INTRODUCTION. The cardiovascular safety evaluation of medicines using in vivo models is a necessary preclinical step that is performed either in safety pharmacology studies or in toxicity studies. The design of safety pharmacology studies primarily involves assessing the potential of a test substance to prolong cardiac ventricular repolarisation, without in-depth investigation of potential structural damage to the heart and blood vessels. Toxicity studies usually do not include electrophysiological testing. The regulatory standards of the Eurasian Economic Union (EAEU) and the International Council for Harmonisation (ICH) lack detailed guidance on the use of specific markers of cardiovascular dysfunction.

AIM. This study aimed to develop an integrated approach to assessing the cardiac and vascular toxicity of medicinal products in preclinical in vivo studies.

DISCUSSION. Cardiovascular function can be assessed in both small laboratory animals (rodents) and larger animals, such as rabbits, ferrets, dogs, minipigs, and primates. The toxic effects of a test medicinal product on the cardiovascular system of animals may be manifested as physiological, biochemical, and structural changes in the systems and organs. Therefore, the assessment of cardiovascular function should be based on a combination of instrumental, laboratory, and histological methods. First of all, physiological and laboratory studies are applicable. It is recommended to perform electrocardiography, heart rate and blood pressure measurements, and quantification of markers of cardiovascular dysfunction and structural cell damage. For more in-depth analysis, histological and immunohistochemical studies of cardiac and vascular tissues are recommended to assess changes at the tissue and cellular levels.

CONCLUSIONS. An effective strategy for detecting cardiovascular disorders is the use of an integrated approach that, on the one hand, facilitates a comprehensive assessment of the possible toxic effects of a medicinal product and, on the other hand, increases the translational potential of the data obtained at the preclinical stage of research.

INTRODUCTION. Antipsychotic-induced metabolic syndrome (AIMetS) is a common adverse reaction to the pharmacotherapy of psychiatric and addiction disorders. However, interindividual variability in the metabolism of antipsychotics may limit the sensitivity and specificity of known blood-based biochemical biomarkers of AIMetS for assessing the safety of psychopharmacotherapy and the risk of AIMetS in patients with schizophrenia spectrum disorders. In recent years, circulating microRNAs have been considered as new and promising epigenetic biomarkers of AIMetS.

AIM. This study aimed to evaluate the potential of circulating microRNAs as epigenetic biomarkers for the prediction and early diagnosis of AIMetS.

DISCUSSION. The authors analysed the results of academic and clinical research published from 2012 to 2024 with a focus on the role of circulating microRNAs involved in the key AIMetS pathogenesis and progression pathways. This review presents novel international approaches to using primary and additional clinical and biochemical biomarkers of AIMetS and demonstrates the advantages of microRNAs as epigenetic biomarkers of AIMetS. The article summarises data on the roles of microRNAs in the mechanisms of AIMetS development (oxidative stress, systemic inflammation, adipocyte differentiation, lipid and glucose metabolism, appetite regulation, and changes in neuropeptide Y and orexin expression, leptin sensitivity, and testosterone, thyroid and parathyroid hormone levels).

CONCLUSIONS. Detecting changes in the expression of circulating microRNAs in easily accessible samples (blood, saliva, urine, etc.) is a promising alternative method for predicting and diagnosing AIMetS. The second part of this review will explore the role of circulating microRNAs as epigenetic biomarkers for developing the main manifestations of MetS and AIMetS and will classify microRNA signatures according to the risk of developing AIMetS.

INTRODUCTION. The first part of this article discussed antipsychotic-induced metabolic syndrome (AIMetS) as a common adverse reaction to the pharmacotherapy of psychiatric and addiction disorders. The authors presented a review of basic and additional clinical and biochemical biomarkers of metabolic syndrome (MetS) in general and AIMetS in particular in patients with schizophrenia spectrum disorders and outlined approaches to measuring these biomarkers. Detecting changes in the expression of circulating microRNAs in the blood can be considered a promising method for predicting and diagnosing AIMetS.

AIM. This study aimed to evaluate the role of circulating microRNAs as epigenetic biomarkers of the key components of AIMetS pathogenesis.

DISCUSSION. The authors reviewed and collated the results of academic and clinical research (2012–2024) with a focus on the role of circulating microRNAs involved in the key AIMetS pathogenesis and progression pathways. The authors analysed the results of studies on the role of circulating microRNAs in the blood as regulators of the key components of MetS and AIMetS pathogenesis. The studied components of pathogenesis included oxidative stress, systemic inflammation, adipogenesis regulation (and abdominal adiposity development), lipid metabolism, high- and low-density lipoprotein cholesterol homeostasis, atherogenesis, and hepatic steatosis, as well as the regulation of insulin and leptin sensitivity, glucose metabolism and appetite, and insulin, neuropeptide Y, orexin, thyroid and parathyroid hormone expression. A personalised assessment of the safety of pharmacotherapy may depend on the pattern of circulating microRNAs that induce or inhibit the main components of AIMetS pathogenesis. The differences in the results of the reviewed microRNA studies may be due to the differences in the design of these academic (mainly) and clinical studies and their lack of consideration for modifiable and unmodifiable risk factors for developing AIMetS. The authors proposed a microRNA classification according to the level of risk of developing AIMetS.

CONCLUSIONS. The findings demonstrate that the sensitivity and specificity of epigenetic biomarkers of AIMetS can vary widely, depending on the nature of their influence (predictive or protective) on one or several pathogenetic components of this widespread adverse reaction to psychopharmacotherapy. The most studied microRNAs are predictive biomarkers of oxidative stress (miR-1, miR-21, miR-23b, miR-27a, etc.) and systemic inflammation (miR-21, miR-23a, miR-27a, etc.) in patients at high risk of developing MetS and AIMetS. Promising epigenetic biomarkers of AIMetS include microRNAs that affect the expression of and sensitivity to neuropeptides, including neuropeptide Y (miR-let7b, miR-29b, miR-33, etc.), leptin (miR-let7a, miR-9, miR-30e, etc.), and orexin (miR-137, miR-637, miR-654, etc.).

INTRODUCTION. Allergic drug reactions in hospitalised patients limit the opportunities for rational pharmacotherapy and increase the risk of polypharmacy due to the need for managing the patient’s condition and prescribing anti-allergic agents. An objective assessment of the prevalence of inpatient allergic drug reactions and a categorisation of medicinal products are critical for treatment adjustment and will lead to both a significant improvement in clinical outcomes for patients and a reduction in the financial burden for the healthcare system. The Global Trigger Tool (GTT) methodology is based on analysing medical records and capturing specific triggers, which makes the GTT easily applicable in clinical practice.

AIM. This study aimed to investigate the applicability of the GTT in studying the prevalence of allergic drug reactions in patients admitted to a multidisciplinary hospital.

MATERIALS AND METHODS. This study used the GTT in retrospective pharmacoepidemiological analysis of medical records of patients admitted to City Clinical Hospital 24 of the Moscow City Health Department from 1 October 2022 to 1 April 2023. The study included medical records of patients treated in the internal medicine and surgery departments during the specified period and excluded those of allergology patients.

RESULTS. A total of 8,934 patients were admitted to the internal medicine and surgery departments during the analysed period. Triggers suggestive of allergic drug reactions were identified in 229 (2.6%) of their medical records. This would correspond to a prevalence of 2,563 cases per 100,000 patients. However, the analysis of prescriptions, diary cards, and clinical and laboratory findings identified only 52 (22.7%) true triggers of allergic drug reactions. In the remaining 177 (77.3%) cases, the triggers were classified as false positives, as anti-allergic agents were prescribed before or concomitantly with the suspected medicinal product, presumably, to prevent potential allergic reactions. The main groups of medicinal products suspected to cause allergic reactions were systemic antimicrobial agents (22 (40.7%) products, in particular, 14 (20.3%) beta-lactam antibiotics) and monoclonal antibodies (21 (38.9%) products).

CONCLUSIONS. The true prevalence of allergic drug reactions was 0.58%, which corresponds to 582 cases per 100,000 patients. The study demonstrated the effectiveness of the GTT in identifying allergic drug reactions in real-world clinical practice. The exclusion of false triggers, first of all, anti-allergic agents prescribed as prophylaxis, significantly reduces the bias in estimating the true prevalence of allergic drug reactions and the risk of overdiagnosis.

INTRODUCTION. Hepatotoxicity is the leading cause of isoniazid discontinuation, significantly reducing the efficacy of antituberculosis therapy, increasing the risk of disease relapse, and contributing to secondary drug resistance in Mycobacterium tuberculosis. The development of hepatotoxic reactions to isoniazid is associated with genetic variations in the activity of N-acetyltransferase 2 (NAT2), an enzyme responsible for hepatic biotransformation of the medicinal product. Dose reduction may prevent liver damage in slow acetylators. However, there is no unified algorithm for dosing this antituberculosis medicinal product based on the results of pharmacogenetic testing.

CASE DESCRIPTION. A 35-year-old man, a Yakut, was diagnosed with A16.0 Focal tuberculosis in the upper lobes of both lungs (S1–2) at the stage of infiltration without isolation of Mycobacterium tuberculosis in 2022 and was treated in the respiratory tuberculosis department of the E.N. Andreev Phthisiology Research-Practice Center, Republic of Sakha (Yakutia). Diagnosis was confirmed via clinical, laboratory, and imaging findings. Initial therapy included a daily oral combination comprising isoniazid (500 mg), rifampicin (600 mg), pyrazinamide (1750 mg), and ethambutol (1200 mg). During the intensive of therapy, the patient developed moderate hepatocellular liver damage, which manifested as nausea, vomiting (one episode), weakness, and epigastric pain. Serum alanine transaminase (ALT) increased to 665.5 U/L and aspartate transaminase (AST) increased to 218.8 U/L. Ultrasound examination revealed hepatomegaly, diffuse hepatic and splenic parenchymal changes, chronic cholecystitis, and reactive pancreatitis. Pharmacogenetic testing identified NAT2 allelic variants (*5, *11, *12) associated with slow isoniazid acetylation. When treatment continued, the dose of isoniazid was reduced to 300 mg/day; the patient took the other medicines at the same doses. The tolerability of antituberculosis therapy was satisfactory, and hepatotoxic reactions did not develop. The intensive phase of tuberculosis treatment was 64 days. Showing clinical and radiological improvement, the patient was discharged from the hospital. Therapy in the continuation phase included a combination of isoniazid (300 mg) and rifampicin (600 mg) once a day for 120 days. After completion of therapy, the patient was considered clinically cured and was transferred to group III of dispensary observation (regular follow-up visits).

CONCLUSIONS. Individualisation of isoniazid dosing according to the results of pharmacogenetic testing allowed the medical team to continue treatment of the patient with drug-sensitive pulmonary tuberculosis and to avoid recurrent development of isoniazid-induced liver damage.