepatita, indutsirovannogo u krys Wistar vvedeniem atsetaminofena v doze 1000 mg/kg. Ustanovleno, chto vodnoe izvlechenie C. jubata proiavlialo vyrazhennoe gepatoprotektornoe deĭstvie, sopostavimoe s preparatom sravneniia “Karsil”. Éto proiavilos' normalizatsieĭ biokhimicheskikh pokazateleĭ krovi (alaninaminotransferazy, aspartataminotransferazy, shchelochnoĭ fosfatazy, kholesterina, obshchego bilirubina) i antioksidantnoĭ aktivnosti gomogenatov pecheni, kotoruiu opredeliali khemiliuminestsentnym metodom, osnovannym na okislenii liuminola, indutsirovannom 2,2¢-azobis(2-amidinopropanom). Pri gistologicheskom issledovanii vyiavlena normalizatsiia morfofunktsional'nykh pokazateleĭ pecheni krys, kotorye poluchali vodnoe izvlechenie karagany grivastoĭ.

The double anodic C–H functionalization of N-methyl-1H-pyrrole and N,N-dimethylaniline using both thiocyanate and 4-nitro-1H-pyrazolate ions as nucleophiles has been accomplished for the first time. The mild reaction conditions and considerable pharmacological activity of the target products make such C–S and C–N coupling strategy to be highly attractive for further applications.

A high-performance thin-layer chromatography with microchemical derivatization and bioassay guided detection was used for bioanalytical profiling of selected marigold plant extracts. Anisaldehyde/sulfuric acid reagent and thymol/sulfuric acid reagent were used to visualize separated components on the chromatograms. Antioxidant activity and α-amylase inhibition were assessed with 2 bioassays, DPPH assay to detect free radical scavengers and starch-iodine assay method to detect compounds that inhibit α-amylase. The highest antioxidant activity of 10.12 μg of gallic acid equivalents (GAE) per 20 µL of extract was measured in extract from Tagetes flowers and the lowest in the extract from Calendula leaves with 5.10 μg of GAE. Multiple zones of α-amylase inhibition were detected. A detailed analysis of the ATR-FTIR spectra from the bands at RF = 0.24 suggest that faradiol esters and saturated fatty acids esters, palmitic acid, myristic acid, and lauric acid are responsible for α-amylase inhibition, unsaturated fatty acids for the band at RF = 0.51 and phytoecdysteroids for the band at RF = 0.53.

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 × 4.6 mm, 5 µm)) 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 was5.6% and the between-run precision was3.9%. 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.

This review is about the significance of the use of lipidomic analysis for identifying susceptibility to skin diseases., This review is about the significance of the use of lipidomic analysis for identifying susceptibility to skin diseases. Exactly this article describes the use of lipidomic analysis in different studies to detect abnormalities in the lipid composition of the skin to diagnose and prevent various dermatological diseases.

To compare release parameters of various betahistine drugs in vitro using a comparative dissolution kinetics test.Objects of research are solid dosage forms (tablets) containing betahistine in a dose of 24 mg permitted for medical use in the Russian Federation. A method of comparative dissolution kinetics test was carried out as follows. The study was performed on a paddle stirrer at a speed of 50 rpm in three different pH dissolution media (pH 1.2, 4.5, 6.8), simulating the main sections of the digestive tract in which the active ingredient was decomposed, released and absorbed. This was performed in a quality controlled environment using a citrate buffer solution with pH 6.8. The time points for sampling the medium were 10 min, 15 min, 20 min and 30 min.The results of betahistine release were significant (RSD10%) for all time points, except the first time point (RSD20%). Regardless of pH, there was a complete release (≥85% over 15 minutes,10%) of betahistine from betaserc, 24 mg, tablets (manufactured by Mylan Laboratories SAS). The dissolution profiles of betahistine in other investigational drugs did not show complete drug release (parameter85% in 15 minutes,10%) in different pH media. Therefore, dissolution profiles of the studied drugs were not comparable to the reference profile.Starting from 10 minutes, the reference drug of betahistine (betaserc, 24 mg) has a consistently higher release at different pH levels (representing the various stages of gastric digestion), vs. other studied generic analogues showing significantly lower levels of betahistine release. None of the studied drugs were found to be equivalent in vitro.Цель исследования. Провести сравнительный анализ параметров высвобождения различных препаратов бетагистина в условиях in vitro с использованием сравнительного теста кинетики растворения. Материал и методы. Объекты исследования - лекарственные средства в твердой дозированной лекарственной форме (таблетки), содержащие бетагистин в дозе 24 мг, разрешенные к медицинскому применению в Российской Федерации. Методика проведения сравнительного теста кинетикb растворения: исследование проводили на аппарате 'лопастная мешалка' при скорости 50 об/мин в трех средах растворения с различным значением pH (рН 1,2; 4,5; 6,8), моделирующих основные разделы ЖКТ, в которых происходит распадение таблетки, высвобождение и абсорбция активного ингредиента. Также исследование было проведено в среде контроля качества с использованием цитратного буферного раствора с рН 6,8. Временными точками отбора проб среды были 10, 15, 20 и 30 мин. Результаты. Полученные результаты высвобождения бетагистина из всех исследуемых препаратов были признаны достоверными (RSD10%) для всех временных точек, за исключением первой временной точки (RSD20%). Вне зависимости от величины рН наблюдалось полное высвобождение (≥85% за 15 мин, RSD10%) бетагистина из препарата Бетасерк, 24 мг, таблетки (производства 'Майлан Лэбораториз САС'). Профили растворения бетагистина других исследуемых препаратов не обнаружили полного высвобождения лекарственного вещества (85% за 15 мин, RSD10%) в средах с различным рН. Таким образом, профили растворения воспроизведенных препаратов были признаны несопоставимыми референтному. Заключение. Начиная с 10-й минуты, референтный препарат бетагистина (Бетасерк, 24 мг) обладает стабильно высоким высвобождением in vitro при различных параметрах рН (моделирующих различные стадии пищеварения) по сравнению с другими исследуемыми воспроизведенными аналогами, показавшими значительно более низкие уровни высвобождения бетагистина. Ни один из исследуемых препаратов не был признан эквивалентным in vitro препарату Бетасерк, 24 мг, таблетки, согласно тесту кинетики растворения.

The problem of laboratory diagnosis of acute and fatal poisoning by hellebore, which is possible when used in traditional medicine, the erroneous use of hellebore preparations orally or use of various types of this plant for food, remains relevant. Currently, in the practice of chemical-toxicological laboratories and the bureau of forensic medical examination there is no single approach to the laboratory diagnosis of such poisoning. The diagnosis is most often based on anamnesis. In this regard, the development and validation of a legally significant methodology for the determination of hellebore alkaloids in various biological objects seems relevant. The physicochemical and toxic properties of alkaloids of various types of hellebore are characterized. It was shown that for the identification of hellebore alkaloids, it is advisable to use HPLC-MS/MS as the most sensitive and specific instrumental method corresponding to the characteristics of hellebore alkaloids (high molecular weight, high thermal lability, high polarity).Проблема лабораторной диагностики острых и смертельных отравлений чемерицей, которые возможны при использовании ее в народной медицине, ошибочном употреблении препаратов чемерицы внутрь или различных видов этого растения в пищу, сохраняет актуальность. В настоящее время в практике химико-токсикологических лабораторий и бюро судебно-медицинской экспертизы отсутствует единый подход к лабораторной диагностике таких отравлений. Диагноз чаще всего основывается на данных анамнеза. В этой связи представляются актуальными разработка и валидация юридически значимой методики определения алкалоидов чемерицы в различных биологических объектах. Охарактеризованы физико-химические и токсические свойства алкалоидов различных видов чемерицы. Показано, что для идентификации алкалоидов чемерицы целесообразно использовать ВЭЖХ-МС/МС как наиболее чувствительный и специфичный инструментальный метод, соответствующий характеристикам алкалоидов чемерицы (большая молекулярная масса, высокая термическая лабильность, высокая полярность).

2-ethyl-6-methyl-3-hydroxypyridine (EMHP) succinate is the original antioxidant and antihypoxic drug commonly prescribed in Russia. The objective of this study was to develop a rapid, simple and sensitive high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method for EMHP quantitation in rat brain tissue with the use of a bead beating homogenizer. The comparison between two approaches to brain tissue preparation was performed, when spiking the blank brain tissue with EMHP reference standard and internal standard (IS) before and after homogenization step. Chromatographic separation was achieved using Zorbax Eclipse Plus C18 column (1.8 μm, 2.1 × 50 mm) and elution was performed with the mobile phase, consisting of 10 mM of ammonium formate aqueous solution with 0.1% formic acid as solvent A and 0.1% formic acid in methanol as solvent B [44%(А):56%(В), v/v]. Flow rate was 0.4 mL/min and the total run time for each sample analysis was 2.0 min. EMHP and amantadine, IS of this study, were analyzed in positive ionization mode. Ion transitions of m/z 138.0 → 123.0 for EMHP and m/z 152.0 → 135.0 for amantadine were selected in multiple reaction monitoring mode. The developed method for EMHP determination in rat brain samples was validated for selectivity, linearity, accuracy, precision, matrix effects, and stability. The lower and upper limits of quantification were determined to be 1 and 1500 ng/g, respectively. The developed and validated HPLC-MS/MS method was successfully applied to determine EMHP concentrations in rat brain tissue following the intraperitoneal administration at a dose of 3.4 mg/kg.

An analytical review of widely discussed issues on the classification of drugs based on the methods/sources of their preparation and the complexity of their structures is presented. According to the classification, drugs are divided into three types: (A) low-molecular-weight synthetic “conventional” drugs that are completely characterized chemically; (B) biological complex drugs that are not fully characterized chemically (BCD); and (C) non-biological/synthetic complex drugs that are not fully characterized chemically (NBCD). This classification has both scientific and practical significance due to the fact that NBCDs (liposomal drugs, complex iron—carbohydrate complexes, glatiramoids, low-molecular-weight heparins) are similar to BCDs with respect to both structure (a mixture of strongly bound macromolecular fragments not amenable to isolation and complete identification) and biological/pharmacological effects (immunogenicity, insufficient information about the mechanism of action). Recent practice shows that NBCD generic versions in addition to biosimilar drugs are actually not identical to the original drugs because of differences in the manufacturing technology. For this reason, the expedited review and registration of these drugs, which is analogous to that used for conventional low-molecular-weight drugs, seems to be insufficient.

A method for assaying the antituberculosis drug thiozonide in plasma was developed and validated. Sample preparation consisted of precipitation of proteins with acetonitrile. Assay was by HPLC with a mass-selective detector. The method developed here was validated in terms of the following validation properties: selectivity, linearity, accuracy, precision, quantitative detection limit, sample transfer, and solution stability. The analytical range of the method was 1 – 1000 ng/ml thiozonide in plasma. This analytical range allows this method to be used for further studies of the pharmacokinetics of the innovative drug thiozonide.

We present here our results from studies of the pharmacokinetic parameters of the original antituberculosis agent thiozonide, 100-mg capsules (ZAO Farm-Sintez, Moscow) using single increasing doses in different groups of healthy volunteers in a phase I clinical trial.

A method is developed for the detection of some antihypertensive drugs, atenolol, bisoprolol, enalapril, metoprolol, nifedipine and propranolol by gas chromatography coupled with mass spectrometry. It is also applicable to screening in clinical toxicology and the identification of both intact APDs and their metabolites. The chances that propranolol, bisoprolol, atenolol, enalapril, and nifedipine form some artifacts in the analysis are assessed. The structures of these compounds are elucidated and a mechanism of their formation in the chromatograph injector is proposed.

The composition and content of the main biologically active substances (iridoids, flavonoids, hydroxycinnamic acids) of motherwort herb and related preparations were determined using HPLC-UV/MS. The antiradical activity of motherwort raw material and preparations was evaluated in an in vitro DPPH test. The obtained results showed that these methods could be used to evaluate the authenticity and quality of motherwort herb in addition to drugs, extracts, and food supplements based on it.

Fresh-frozen European guelder berry (Viburnum opulus L.) fruits collected in the Tambov, Moscow, and Tver Provinces were studied. The total contents and profiles of biologically active substances (BAS) in European guelder berry fruits were studied, including anthocyanins, proanthocyanidins, flavonones, diydroxycinnamic acids, iridoids, organic acids, and carbohydrates; antiradical activity in the in vitro DPPH test was also studied. These data on specific minor BAS can be used for standardization in assessments of the potential activity of drugs and biologically active food additives based on European guelder berry fruits.

A procedure involving ion-pair HPLC combined with UV detection was developed for determination of the innovative antituberculosis drug perchlozone in human blood plasma and validated in terms of selectivity, calibration curve, accuracy, precision, sensitivity, and stability. The procedure enables determination of the perchlozone concentration in the blood plasmas of patients taking other antituberculosis medication and can be used for both pharmacokinetic investigations and therapeutic monitoring.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing piroxicam in the free acid form are reviewed. Piroxicam solubility and permeability, its therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA), and corresponding dissolution data are taken into consideration. The available data suggest that according to the current biopharmaceutics classification system (BCS) and all current guidances, piroxicam would be assigned to BCS Class II. The extent of piroxicam absorption seems not to depend on manufacturing conditions or excipients, so the risk of bio in equivalence in terms of area under the curve (AUC) is very low, but the rate of absorption (i.e., BE in terms of C max ) can be affected by the formulation. Current in vitro dissolution methods may not always reflect differences in terms of C max for BCS Class II weak acids; however, minor differences in absorption rate of piroxicam would not subject the patient to unacceptable risks: as piroxicam products may be taken before or after meals, the rate of absorption cannot be considered crucial to drug action. Therefore, a biowaiver for IR piroxicam solid oral dosage form is considered feasible, provided that (a) the test product contains only excipients, which are also present in IR solid oral drug products containing piroxicam, which have been approved in ICH or associated countries, for instance, those presented in Table 3 of this paper; (b) both the test and comparator drug products dissolve 85% in 30 min or less at pH 1.2, 4.5, and 6.8; and (c) the test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. When not all of these conditions can be fulfilled, BE of the products should be established in vivo .

A new method for the synthesis of arylthiocyanates from derivatives of aniline, pyrrole, and indole is described. Products had antimicrobial activity. Dithiocyanates N-methylpyrrole and N-phenylpyrrole were active against Candida albicans, Candida tropicalis, Candida krusei, and Aspergillus niger with activity levels comparable to those of fluconazole and amphotericin.

The application of HPLC and UPLC techniques to the analysis of drugs in blood plasma during bioequivalence investigations and clinical monitoring was reviewed. Various methods of sample preparation, chromatography, and detection were considered and their specific features were pointed out.