Pub Date : 2023-10-26DOI: 10.30895/2312-7821-2023-386
N. A. Shnayder, V. V. Grechkina, V. V. Arkhipov, R. F. Nasyrova
Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs. Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice. Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles. Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.
{"title":"Pharmacogenetics-Informed Pharmacometabolomics as an Innovative Approach to Assessing the Safety and Risk of Pharmacotherapy with Valproic Acid","authors":"N. A. Shnayder, V. V. Grechkina, V. V. Arkhipov, R. F. Nasyrova","doi":"10.30895/2312-7821-2023-386","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-386","url":null,"abstract":"Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs. Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice. Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles. Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134972392","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 : 2023-10-02DOI: 10.30895/2312-7821-2023-337
M. V. Zhuravleva, E. V. Kuznetsova, N. G. Berdnikova, A. B. Prokofiev, T. R. Kameneva, E. Yu. Demchenkova
Scientific relevance. Vancomycin and linezolid are the antibacterial agents of choice for severe infections caused by multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). However, few studies have been conducted in Russia to analyse the safety of these medicinal products. Aim. The study aimed to compare the safety of vancomycin and linezolid using the Moscow segment of the Russian Federal Service for Surveillance in Healthcare’s database for adverse drug reaction (ADR) reports. Materials and methods. The study used information from the spontaneous reporting database for 2018–2022, which contained 147 ADR reports for vancomycin (122 reports) and linezolid (25 reports). The authors analysed the ADR distribution and assessed the statistical significance of the identified differences by sex, weight, and age of patients, conditions of medical care, route of administration, single dose, daily dose, therapy duration, ICD-10 codes, ADR severity, and ADR outcome. Results. The distribution of adverse reactions to vancomycin and linezolid by patient age was relatively uniform. Outpatient linezolid was associated with a significantly higher rate of ADRs (3 of 5 reports) than outpatient vancomycin (21 of 129 reports; p =0.0408). For ADR severity, 5 of 20 ADRs reported with linezolid required hospitalisation or prolongation of hospitalisation—considerably more than with vancomycin (16 of 94 reports; p =0.528). The average single dose of vancomycin (794 mg) was higher than that of linezolid (467 mg; p =0.007); the same was noted for average daily doses (1273 mg vs 998 mg; p =0.3664). The mean duration of treatment with linezolid before ADR onset was 5.26 days, which was significantly longer than the mean duration of treatment with vancomycin (2.44 days; p =0.0053). Oral linezolid was associated with a significantly higher ADR rate (4 of 19 cases) than oral vancomycin (5 of 96 cases; p =0.0027). Conclusions. The ADRs observed with vancomycin and linezolid were predictable and class-specific. According to the results of the ADR report analysis, adverse reactions to vancomycin and linezolid were associated with different factors. Similar results of the literature analysis confirmed this conclusion. However, according to the results of the linear regression analysis, none of the factors considered in this study had a statistically significant influence on the probability of developing an adverse reaction to vancomycin or linezolid.
{"title":"Clinical Pharmacology of Antimicrobials: Focus on the Safety of Vancomycin and Linezolid","authors":"M. V. Zhuravleva, E. V. Kuznetsova, N. G. Berdnikova, A. B. Prokofiev, T. R. Kameneva, E. Yu. Demchenkova","doi":"10.30895/2312-7821-2023-337","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-337","url":null,"abstract":"Scientific relevance. Vancomycin and linezolid are the antibacterial agents of choice for severe infections caused by multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). However, few studies have been conducted in Russia to analyse the safety of these medicinal products. Aim. The study aimed to compare the safety of vancomycin and linezolid using the Moscow segment of the Russian Federal Service for Surveillance in Healthcare’s database for adverse drug reaction (ADR) reports. Materials and methods. The study used information from the spontaneous reporting database for 2018–2022, which contained 147 ADR reports for vancomycin (122 reports) and linezolid (25 reports). The authors analysed the ADR distribution and assessed the statistical significance of the identified differences by sex, weight, and age of patients, conditions of medical care, route of administration, single dose, daily dose, therapy duration, ICD-10 codes, ADR severity, and ADR outcome. Results. The distribution of adverse reactions to vancomycin and linezolid by patient age was relatively uniform. Outpatient linezolid was associated with a significantly higher rate of ADRs (3 of 5 reports) than outpatient vancomycin (21 of 129 reports; p =0.0408). For ADR severity, 5 of 20 ADRs reported with linezolid required hospitalisation or prolongation of hospitalisation—considerably more than with vancomycin (16 of 94 reports; p =0.528). The average single dose of vancomycin (794 mg) was higher than that of linezolid (467 mg; p =0.007); the same was noted for average daily doses (1273 mg vs 998 mg; p =0.3664). The mean duration of treatment with linezolid before ADR onset was 5.26 days, which was significantly longer than the mean duration of treatment with vancomycin (2.44 days; p =0.0053). Oral linezolid was associated with a significantly higher ADR rate (4 of 19 cases) than oral vancomycin (5 of 96 cases; p =0.0027). Conclusions. The ADRs observed with vancomycin and linezolid were predictable and class-specific. According to the results of the ADR report analysis, adverse reactions to vancomycin and linezolid were associated with different factors. Similar results of the literature analysis confirmed this conclusion. However, according to the results of the linear regression analysis, none of the factors considered in this study had a statistically significant influence on the probability of developing an adverse reaction to vancomycin or linezolid.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"80 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135830194","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 : 2023-09-29DOI: 10.30895/2312-7821-2023-366
K. O. Shnaider, M. L. Maximov, V. A. Baranova, A. A. Nekipelova
Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance. Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMG-CoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies. Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effective therapeutic strategy for hyperlipidaemia in patients with statin intolerance.
{"title":"PCSK9 Inhibitor Therapy as an Alternative for Statin Intolerance","authors":"K. O. Shnaider, M. L. Maximov, V. A. Baranova, A. A. Nekipelova","doi":"10.30895/2312-7821-2023-366","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-366","url":null,"abstract":"Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance. Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMG-CoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies. Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effective therapeutic strategy for hyperlipidaemia in patients with statin intolerance.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135199699","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-279-291
A. A. Nekipelova, R. N. Alyautdin
Scientific relevance . Cardiovascular diseases (CVD) are the leading cause of death worldwide. Dyslipidemia, as the pathophysiological basis of atherosclerosis, is the most important cause of CVD. Among the factors that modify this pathology, the World Health Organisation lists statins, which effectively reduce the cholesterol level. However, statin treatment compliance is not sufficient to achieve population-based lipid targets. This is a powerful stimulus for the creation of fundamentally new groups of lipid-lowering agents, in particular, antagonists of proprotein convertase subtilisin/kexin type 9 (PCSK9). Aim. The study aimed to review innovative approaches to developing a new generation of lipid-lowering agents, PCSK9 antagonists, and to evaluate the effectiveness, safety, and clinical potential of these medicines. Discussion. PCSK9 antagonists significantly increase the effectiveness of lipid-lowering therapy when combined with statins and are an effective monotherapy in patients with contraindications for statins. PCSK9 monoclonal antibodies, as well as inclisiran, have a favourable risk–benefit ratio. However, the high cost of commercially available PCSK9 antagonists limits their clinical use. A number of promising directions exist for developing new PCSK9 antagonists that have fundamentally different mechanisms of action, such as adnectins; genome editing with CRISPR/Cas9; combining small molecules with low molecular weight PCSK9 inhibitors; PCSK9 vaccines; and antisense oligonucleotides. Medicinal products from these groups are currently at various stages of preclinical and clinical development. Conclusions. Therefore, new lipid-lowering agents can be developed by synthesising high and low molecular weight PCSK9 ligands and by altering the genetic mechanisms of PCSK9 synthesis. The innovative medicines considered in this review are highly effective, and most have shown no signs of toxicity at the pre-authorisation stage.
{"title":"PCSK9 Antagonists: Clinical Efficacy and Main Trends in the Development of New Medicines","authors":"A. A. Nekipelova, R. N. Alyautdin","doi":"10.30895/2312-7821-2023-11-3-279-291","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-279-291","url":null,"abstract":"Scientific relevance . Cardiovascular diseases (CVD) are the leading cause of death worldwide. Dyslipidemia, as the pathophysiological basis of atherosclerosis, is the most important cause of CVD. Among the factors that modify this pathology, the World Health Organisation lists statins, which effectively reduce the cholesterol level. However, statin treatment compliance is not sufficient to achieve population-based lipid targets. This is a powerful stimulus for the creation of fundamentally new groups of lipid-lowering agents, in particular, antagonists of proprotein convertase subtilisin/kexin type 9 (PCSK9). Aim. The study aimed to review innovative approaches to developing a new generation of lipid-lowering agents, PCSK9 antagonists, and to evaluate the effectiveness, safety, and clinical potential of these medicines. Discussion. PCSK9 antagonists significantly increase the effectiveness of lipid-lowering therapy when combined with statins and are an effective monotherapy in patients with contraindications for statins. PCSK9 monoclonal antibodies, as well as inclisiran, have a favourable risk–benefit ratio. However, the high cost of commercially available PCSK9 antagonists limits their clinical use. A number of promising directions exist for developing new PCSK9 antagonists that have fundamentally different mechanisms of action, such as adnectins; genome editing with CRISPR/Cas9; combining small molecules with low molecular weight PCSK9 inhibitors; PCSK9 vaccines; and antisense oligonucleotides. Medicinal products from these groups are currently at various stages of preclinical and clinical development. Conclusions. Therefore, new lipid-lowering agents can be developed by synthesising high and low molecular weight PCSK9 ligands and by altering the genetic mechanisms of PCSK9 synthesis. The innovative medicines considered in this review are highly effective, and most have shown no signs of toxicity at the pre-authorisation stage.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719299","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-336-347
S. N. Orekhov, A. A. Mokhov, A. N. Yavorsky
Scientific relevance . In recent years, antimicrobial resistance in pathogenic microorganisms has become a global problem that threatens the health of humans and animals and poses a risk to the biosafety of Russia. Aim. The study aimed to analyse the prevalence of antimicrobial resistance, consider the risks and medical consequences of this biological phenomenon, and suggest ways to optimise the use of existing antimicrobial agents and search for new ones. Discussion. The emergence of antibiotic resistance in bacteria is a natural biological process; the selection of resistant microorganisms occurs constantly with the use of the entire spectrum of antimicrobial agents in healthcare, agriculture, and other fields. The World Health Organisation (WHO) monitors these processes using the Global Antimicrobial Resistance Surveillance System (GLASS). Russia has adopted the Strategy to prevent the spread of antimicrobial resistance in the Russian Federation to 2030. The country has established a regulatory framework that supports the operation of the national antimicrobial resistance prevention system. The strategy to prevent the spread of antimicrobial resistance is being implemented through making organisational arrangements and developing novel medicines with mechanisms of action based on an understanding of the molecular mechanisms of infection and resistance. This review considers the main approaches to designing exploratory studies and evaluating the antimicrobial activity of the innovative molecules obtained. The rapid development of synthetic biology increases the likelihood of creating synthetic biological pathogens with high virulence and resistance to antimicrobial agents, which might pose risks of artificial epidemics. Conclusions. The antimicrobial resistance prevention system in Russia should be considered a strategically essential medical technology ensuring the biosafety of the country and the people.
{"title":"Antimicrobial Resistance: A Risk Factor for the Biosafety System","authors":"S. N. Orekhov, A. A. Mokhov, A. N. Yavorsky","doi":"10.30895/2312-7821-2023-11-3-336-347","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-336-347","url":null,"abstract":"Scientific relevance . In recent years, antimicrobial resistance in pathogenic microorganisms has become a global problem that threatens the health of humans and animals and poses a risk to the biosafety of Russia. Aim. The study aimed to analyse the prevalence of antimicrobial resistance, consider the risks and medical consequences of this biological phenomenon, and suggest ways to optimise the use of existing antimicrobial agents and search for new ones. Discussion. The emergence of antibiotic resistance in bacteria is a natural biological process; the selection of resistant microorganisms occurs constantly with the use of the entire spectrum of antimicrobial agents in healthcare, agriculture, and other fields. The World Health Organisation (WHO) monitors these processes using the Global Antimicrobial Resistance Surveillance System (GLASS). Russia has adopted the Strategy to prevent the spread of antimicrobial resistance in the Russian Federation to 2030. The country has established a regulatory framework that supports the operation of the national antimicrobial resistance prevention system. The strategy to prevent the spread of antimicrobial resistance is being implemented through making organisational arrangements and developing novel medicines with mechanisms of action based on an understanding of the molecular mechanisms of infection and resistance. This review considers the main approaches to designing exploratory studies and evaluating the antimicrobial activity of the innovative molecules obtained. The rapid development of synthetic biology increases the likelihood of creating synthetic biological pathogens with high virulence and resistance to antimicrobial agents, which might pose risks of artificial epidemics. Conclusions. The antimicrobial resistance prevention system in Russia should be considered a strategically essential medical technology ensuring the biosafety of the country and the people.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"31 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135718996","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-246-251
A. A. Spasov
It is strategically critical to secure pharmaceutical independence for Russia by developing the industry using the latest achievements in science and technology. The development of nationally and internationally competitive medicines calls for the harmonisation of national and international requirements for non-clinical and clinical studies. In this interview, Alexander A. Spasov, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Head of the Department of Pharmacology and Bioinformatics of the Volgograd State Medical University, voices his authoritative opinion on the changes to the regulatory requirements for non-clinical and clinical studies of medicinal products that are related to the transition of the Russian Federation to the Eurasian Economic Union marketing authorisation requirements. Alexander A. Spasov touches upon the development and application potential of cutting-edge research methods (in silico, human cell-based and alternative animal-based methods) for the creation and implementation of more reliable and rapid test systems for pharmacology and toxicity studies.
利用最新的科学技术成果发展医药产业，确保俄罗斯的医药独立，具有重要的战略意义。发展具有国内和国际竞争力的药物需要协调国家和国际对非临床和临床研究的要求。在采访中，俄罗斯科学院院士、医学博士、正教授、伏尔加格勒国立医科大学药理学和生物信息学系主任Alexander A. Spasov，就与俄罗斯联邦向欧亚经济联盟过渡有关的药品非临床和临床研究监管要求的变化发表了权威意见。Alexander A. Spasov谈到了尖端研究方法的发展和应用潜力(在硅，基于人类细胞和替代动物为基础的方法)，为药理学和毒性研究创建和实施更可靠和快速的测试系统。
{"title":"Transition to the Non-Clinical Drug Development Principles and Rules of the Eurasian Economic Union: Changes, Challenges, and Prospects","authors":"A. A. Spasov","doi":"10.30895/2312-7821-2023-11-3-246-251","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-246-251","url":null,"abstract":"It is strategically critical to secure pharmaceutical independence for Russia by developing the industry using the latest achievements in science and technology. The development of nationally and internationally competitive medicines calls for the harmonisation of national and international requirements for non-clinical and clinical studies. In this interview, Alexander A. Spasov, Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Full Professor, Head of the Department of Pharmacology and Bioinformatics of the Volgograd State Medical University, voices his authoritative opinion on the changes to the regulatory requirements for non-clinical and clinical studies of medicinal products that are related to the transition of the Russian Federation to the Eurasian Economic Union marketing authorisation requirements. Alexander A. Spasov touches upon the development and application potential of cutting-edge research methods (in silico, human cell-based and alternative animal-based methods) for the creation and implementation of more reliable and rapid test systems for pharmacology and toxicity studies.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"123 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719126","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-348-360
V. V. Arkhipov, N. V. Chebanenko, D. M. Mednaya, K. M. Mantserov
Scientific relevance . Epileptic syndromes associated with focal seizures often develop in children and adolescents and may be accompanied by cognitive impairment, mental disorders, and endocrine disorders, which require additional medication apart from anti-epileptic medicinal products. Currently, the selection of safe and effective therapies for epileptic syndromes, especially in paediatric populations, is a pressing challenge for epileptology. Aim. This study aimed at a comprehensive assessment of the safety and efficacy of lamotrigine in therapeutic doses for children and adolescents with epileptic syndromes associated with focal seizures. Materials and methods. A total of 53 patients aged 3 to 18 years with various epileptic syndromes associated with focal seizures were under observation in 2020–2023. During this period, 37 patients (69.8%) received monotherapy with lamotrigine, and 16 patients (30.2%) received combination therapy including lamotrigine and two or more other medicinal products. When evaluating the safety and efficacy of pharmacotherapy in adolescent patients, the authors selectively used the Software for Post-marketing Studies of Anti-epileptic Medicinal Products developed at the Scientific Centre for Expert Evaluation of Medicinal Products. Results. With lamotrigine, the highest rate of complete clinical remission was observed in patients with focal epilepsy with onset in childhood and adolescence (90.9% of cases). For structural focal epilepsy, 16.7% of patients achieved complete freedom from seizures, and 50% demonstrated a pronounced response to treatment. However, patients with epilepsy due to local structural changes in the neocortex (33.3% of cases) had a prognosis of severe epilepsy. For epileptic encephalopathies with onset in childhood, 66.7% of patients achieved a ≥50% reduction in the frequency of seizures. Seizure reduction improved the quality of life of patients and their parents, especially of those with a long history of unsuccessful treatment attempts. There were no adverse reactions associated with lamotrigine except those listed in the summary of product characteristics. The Software for Post-marketing Studies of Anti-epileptic Medicinal Products provided a means for scoring and plotting the changes in the condition of adolescents without severe cognitive and memory impairment undergoing lamotrigine treatment. Conclusions. According to the study results, lamotrigine is highly effective and has a favourable safety profile in patients with early-onset epileptic syndromes associated with focal seizures. Moreover, lamotrigine is applicable to the treatment of attention, memory, expressive speech disorders, and aggressive behaviour. Therefore, lamotrigine may be recommended for treating children and adolescents with comorbid epileptic syndromes and cognitive and emotional disorders. Specialised software improves the quality of real-world evidence regarding the safety and efficacy of anti-epileptic medication.
{"title":"Current Approaches to Assessing the Safety and Efficacy of Lamotrigine in Children and Adolescents with Epileptic Syndromes Associated with Focal Seizures","authors":"V. V. Arkhipov, N. V. Chebanenko, D. M. Mednaya, K. M. Mantserov","doi":"10.30895/2312-7821-2023-11-3-348-360","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-348-360","url":null,"abstract":"Scientific relevance . Epileptic syndromes associated with focal seizures often develop in children and adolescents and may be accompanied by cognitive impairment, mental disorders, and endocrine disorders, which require additional medication apart from anti-epileptic medicinal products. Currently, the selection of safe and effective therapies for epileptic syndromes, especially in paediatric populations, is a pressing challenge for epileptology. Aim. This study aimed at a comprehensive assessment of the safety and efficacy of lamotrigine in therapeutic doses for children and adolescents with epileptic syndromes associated with focal seizures. Materials and methods. A total of 53 patients aged 3 to 18 years with various epileptic syndromes associated with focal seizures were under observation in 2020–2023. During this period, 37 patients (69.8%) received monotherapy with lamotrigine, and 16 patients (30.2%) received combination therapy including lamotrigine and two or more other medicinal products. When evaluating the safety and efficacy of pharmacotherapy in adolescent patients, the authors selectively used the Software for Post-marketing Studies of Anti-epileptic Medicinal Products developed at the Scientific Centre for Expert Evaluation of Medicinal Products. Results. With lamotrigine, the highest rate of complete clinical remission was observed in patients with focal epilepsy with onset in childhood and adolescence (90.9% of cases). For structural focal epilepsy, 16.7% of patients achieved complete freedom from seizures, and 50% demonstrated a pronounced response to treatment. However, patients with epilepsy due to local structural changes in the neocortex (33.3% of cases) had a prognosis of severe epilepsy. For epileptic encephalopathies with onset in childhood, 66.7% of patients achieved a ≥50% reduction in the frequency of seizures. Seizure reduction improved the quality of life of patients and their parents, especially of those with a long history of unsuccessful treatment attempts. There were no adverse reactions associated with lamotrigine except those listed in the summary of product characteristics. The Software for Post-marketing Studies of Anti-epileptic Medicinal Products provided a means for scoring and plotting the changes in the condition of adolescents without severe cognitive and memory impairment undergoing lamotrigine treatment. Conclusions. According to the study results, lamotrigine is highly effective and has a favourable safety profile in patients with early-onset epileptic syndromes associated with focal seizures. Moreover, lamotrigine is applicable to the treatment of attention, memory, expressive speech disorders, and aggressive behaviour. Therefore, lamotrigine may be recommended for treating children and adolescents with comorbid epileptic syndromes and cognitive and emotional disorders. Specialised software improves the quality of real-world evidence regarding the safety and efficacy of anti-epileptic medication.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135718997","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-303-321
A. V. Kalueff, M. M. Kotova, A. N. Ikrin, T. O. Kolesnikova
Scientific relevance . Since fiscal and regulatory constraints substantially limit bioscreening in rodent models, a wider implementation of additional alternative models in preclinical studies of medicines is gaining momentum. These alternative models include aquatic vertebrates, such as zebrafish (Danio rerio). Aim. The study aimed to examine zebrafish models in terms of their performance in preclinical studies, their current uses, the challenges and opportunities in the field, and strategic directions for the development of preclinical testing in zebrafish. Discussion. Here, the authors summarise the key zebrafish tests that are currently used to assess a wide range of small molecules for their general and endocrine toxicity and effects on the survival of embryos and larvae. The review discusses the strengths and weaknesses of zebrafish models for preclinical testing of neurotropic agents. Additionally, the authors overview various methodological approaches to improving zebrafish toxicity testing. Overall, the use of zebrafish models is gradually becoming internationally established for laboratory testing of small molecules. Conclusions. A wider implementation of zebrafish models in pharmaceutical research and preclinical testing as an additional alternative to rodents, particularly in Russia, may significantly accelerate the development of novel medicinal products and foster a more comprehensive and adequate assessment of the biological risks associated with chemical substances.
{"title":"Using Zebrafish in Preclinical Drug Studies: Challenges and Opportunities","authors":"A. V. Kalueff, M. M. Kotova, A. N. Ikrin, T. O. Kolesnikova","doi":"10.30895/2312-7821-2023-11-3-303-321","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-303-321","url":null,"abstract":"Scientific relevance . Since fiscal and regulatory constraints substantially limit bioscreening in rodent models, a wider implementation of additional alternative models in preclinical studies of medicines is gaining momentum. These alternative models include aquatic vertebrates, such as zebrafish (Danio rerio). Aim. The study aimed to examine zebrafish models in terms of their performance in preclinical studies, their current uses, the challenges and opportunities in the field, and strategic directions for the development of preclinical testing in zebrafish. Discussion. Here, the authors summarise the key zebrafish tests that are currently used to assess a wide range of small molecules for their general and endocrine toxicity and effects on the survival of embryos and larvae. The review discusses the strengths and weaknesses of zebrafish models for preclinical testing of neurotropic agents. Additionally, the authors overview various methodological approaches to improving zebrafish toxicity testing. Overall, the use of zebrafish models is gradually becoming internationally established for laboratory testing of small molecules. Conclusions. A wider implementation of zebrafish models in pharmaceutical research and preclinical testing as an additional alternative to rodents, particularly in Russia, may significantly accelerate the development of novel medicinal products and foster a more comprehensive and adequate assessment of the biological risks associated with chemical substances.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719240","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-292-302
I. A. Mazerkina, T. V. Bukatina, T. V. Aleksandrova
Scientific relevance. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a generally accepted standard treatment for dyslipidaemia. However, adverse reactions and intolerance to statins have motivated the search for lipid-modifying agents with alternative mechanisms of action. Bempedoic acid is one of these alternative agents. Aim. The study aimed to review published data on the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of bempedoic acid used as a lipid-lowering agent. Discussion. Similar to statins, bempedoic acid inhibits cholesterol synthesis from acetyl-CoA. Statins and bempedoic acid differ in their mechanisms of action mainly because the conversion of bempedoic acid into its active metabolite takes place only in the liver. As a result, bempedoic acid does not cause adverse drug reactions in muscles. The main safety and efficacy data on bempedoic acid were obtained in phase III CLEAR trials. Compared to placebo, bempedoic acid reduced LDL-C levels by an additional 18% in combination with maximum tolerated doses of statins and by 25% in monotherapy in patients with statin intolerance. In the CLEAR Outcomes trial, long-term treatment with bempedoic acid reduced the risk of major adverse cardiovascular events in patients with statin intolerance (n=13970) by 13%. A slight increase in gout attack frequency was observed, primarily in patients with pre-existing hyperuricaemia. Conclusions. Therefore, bempedoic acid is a safe and effective treatment option for patients with dyslipidaemia at high risk of atherosclerotic cardiovascular disease. It can be used either in combination with statins or, in the case of statin intolerance, as monotherapy and with ezetimibe.
{"title":"Bempedoic Acid: Safety and Efficiacy of a New Lipid-Lowering Agent","authors":"I. A. Mazerkina, T. V. Bukatina, T. V. Aleksandrova","doi":"10.30895/2312-7821-2023-11-3-292-302","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-292-302","url":null,"abstract":"Scientific relevance. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a generally accepted standard treatment for dyslipidaemia. However, adverse reactions and intolerance to statins have motivated the search for lipid-modifying agents with alternative mechanisms of action. Bempedoic acid is one of these alternative agents. Aim. The study aimed to review published data on the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of bempedoic acid used as a lipid-lowering agent. Discussion. Similar to statins, bempedoic acid inhibits cholesterol synthesis from acetyl-CoA. Statins and bempedoic acid differ in their mechanisms of action mainly because the conversion of bempedoic acid into its active metabolite takes place only in the liver. As a result, bempedoic acid does not cause adverse drug reactions in muscles. The main safety and efficacy data on bempedoic acid were obtained in phase III CLEAR trials. Compared to placebo, bempedoic acid reduced LDL-C levels by an additional 18% in combination with maximum tolerated doses of statins and by 25% in monotherapy in patients with statin intolerance. In the CLEAR Outcomes trial, long-term treatment with bempedoic acid reduced the risk of major adverse cardiovascular events in patients with statin intolerance (n=13970) by 13%. A slight increase in gout attack frequency was observed, primarily in patients with pre-existing hyperuricaemia. Conclusions. Therefore, bempedoic acid is a safe and effective treatment option for patients with dyslipidaemia at high risk of atherosclerotic cardiovascular disease. It can be used either in combination with statins or, in the case of statin intolerance, as monotherapy and with ezetimibe.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719001","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 : 2023-09-26DOI: 10.30895/2312-7821-2023-11-3-322-335
D. A. Babkov
Scientific relevance . Endocrine disruptors affect the functioning of endocrine organs, which leads to adverse drug reactions. Endocrine toxicity requires special attention in preclinical studies of candidate medicinal products. Aim. The study aimed to review international guidelines and approaches to assessing the risk of endocrine toxicity associated with medicinal products. Discussion. This review covers documents that provide a methodological framework for identifying and classifying a chemical compound as an endocrine disruptor. These documents include the following: Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (Organisation for Economic Cooperation and Development, 2018), Nonclinical Evaluation of Endocrine-Related Drug Toxicity (Food and Drug Administration, 2015), and Guidance for the Identification of Endocrine Disruptors in the Context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009. The proposed algorithm for endocrine toxicity assessment involves collecting all available data on the test compound, such as the literature and previously obtained experimental data, including acute and subchronic toxicity data, and in silico predictions. Particular attention should be paid to the standard battery of preclinical chronic toxicity studies, which can identify most side effects associated with the endocrine system. The main endpoints for endocrine toxicity include changes in the mass and histopathology of the major endocrine organs (adrenal glands, testes, epididymides, ovaries, and the thyroid gland), oestrous cycle effects, reproductive toxicity, and transplacental action. A thorough assessment of the data obtained provides for the determination of unfavourable endocrine activity that requires further studies. Conclusions. The OECD guidelines offer a set of validated in vivo and in vitro tests that characterise the most important mechanisms of endocrine toxicity (oestrogen, androgen, thyroid, and steroidogenic endocrine pathways) by identified toxic effects. This approach allows researchers to identify potential endocrine disorders early in the drug development process and to optimise the scope of the required studies accordingly.
{"title":"Current Approaches to the Preclinical Assessment of Endocrine Toxicity","authors":"D. A. Babkov","doi":"10.30895/2312-7821-2023-11-3-322-335","DOIUrl":"https://doi.org/10.30895/2312-7821-2023-11-3-322-335","url":null,"abstract":"Scientific relevance . Endocrine disruptors affect the functioning of endocrine organs, which leads to adverse drug reactions. Endocrine toxicity requires special attention in preclinical studies of candidate medicinal products. Aim. The study aimed to review international guidelines and approaches to assessing the risk of endocrine toxicity associated with medicinal products. Discussion. This review covers documents that provide a methodological framework for identifying and classifying a chemical compound as an endocrine disruptor. These documents include the following: Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (Organisation for Economic Cooperation and Development, 2018), Nonclinical Evaluation of Endocrine-Related Drug Toxicity (Food and Drug Administration, 2015), and Guidance for the Identification of Endocrine Disruptors in the Context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009. The proposed algorithm for endocrine toxicity assessment involves collecting all available data on the test compound, such as the literature and previously obtained experimental data, including acute and subchronic toxicity data, and in silico predictions. Particular attention should be paid to the standard battery of preclinical chronic toxicity studies, which can identify most side effects associated with the endocrine system. The main endpoints for endocrine toxicity include changes in the mass and histopathology of the major endocrine organs (adrenal glands, testes, epididymides, ovaries, and the thyroid gland), oestrous cycle effects, reproductive toxicity, and transplacental action. A thorough assessment of the data obtained provides for the determination of unfavourable endocrine activity that requires further studies. Conclusions. The OECD guidelines offer a set of validated in vivo and in vitro tests that characterise the most important mechanisms of endocrine toxicity (oestrogen, androgen, thyroid, and steroidogenic endocrine pathways) by identified toxic effects. This approach allows researchers to identify potential endocrine disorders early in the drug development process and to optimise the scope of the required studies accordingly.","PeriodicalId":32736,"journal":{"name":"Bezopasnost'' i risk farmakoterapii","volume":"122 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135719522","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}
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