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.

Scientific relevance. Being the main class of medicinal products for dyslipidaemia treatment, statins are widely used in clinical practice in various patient populations. However, statins can cause statin-associated muscle symptoms (SAMS), which are the most frequent and, in some cases, even life-threatening adverse reactions associated with these medicinal products.

Aim. The study aimed to perform a systematic review of the epidemiology, classification, and physiological pathogenesis of SAMS, risk factors for this complication, and clinical guidelines for primary care physicians regarding the identification and treatment of patients with SAMS.

Discussion. SAMS is an umbrella term that covers various forms of myopathies associated with satin therapy. According to the published literature, the prevalence of SAMS varies considerably and may depend on the study design, inclusion criteria, and the medicinal product used. SAMS has multiple putative pathogenic pathways that include genetically determined processes, abnormalities in mitochondrial function, defects in intracellular signalling and metabolic pathways, and immune-mediated reactions. The main known risk factors for developing SAMS include high-dose statins, drug–drug interactions, genetic polymorphisms, female sex, older age, Asian race, history of kidney, liver, and muscle disease, and strenuous physical activity. Given the lack of universally recognised algorithms for diagnosing SAMS, clinicians should consider the clinical presentation and the temporal relationship between statin therapy and symptoms. Other factors to consider include changes in muscle-specific enzyme levels and, in some cases, the results of blood tests for antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase.

Conclusions. To ensure the safety of statin therapy, it is essential to raise clinicians’ awareness of the risk factors for SAMS, indicative clinical and laboratory findings, and the need for dynamic patient monitoring, including the involvement of clinical pharmacologists.

Scientific relevance. Since statins are widely used to prevent cardiovascular diseases, the control of statin-related complications is essential from both medical and social perspectives.
Aim. The study aimed to analyse unsolicited reports on adverse drug reactions (ADRs) to control the safety of statin therapy.
Materials and methods. The study analysed information on ADRs observed during statin treatment from the reporting forms submitted by medical organisations in Irkutsk to the database of the Regional Centre for Drug Safety Monitoring of the Irkutsk Region in 2011–2022. The causal relationship between ADRs and statin therapy was assessed using the Naranjo scale.
Results. The database contained 1068 ADR reporting forms; 12 (1.1%) were spontaneous reports of statin-related complications, including 4 cases (33.4%) of myalgia, 7 cases (58.3%) of myalgia with moderately elevated transaminase levels (3–5 times the upper limit of normal), and 1 case of rhabdomyolysis that required statin discontinuation. In all cases, a reduction in the statin dose resulted in a regression in the clinical symptoms of ADRs. Most ADRs were observed in women with comorbidities (diabetes mellitus, obesity, and hypothyroidism), but the small sample size prevented the authors from testing the identified differences for statistical significance.
Conclusions. According to the study results, statins have a reliable safety profile. Adequate and patient-specific selection of statin doses and ADR prevention are important responsibilities of clinical practitioners.

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.

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.

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.

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.

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.

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.