Pub Date : 2019-09-10DOI: 10.30895/1991-2919-2019-9-3-146-152
O. Goroshko, L. M. Krasnykh, V. Kukes, V. Zozina
The article examines the role of ubiquinone as a redox molecule whose functions consist in electron transport in the mitochondrial respiratory chain and regeneration of endogenous antioxidants. Changes in electron redox pathways cause uncontrolled release of reactive oxygen species, which leads to oxidative stress and development of pathologies. The objective of the study was to determine the content of coenzyme Q10 and its redox status in the human body as a biomarker of oxidative stress in various pathologies. This was achieved by assessing and consolidating data on changes in concentrations of the oxidized, reduced ubiquinone forms and total ubiquinone in various pathologies. Total serum ubiquinone was reduced in patients with chronic heart failure (0.68 μmol/L) compared with the control group (0.97 μmol/L). The redox status, expressed as the [ubiquinol]/ [ubiquinone] concentration ratio, decreased in patients with coronary heart disease (0.49 ± 0.34), diabetes (0.26 ± 0.16) compared with the healthy subjects (1.23–1.41). A negative correlation with malonic dialdehyde was observed. The authors analysed the possibility of assessing the efficacy of statin therapy by plasma ubiquinone concentration in patients. Patients with hyperlipidemia who received statins showed a statistically significant reduction in ubiquinol concentration after taking the drug (from 0.81 to 0.46 μg/mL) and the [ubiquinone]/[total ubiquinone] ratio (from 11 to 10 %), which confirms the potential mechanism of statinassociated muscle injury development. Thus, coenzyme Q10 redox status, as well as the concentrations of oxidized, reduced and total ubiquinone can be effective biomarkers of oxidative stress in cardiovascular diseases, diabetes, as well as an important indicator in evaluating the efficacy of hyperlipidemia treatment.
{"title":"Evaluation of Coenzyme Q10 Redox Status as a Biomarker of Oxidative Stress","authors":"O. Goroshko, L. M. Krasnykh, V. Kukes, V. Zozina","doi":"10.30895/1991-2919-2019-9-3-146-152","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-146-152","url":null,"abstract":"The article examines the role of ubiquinone as a redox molecule whose functions consist in electron transport in the mitochondrial respiratory chain and regeneration of endogenous antioxidants. Changes in electron redox pathways cause uncontrolled release of reactive oxygen species, which leads to oxidative stress and development of pathologies. The objective of the study was to determine the content of coenzyme Q10 and its redox status in the human body as a biomarker of oxidative stress in various pathologies. This was achieved by assessing and consolidating data on changes in concentrations of the oxidized, reduced ubiquinone forms and total ubiquinone in various pathologies. Total serum ubiquinone was reduced in patients with chronic heart failure (0.68 μmol/L) compared with the control group (0.97 μmol/L). The redox status, expressed as the [ubiquinol]/ [ubiquinone] concentration ratio, decreased in patients with coronary heart disease (0.49 ± 0.34), diabetes (0.26 ± 0.16) compared with the healthy subjects (1.23–1.41). A negative correlation with malonic dialdehyde was observed. The authors analysed the possibility of assessing the efficacy of statin therapy by plasma ubiquinone concentration in patients. Patients with hyperlipidemia who received statins showed a statistically significant reduction in ubiquinol concentration after taking the drug (from 0.81 to 0.46 μg/mL) and the [ubiquinone]/[total ubiquinone] ratio (from 11 to 10 %), which confirms the potential mechanism of statinassociated muscle injury development. Thus, coenzyme Q10 redox status, as well as the concentrations of oxidized, reduced and total ubiquinone can be effective biomarkers of oxidative stress in cardiovascular diseases, diabetes, as well as an important indicator in evaluating the efficacy of hyperlipidemia treatment.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"2003 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88325693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-10DOI: 10.30895/1991-2919-2019-9-3-173-176
A. A. Bezyazychnaya, V. K. Shormanov, L. E. Siplivaya
. Cefepime (active substance — cefepime dihydrochloride monohydrate) is a fourth-generation antibiotic with a broad spectrum of action. The study of the chemical and toxicological properties of cefepime is especially relevant because there have been some cases of poisoning with this antibiotic which resulted in a fatal outcome, and because there is a lack of simple and up-to-date methods of its determination. The study objective was to select conditions for cefepime extraction from biological material for subsequent use in forensic examination. Materials and methods: the determination of conditions for cefepime extraction from biological material was performed using model mixtures and included selection of an adequate extracting agent and the required amount of the agent, as well as selection of the duration and number of digestion steps. Identification, purification and quantification of cefepime were performed using thin-layer chromatography and spectrophotometry methods. Results: an acceptable agent that could be used for cefepime extraction from biological material is an acetone-water mixture (1:1), the amount of the extracting component should be twice the amount of the biological material, the time of contact between the extracting agent and the biological material should be at least 30 min. Conclusions: the results of the study allowed us to identify an acceptable extracting agent and the conditions for cefepime extraction from biological material for identification and quantification of the antibiotic during forensic examination.
{"title":"Optimisation of the Procedure of Cefepime Extraction from Biological Material","authors":"A. A. Bezyazychnaya, V. K. Shormanov, L. E. Siplivaya","doi":"10.30895/1991-2919-2019-9-3-173-176","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-173-176","url":null,"abstract":". Cefepime (active substance — cefepime dihydrochloride monohydrate) is a fourth-generation antibiotic with a broad spectrum of action. The study of the chemical and toxicological properties of cefepime is especially relevant because there have been some cases of poisoning with this antibiotic which resulted in a fatal outcome, and because there is a lack of simple and up-to-date methods of its determination. The study objective was to select conditions for cefepime extraction from biological material for subsequent use in forensic examination. Materials and methods: the determination of conditions for cefepime extraction from biological material was performed using model mixtures and included selection of an adequate extracting agent and the required amount of the agent, as well as selection of the duration and number of digestion steps. Identification, purification and quantification of cefepime were performed using thin-layer chromatography and spectrophotometry methods. Results: an acceptable agent that could be used for cefepime extraction from biological material is an acetone-water mixture (1:1), the amount of the extracting component should be twice the amount of the biological material, the time of contact between the extracting agent and the biological material should be at least 30 min. Conclusions: the results of the study allowed us to identify an acceptable extracting agent and the conditions for cefepime extraction from biological material for identification and quantification of the antibiotic during forensic examination.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74914952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-10DOI: 10.30895/1991-2919-2019-9-3-162-166
E. A. Sоkоvа, R. Chilova, O. A. Demidova, K. Akopov
Spontaneous preterm birth is one of the most pressing issues in obstetrics, as it remains one of the leading causes of newborn morbidity and mortality. Pending issues of aetiology, pathogenesis, and absence of medicinal products indicated for the treatment of spontaneous preterm labour pose a challenge for rational pharmacotherapy. The paper presents the results of a scientific literature review on the problem of rational pharmacotherapy of spontaneous preterm labour using tocolytic drugs — calcium channel blockers, cyclooxygenase inhibitors. The paper summarises specific pharmacokinetic parameters of these drugs during pregnancy. It discusses pharmacogenetic aspects of using tocolytic drugs in pregnant women and their potential clinical effects. It was demonstrated that women with threatened miscarriage had high interindividual variability in nifedipine plasma concentrations depending onCYP3A5genotype. It was shown that certain genetic polymorphisms ofCYP2C9may lead to an increased metabolic rate and an increase in indomethacin clearance resulting in the reduction of its efficacy. Yet, there is minimal research regarding this issue. Therefore, further research is needed to assess the impact ofCYP3A5andCYP2C9genotypes on the efficacy and safety of nifedipine and indomethacin used as tocolytic drugs in obstetrics.
{"title":"Clinical Pharmacology Aspects of Some Tocolytic Drugs Used in Pregnant Women at Risk of Preterm Birth","authors":"E. A. Sоkоvа, R. Chilova, O. A. Demidova, K. Akopov","doi":"10.30895/1991-2919-2019-9-3-162-166","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-162-166","url":null,"abstract":"Spontaneous preterm birth is one of the most pressing issues in obstetrics, as it remains one of the leading causes of newborn morbidity and mortality. Pending issues of aetiology, pathogenesis, and absence of medicinal products indicated for the treatment of spontaneous preterm labour pose a challenge for rational pharmacotherapy. The paper presents the results of a scientific literature review on the problem of rational pharmacotherapy of spontaneous preterm labour using tocolytic drugs — calcium channel blockers, cyclooxygenase inhibitors. The paper summarises specific pharmacokinetic parameters of these drugs during pregnancy. It discusses pharmacogenetic aspects of using tocolytic drugs in pregnant women and their potential clinical effects. It was demonstrated that women with threatened miscarriage had high interindividual variability in nifedipine plasma concentrations depending onCYP3A5genotype. It was shown that certain genetic polymorphisms ofCYP2C9may lead to an increased metabolic rate and an increase in indomethacin clearance resulting in the reduction of its efficacy. Yet, there is minimal research regarding this issue. Therefore, further research is needed to assess the impact ofCYP3A5andCYP2C9genotypes on the efficacy and safety of nifedipine and indomethacin used as tocolytic drugs in obstetrics.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76102205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-10DOI: 10.30895/1991-2919-2019-9-3-167-172
V. M. Shchukin, A. Erina, E. A. Lisman, O. A. Vaganova
Algae tend to accumulate elemental toxic substances in high concentrations. Algae are widely used in the food and pharmaceutical industries, and this dictates the need to establish limits for the content of toxic substances that they may contain. The aim of the study was to analyse the requirements of the Russian and foreign pharmacopoeias and other regulatory documents concerning the limits for the content of arsenic in brown algae. The paper presents the results of analysis of monographs from the State Pharmacopoeia of the Russian Federation, XIII and XIV editions, draft version of the Pharmacopoeia of the Eurasian Economic Union, United States Pharmacopoeia, Japanese Pharmacopoeia, European Pharmacopoeia, and Ayurvedic Pharmacopoeia of India containing limits for the content of arsenic in herbal medicinal products (HMPs). In addition, the authors analysed Russian, international and foreign food industry and dietary supplements regulations, as well as scientific publications on arsenic content in brown algae. They also considered the nomenclature of arsenic compounds to be determined and controlled in medicinal products, highlighted the main approaches to and identified global trends in establishing the limits for their content in HMPs. The paper summarises specific aspects of inorganic arsenic compounds accumulation by brown algae. It was demonstrated that the majority of foreign pharmacopoeias either have specific norms for arsenic content in brown algae, which differ from the norms for HMPs, or have general norms that take into account different toxicity levels of organic and inorganic arsenic compounds. There is a tendency to control the content of elemental toxic substances based on their maximum allowable daily intake. The paper substantiates the need for separate determination of toxic inorganic arsenic compounds and potentially toxic methyl arsonate and dimethyl arsinate in HMPs.
{"title":"Problems of Establishing Limits for Arsenic Content in Brown Algae and Brown Algae-Containing Medicinal Products","authors":"V. M. Shchukin, A. Erina, E. A. Lisman, O. A. Vaganova","doi":"10.30895/1991-2919-2019-9-3-167-172","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-167-172","url":null,"abstract":"Algae tend to accumulate elemental toxic substances in high concentrations. Algae are widely used in the food and pharmaceutical industries, and this dictates the need to establish limits for the content of toxic substances that they may contain. The aim of the study was to analyse the requirements of the Russian and foreign pharmacopoeias and other regulatory documents concerning the limits for the content of arsenic in brown algae. The paper presents the results of analysis of monographs from the State Pharmacopoeia of the Russian Federation, XIII and XIV editions, draft version of the Pharmacopoeia of the Eurasian Economic Union, United States Pharmacopoeia, Japanese Pharmacopoeia, European Pharmacopoeia, and Ayurvedic Pharmacopoeia of India containing limits for the content of arsenic in herbal medicinal products (HMPs). In addition, the authors analysed Russian, international and foreign food industry and dietary supplements regulations, as well as scientific publications on arsenic content in brown algae. They also considered the nomenclature of arsenic compounds to be determined and controlled in medicinal products, highlighted the main approaches to and identified global trends in establishing the limits for their content in HMPs. The paper summarises specific aspects of inorganic arsenic compounds accumulation by brown algae. It was demonstrated that the majority of foreign pharmacopoeias either have specific norms for arsenic content in brown algae, which differ from the norms for HMPs, or have general norms that take into account different toxicity levels of organic and inorganic arsenic compounds. There is a tendency to control the content of elemental toxic substances based on their maximum allowable daily intake. The paper substantiates the need for separate determination of toxic inorganic arsenic compounds and potentially toxic methyl arsonate and dimethyl arsinate in HMPs.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74711650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-10DOI: 10.30895/1991-2919-2019-9-3-191-196
K. Koshechkin, Yu. V. Olefir
Improvement of drug supply is one of the key factors contributing to the quality of medical services, but it cannot be achieved without introduction of digital technologies. This is a complex task that requires a systematic approach which includes planning, design, development, implementation and operation of information systems.The purpose of this study was to develop and test a procedure for assessing the effectiveness of information systems supporting medicines evaluation.Materials and methods: the paper analyses Russian and foreign scientific publications devoted to the assessment of effectiveness of information systems implementation. The author conducted a system analysis using the procedure for constructing a model of a data processing system.Results: the analysis of literature sources helped to determine methods that could be used to assess the effectiveness of information systems implementation. The «Document management — Medicines evaluation» system was used to construct a model system, and the analysis of the system’s effectiveness made it possible to propose ways for further improvement.Conclusion: the analysis of the literature sources demonstrated that the use of digital modelling methods helps to assess the effectiveness of information systems supporting medicines evaluation. The paper analysed the «Document management — Medicines evaluation» system used for receipt and registration of medicine samples. This system makes it possible to preplan the order in which applications will be received and rule out the possibility of simultaneous receipt of several applications. Based on the results of the analysis it is suggested that an additional receiving point should be set up in order to improve the throughput of the system.
{"title":"Assessment of the Effectiveness of Implementation of Information Systems for Medicines Evaluation","authors":"K. Koshechkin, Yu. V. Olefir","doi":"10.30895/1991-2919-2019-9-3-191-196","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-191-196","url":null,"abstract":"Improvement of drug supply is one of the key factors contributing to the quality of medical services, but it cannot be achieved without introduction of digital technologies. This is a complex task that requires a systematic approach which includes planning, design, development, implementation and operation of information systems.The purpose of this study was to develop and test a procedure for assessing the effectiveness of information systems supporting medicines evaluation.Materials and methods: the paper analyses Russian and foreign scientific publications devoted to the assessment of effectiveness of information systems implementation. The author conducted a system analysis using the procedure for constructing a model of a data processing system.Results: the analysis of literature sources helped to determine methods that could be used to assess the effectiveness of information systems implementation. The «Document management — Medicines evaluation» system was used to construct a model system, and the analysis of the system’s effectiveness made it possible to propose ways for further improvement.Conclusion: the analysis of the literature sources demonstrated that the use of digital modelling methods helps to assess the effectiveness of information systems supporting medicines evaluation. The paper analysed the «Document management — Medicines evaluation» system used for receipt and registration of medicine samples. This system makes it possible to preplan the order in which applications will be received and rule out the possibility of simultaneous receipt of several applications. Based on the results of the analysis it is suggested that an additional receiving point should be set up in order to improve the throughput of the system.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87745780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-07-24DOI: 10.30895/1991-2919-2019-9-3-184-190
D. Goryachev, N. E. Uvarova
Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.
{"title":"Evaluation of Bioequivalence of Generic Imatinib Products and Generic Tacrolimus Products Based on Indirect Comparison of the Results of Their Bioequivalence Studies","authors":"D. Goryachev, N. E. Uvarova","doi":"10.30895/1991-2919-2019-9-3-184-190","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-184-190","url":null,"abstract":"Generic drugs are widely discussed in the scientific literature. Their key advantage is high availability in the medical practice due to the possibility of a significant reduction in developer costs. In most cases the efficacy and safety of generic oral drugs are confirmed based on the acceptable results of pharmacokinetic evaluation of their bioequivalence with the reference drug. However, generic drugs are not directly compared with one another, and this calls into question the validity of the conclusion about the interchangeability of the generic drugs.The aim of this study was to evaluate the results of indirect comparison of generic drugs by the ratios of their AUC0-t and Сmax based on the information obtained in bioequivalence studies involving the reference drug.Materials and methods: the authors performed an indirect comparison of the results of bioequivalence studies of generic drugs containing one active pharmaceutical ingredient. The analysis was based on bioequivalence study reports over the last 7 years dealing with risk/benefit assessment of imatinib and tacrolimus products.Results: the results of indirect assessment of 90 % confidence intervals of the ratios of imatinib products’ geometric means show that in 46.7 % of cases the intervals fall outside the generally accepted limits (80–125 %) for at least one of the estimated parameters. As for tacrolimus products, the intervals did not go beyond the generally accepted limits (80–125 %) for the AUC0-t ratio, but a discrepancy was found in 10 % of cases for the Cmax ratio. However, when narrower limits of 90–111 % were used to assess the AUC0-t ratio, 90 % of the compared pairs did not meet the recommended standards. Conclusions: thus, conclusions on the acceptable degree of bioequivalence of two generic drugs to the reference product cannot constitute a scientifically sufficient reason for regarding these generic drugs as clinically equivalent.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83911677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-05DOI: 10.30895/1991-2919-2019-9-2-131-139
V. Pisarev, M. Ulyashova, Gelia N Gildeeva
An integral part of preclinical pharmacokinetic studies is the development of a bioanalytical method for determination of the drug in a biological fluid.The aim of the research was to assess the suitability of the test system based on enzyme-linked immunosorbent assay (ELISA) for quantitative determination of rituximab in the blood serum of laboratory animals after intravenous administration of rituximab at a dose corresponding to the therapeutic dose in humans. Th test system was developed by the Scientific and Production Center Probiotech.Materials and methods: the determination of rituximab in biological samples was carried out using a two-stage sandwich-type ELISA, followed by detection based on horseradish peroxidase. The ELISA results were recorded using a microplate photometer at a wavelength of 450 nm.Results: the experiments helped to establish the detection limit (0.24 ng/mL) and the lower limit of quantitation (1.00 ng/mL) of rituximab in rabbit blood serum, they also demonstrated high selectivity of analyte determination in a multicomponent biological matrix. The mean rituximab concentration was within 14 % of the nominal value in the entire working range of the method. The within-run and between-run precision of the assay did not exceed 7.4 %, the total error of the method did not exceed 20.1 %. The linearity of dilution makes it possible to use the assay for the analysis of biological samples with a wide range of rituximab concentrations. The stability of the analyte in the rabbit blood serum was confirmed by storing samples for 6 hours at room temperature, for 50 days at —35 °C, and after 3 freeze-thaw cycles. The validated immunoassay was successfully used to determine the rituximab concentration in biological samples obtained in the rituximab pharmacokinetic trial in rabbits. The accuracy of the results was confirmed for the entire range of the determined concentrations; parallelism was demonstrated between the calibration curve and the results of analysis of serially diluted rabbit serum samples with the maximum concentration of rituximab.Conclusions: the proposed enzyme immunoassay test system can be used for quantitative determination of rituximab in the blood serum of laboratory animals, as it meets acceptance criteria for all validation parameters described in the international guidelines on validation of bioanalytical methods.
{"title":"Validation of Enzyme Immunoassay for Preclinical Pharmacokinetic Trials of Rituximab","authors":"V. Pisarev, M. Ulyashova, Gelia N Gildeeva","doi":"10.30895/1991-2919-2019-9-2-131-139","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-2-131-139","url":null,"abstract":"An integral part of preclinical pharmacokinetic studies is the development of a bioanalytical method for determination of the drug in a biological fluid.The aim of the research was to assess the suitability of the test system based on enzyme-linked immunosorbent assay (ELISA) for quantitative determination of rituximab in the blood serum of laboratory animals after intravenous administration of rituximab at a dose corresponding to the therapeutic dose in humans. Th test system was developed by the Scientific and Production Center Probiotech.Materials and methods: the determination of rituximab in biological samples was carried out using a two-stage sandwich-type ELISA, followed by detection based on horseradish peroxidase. The ELISA results were recorded using a microplate photometer at a wavelength of 450 nm.Results: the experiments helped to establish the detection limit (0.24 ng/mL) and the lower limit of quantitation (1.00 ng/mL) of rituximab in rabbit blood serum, they also demonstrated high selectivity of analyte determination in a multicomponent biological matrix. The mean rituximab concentration was within 14 % of the nominal value in the entire working range of the method. The within-run and between-run precision of the assay did not exceed 7.4 %, the total error of the method did not exceed 20.1 %. The linearity of dilution makes it possible to use the assay for the analysis of biological samples with a wide range of rituximab concentrations. The stability of the analyte in the rabbit blood serum was confirmed by storing samples for 6 hours at room temperature, for 50 days at —35 °C, and after 3 freeze-thaw cycles. The validated immunoassay was successfully used to determine the rituximab concentration in biological samples obtained in the rituximab pharmacokinetic trial in rabbits. The accuracy of the results was confirmed for the entire range of the determined concentrations; parallelism was demonstrated between the calibration curve and the results of analysis of serially diluted rabbit serum samples with the maximum concentration of rituximab.Conclusions: the proposed enzyme immunoassay test system can be used for quantitative determination of rituximab in the blood serum of laboratory animals, as it meets acceptance criteria for all validation parameters described in the international guidelines on validation of bioanalytical methods.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85134001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-05DOI: 10.30895/1991-2919-2019-9-2-79-84
D. Goryachev, N. E. Uvarova
The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.
{"title":"Assessment of the Feasibility of Therapeutic Equivalence Studies","authors":"D. Goryachev, N. E. Uvarova","doi":"10.30895/1991-2919-2019-9-2-79-84","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-2-79-84","url":null,"abstract":"The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90590460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-06-05DOI: 10.30895/1991-2919-2019-9-2-93-100
O. Talibov
The article describes specific aspects of biosimilars research and development. The aim of the study was to analyse the ways to conduct comparative studies of biotechnological medicinal products and the main approaches to the assessment of the obtained data. The paper highlights that biotechnological products are associated with a much higher potential variability of chemical and pharmacological characteristics than small molecules. The author analyses the reasons of this phenomenon, describes mechanisms underlying the microheterogeneity of protein molecules, primarily post-translational modification. The latter has an impact on the pharmacokinetic parameters, pharmacodynamics and immunogenicity of complex protein molecules, which increases the variability of test results and makes it difficult to conduct bioequivalence studies. In addition to bioequivalence studies, biosimilars research should include comparative studies of pharmacodynamics, evaluation of therapeutic equivalence and immunogenicity. Assessment of the medicines comparability should be based on the analysis of all data provided, which requires a more flexible and sometimes individual approach on the part of regulatory authorities.
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Pub Date : 2019-06-05DOI: 10.30895/1991-2919-2019-9-2-72-78
N. P. Rukavitsyna, E. I. Sakanyan, O. Evdokimova
The «cut-and-pressed granules» dosage form was developed to improve the technological properties of cut and powdered herbal substances in order to compensate for their insufficient flowability, as well as to facilitate dosing, reduce the contamination of the production equipment with dust and contamination of water extracts with dietary fibers. Based on the results of the information research the authors chose an optimal technology for the production of cut-and-pressed granules from some types of herbal substances (Rose hips, Bearberry leaf, Thyme herb, Melissa herb, Oregano herb, Motherwort grass, Matricaria flower). The authors standardised the new dosage form, developed the list of test parameters, test methods, and regulatory requirements for the quality of medicinal products based on the technological features of the new dosage form. Cut-and-pressed granules should not be produced from herbal substances that contain essential oils and coumarins, as it was demonstrated that the content of these compounds may decrease in the process of wet granulation. To determine whether it is possible to produce cut-and-pressed granules from a particular type of raw material, it is necessary to conduct comparative experimental studies confirming that the quality of aqueous extracts obtained from powdered herbal substances in sachets is comparable to that of tinctures or decoctions obtained from cut-and-pressed granules packed in sachets. The materials of the study were used to draft the general chapter OFS.1.4.1.0022.15 «Cut-and-pressed granules». This dosage form is not described in any foreign pharmacopoeias.
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