INTRODUCTION. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are used for the treatment of type 2 diabetes mellitus, obesity, weight reduction, and weight control. Owing to their weight-loss and appetite-suppressant effects, information about these agents has spread widely in the mass media and social networks. A notable aspect of their use worldwide is the widespread practice of self-medication. We present a case of off-label self-medication with the prescription drug tirzepatide. CASE REPORT. A 51-year-old woman (BMI 22.9 kg/m 2 , without type 2 diabetes mellitus) self-injected 5 mg of tirzepatide to lose 2–3 kg of body weight. The subsequent self-administration of the prescription medications metoclopramide and furosemide without consulting a physician to relieve nausea, vomiting, and elevated blood pressure led to adverse drug interactions with fluoxetine and bisoprolol, which the patient was taking regularly, and resulted in multiple life-threatening conditions (extrapyramidal disorders, serotonin syndrome, severe electrolyte disturbances, QTc interval prolongation, and rhabdomyolysis) requiring hospitalization. CONCLUSIONS. Self-medication with tirzepatide at an inadequately high starting dose of 5 mg was the trigger that initiated a cascade of predictable but severe adverse drug reactions. The subsequent uncontrolled use of prescription medications to relieve the symptoms without adherence to dosage regimens and frequency of administration, as well as without consideration of potential drug interactions, led to the development of life-threatening conditions. This clinical case highlights the problem of popularization of GLP-1/GIP receptor agonists in the mass media and underscores the need for physician supervision and proactive patient education about the risks, especially in the presence of concomitant pharmacotherapy.
INTRODUCTION. Amfedazole, which belongs to the class of benzimidazole derivatives, exceeds quinidine, novocainamide, etmozine, and amiodarone in terms of antiarrhythmic activity in supraventricular rhythm disorders. Amfedazole increases the effective refractory period, affects transmembrane ion currents and prolongs the action potential, prolongs the QT and QTc intervals, and also produces anti-ischemic and antifibrillatory effects. Thus, conducting preclinical studies of this compound is promising. AIM. To study the toxicokinetic properties, biotransformation, interaction with cytochrome P450 isoforms, and excretion of amfedazole to gain insight into its toxic effects. MATERIALS AND METHODS. Toxicokinetic experiments were performed on 119 adult male white Wistar rats weighing 225±25 g and aged 4–5 months, and 54 adult male white outbred mice weighing 23±3 g and aged 2–3 months. Amfedazole was administered intraperitoneally as a single dose of 6 mg/kg (subtoxic dose). Blood, organ, tissue, and excreta samples were collected over 172 hours. Quantitative analysis was performed using a Shimadzu high-performance liquid chromatography (HPLC) system with a diode matrix (DM) detector. The possible metabolites of amfedazole were predicted using the PALLAS program (CompuDrug Chemistry Ltd.). The effect of amfedazole on the biotransformation enzyme system was studied using the test substrates hexobarbital, midazolam, alprazolam, and chloral hydrate (doses of 1.7 and 6 mg/kg). RESULTS. When administered as a subtoxic dose, amfedazole was detected in the animals’ blood for up to 5 hours postdose, with C max at 30 minutes after administration: AUC=24.39 µg/mL×h, t 1/2 =2.33 h. Amfedazole was extensively distributed into the studied organs and tissues and was excreted mainly via the kidneys. Amfedazole was biotransformed, presumably by the CYP3A isoenzyme. Amfedazole, administered at a subtoxic dose, was excreted mainly via the kidneys and, to a lesser extent, via the intestines within 72 hours. CONCLUSIONS. The toxicokinetic study of amfedazole showed that it was detected in the blood almost immediately after administration. The peak concentration of the active substance was reached at 30 minutes, and by 5 hours its level decreased below the limit of quantification. Amfedazole was distributed into the liver, kidneys, and heart. Administered at a subtoxic dose, amfedazole was excreted within 72 hours, mainly via the kidneys.
INTRODUCTION. Lasmiditan, a new selective 5-HT1F receptor agonist (approved by FDA in 2019), relieves migraine attacks via neuronal inhibition and acts in the central and peripheral nervous systems. Unlike triptans (5-HT 1B/1D receptor agonists), the major group of preparations used in severe migraines, lasmiditan does not cause vasoconstriction.AIM. This study aimed to evaluate the role of lasmiditan, a representative of a new class of neuroactive anti-migraine drugs (ditans), in migraine management based on its mechanism of action as well as effectivnes and safety review.DISCUSSION. Anti-migraine mechanism of action of lasmiditan is due to its selective effect on 5-HT1F serotonin receptors at the trigeminovascular level and in central nervous system pain-modulating pathways.Lasmiditan demonstrated efficacy superior to placebo in three randomized clinical trials (SAMURAI, SPARTAN, CENTURION, n=5,910). In the population of patients with high cardiovascular risk, pain relief was achieved in 31.4% patients (100 mg) and 38.8% (200 mg) compared to 21.3% in the placebo group; the most bothersome symptom was reversed in 44.2% (100 mg) and 48.7% (200 mg) compared to 33.5% in the placebo group. The sustained pain relief was maintained in 13.6% and 17.3% of patients (100 and 200 mg, respectively).Adverse events had the central character and were dose-dependent: dizziness (14.7%), paresthesia (5.7%), somnolence (5.5%), fatigue (3.8%), nausea (3.4%), muscle weakness (1.3%), and hypoesthesia (1.2%); no patient groups (including coronary disease) showed cardiovascular complications. Most adverse events were mild to moderate, while their incidence decreased with the long-term use of lasmiditan. There were rare reports of serotonin syndrome in randomized clinical trials and post-marketing experience. Impaired alertness and response rate was also observed for 8 h after lasmiditan intake.CONCLUSIONS. Lasmiditan may serve as an alternative to triptans in patients at high cardiovascular risk or with poor response to triptans. The potential for central nervous system adverse events should be assessed, alongside with the potential neuropsychiatric complications, concomitant therapy, and occupational factors.
INTRODUCTION. Inconsistent assessment of adverse drug reaction (ADR) remains a relevant pharmacovigilance challenge, particularly regarding insulin biosimilars widely used in the medical practice. This is especially critical for ADRs associated with the pharmacological effects of insulin (hypo- and hyperglycemia) and hypersensitivity reactions, frequently classified as serious due to a lack of adequate clinical context. This discrepancy reduces analytical value of the available data and results in consequent accumulation of inaccurate safety data on a medicinal product.AIM. This study aimed to identify quality improvement approaches to data provided in spontaneous reports and to compare the assessment of ADR seriousness for insulin preparations (insulin aspart, insulin lispro, and insulin glargine) performed by reporters and by pharmacovigilance department of the marketing authorization holder.MATERIALS AND METHODS. A retrospective observational study was conducted using spontaneous ADR reports submitted since the registration of insulin aspart, insulin lispro, and insulin glargine manufactured in the Russian Federation (2021–2024, GEROPHARM LLC). Valid cases were coded using MedDRA v.25.1 and then analyzed. Seriousness criteria were defined according to ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting and the EAEU Good Pharmacovigilance Practice. Descriptive statistics and comparative analysis of MedDRA Preferred Terms were applied.RESULTS. Significant discrepancies were identified: assessments by reporters and marketing authorization holder matched only in 41.3% of cases, while 58.7% demonstrated inconsistency. In 99.6% of the latter cases, reporters classified ADRs as serious, while marketing authorization holder assigned them as non-serious. The most disputable criteria selected by reporters were Important Medical Events (71.1% of all discrepancies) and Life-Threatening Events (25.0%). Disagreements predominantly involved ADRs related to pharmacological effects of insulins and hypersensitivity reactions. More than half of the spontaneous reports contained insufficient information, limiting the accuracy of medical assessment.CONCLUSIONS. The substantial differences in seriousness assessment may be associated with insufficient quality and completeness of the submitted data, frequent use of subjective criteria (such as Life-Threatening and Important Medical Event), and persistent skepticism about biosimilar insulin products. Improving pharmacovigilance accuracy requires educational initiatives and measures aimed at enhancing the quality of spontaneous ADR reporting.
INTRODUCTION. Breast cancer (BC) ranks as second most lethal cancer type among female population. Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant molecular biological subtypes. The metastatic form of triple-negative breast cancer (mTNBC) is an urgent problem in breast cancer therapy, since the treatment effectiveness depends on multiple factors. Analysis and assessment of adverse chemotherapy reactions is essential for high-quality medical care.AIM. This study aimed to assess the risks of adverse drug reactions and the severity of their consequences during mTNBC chemotherapy in order to develop management and prevention strategies for these reactions.MATERIALS AND METHODS. The methods included content analysis of scientific publications, regulations, Russian national standards of BC medical care in adults, clinical recommendations for adult BC therapy and a retrospective analysis of primary medical records covering BC patients at Astrakhan Regional Clinical Oncological Dispensary in 2023-2024.RESULTS. The study established therapeutic strategies of the first- (doxorubicin + cyclophosphamide, docetaxel) and second-line drug therapy (paclitaxel + carboplatin, eribulin) for mTNBC. Established adverse drug reactions that occur after administration include febrile neutropenia, cardiotoxicity, peripheral neuropathy, drug resistance, nausea, and vomiting. The highest risk category for the two lines of therapy was assigned to febrile neutropenia, the lowest — to nausea and vomiting.CONCLUSIONS. The incidence and profile of adverse reactions vary significantly depending on chemotherapy protocols and lines used in patients with mTNBC. Haematological toxicity being predominant for each of the protocols, anthracycline-cyclophosphamide strategy bears the highest risk of adverse drug reactions. Eribulin and docetaxel monotherapies are the safest options. The study results can serve as a basis for improving and optimising mTNBC chemotherapy.
INTRODUCTION. Gonadotropin-releasing hormone (GnRH) products are used to treat reproductive system disorders both in females (for temporary medically induced menopause) and males (in order to suppress certain functions in benign and malignant diseases). The urinary and reproductive systems are closely linked in their ontogenesis and phylogenesis. A summary and critical analysis of the existing data will allow us to assess the effects of GnRH products on the urinary system and identify areas for further research.AIM. This study aimed to identify benefits and risks of GnRH therapy for the urinary system in order to optimize hormone therapy in various conditions.DISCUSSION. Analysed preclinical and clinical studies showed that GnRH and its metabolites are primarily excreted by the kidneys. GnRH therapy affects the renal system: nephrolithiasis may develop due to calcium olism disorders; cases of acute kidney injury, including acute renal failure, have been reported as well. Bladder structures include GnRH receptors, resulting in high GnRH binding to bladder cells and effective GnRH therapy. However, there are sex-specific differences; high GnRH and its receptors in bladder cancer are associated with better overall survival in men. High expression of GnRH receptors on cancer cells determines the success of GnRH therapy in the bladder tumours. GnRH analogues show a positive clinical effect in women with age-related menopausal incontinence, directly influencing bladder tissue, the sphincter system, and urethra. However, the data in some of the reviewed articles were insufficiently substantiated and lacked statistical validation. A number of studies reported no effect of GnRH therapy on renal and urethral function, or on bladder tumour outcomes.CONCLUSIONS. The apparent lack of data and inconsistent publications on each aspect of GnRH influencing the urinary system indicate a paucity of research for this issue. Further applied and fundamental research of GnRH effects on the urinary tract is warranted to assess the benefit-risk ratio, develop less toxic anticancer agents, and effectively prevent and treat adverse reactions during hormone therapy for various diseases.
INTRODUCTION. Chronic obstructive pulmonary disease (COPD) is a leading cause of death and significant economic losses for the healthcare system. While there is a trend towards decreasing COPD incidence in Europe, Russia saw the incidence increase by 5%, and the economic burden rose from 0.20% to 0.34% of GDP in 2022–2023. International and nationwide best practices necessitate a further analysis to identify the ways of reducing financial burden on the Russian healthcare system.AIM. This study aimed to identify and evaluate feasibility for the most effective ways to reduce the financial burden when managing COPD patients in the Russian Federation.DISCUSSION. Key differences in COPD epidemiology and cost structure were identified between Russia and EU countries. In the European Union (2001–2019), COPD incidence decreased among men (–9.7%) and increased among women (+4.3%) due to higher smoking rates. In Russia, the incidence continued to grow (+5%), while the mortality remained high (26% of the total death causes). In the EU, main direct costs were attributed to inpatient care (35–64%) and drug therapy (~25%), while the share of indirect costs reached 61–83%. Russian cost structure differed: the share of indirect costs was 92.6%, while among the direct costs, 76.1% was attributed to medicines supply, and only 18.7% covered inpatient care.Effective burden reduction included: smoking cessation (reduced exacerbation risk by 39.7%; hazard ratio 0.65 for abstinence >10 years); prophylactic vaccinations (reduced hospitalizations by 50%, while vaccine refusal increased mortality 162-fold); modern pharmacotherapy (triple therapy: long-acting anticholinergic agents + long-acting beta2-agonists + inhaled glucocorticoids, reduced exacerbation frequency by 24% and mortality by 49%), and pulmonary rehabilitation (OR for hospital readmissions 0.44) still presented poorly in Russia (~10%).CONCLUSIONS. To reduce COPD economic burden in the Russian Federation, it is necessary to increase the coverage with preventive measures (tobacco control programs, immunization), develop pulmonary rehabilitation programs using digital technologies, implement modern pharmacotherapy regimens, and improve physicians’ expertise via continuing medical education.
INTRODUCTION. Bacteriophage preparations are effective in bacterial infections, including multi-drug resistant pathogens. In order to develop and widely use standardized and personalized phage therapy, current regulations and guidelines governing the development, clinical trials, registration, and distribution of bacteriophage preparations necessitate an update.AIM. This study aimed to analyze global trends in the development, registration, as well as efficacy and safety assessment of bacteriophage preparations to identify promising areas for development of phage therapy in the Russian Federation.DISCUSSION. Despite the proven efficacy, rapidly expanding resistance of pathogens, complicated delivery to the infection focal point, and poorly understood safety of phage therapy prevent wide implementation of bacteriophages in clinical practice. In case standardized bacteriophage preparations show decreased effectiveness, a modified formulation may be warranted, with the updated strains; however, no appropriate legislative mechanisms exist so far. To date, 14 standardized bacteriophage preparations were registered and used in the Russian Federation, with completed clinical trials. Personalized phage therapy is used to a lesser extent. In the United States and the European Union (EU) member states, strict requirements for safety and efficacy evidence are placed; phage therapy is not an official treatment method but is used in individual cases. In some countries, particularly Poland and Belgium, phage therapy is under close supervision, while the use of bacteriophages remains individualized. In 2025, a draft of a concept document stipulating development and production of bacteriophage agents for human use was developed in the EU. However, none of the drugs for phage therapy was approved according to the EU and US requirements.CONCLUSIONS. Russian Federation has a unique experience of using standardized phage preparations. Regulatory algorithms of modifying the formulation of a registered bacteriophage preparation are still to be developed both in the Russian Federation and other countries. Worldwide harmonization of the regulatory base is an essential element of global development; points to consider include new EU and US initiatives on developing regulatory documents, intensified research aimed at overcoming bacterial resistance to bacteriophages, and long-term safety studies.
INTRODUCTION. Social media (social networks, forums, review websites, etc.) contain a lot of essential information about adverse drug reactions (ADRs). So far, no previous studies of social media were conducted in the Russian Federation.AIM. This study aimed to evaluate the possibility of using VKontakte social network as an additional source of ADR reports exemplified by users mentioning the use of metformin, azithromycin, metronidazole, and clotrimazole.MATERIALS AND METHODS. VKontakte social network was monitored for the period of 09.01.2023 to 03.31.2024 using LITVISOR® software to collect entries mentioning the use of metformin, azithromycin, metronidazole, and clotrimazole (International Non-proprietary Names). We analyzed the completeness of information about the reporters and the patients, as well as ADRs and special safety situations. The identified safety information was encoded using MedDRA terminology; their seriousness and listedness were assessed.RESULTS. A monitoring of VKontakte social network resulted in 4,969 entries on the use of azithromycin, metformin, metronidazole, and clotrimazole. We identified 195 ADRs related to 15 systemic organ classes; of them, 93.3% were classified as non-serious and 6.7% as serious. 85.56% of ADRs were expected, while 14.4% were unexpected. Cases of off-label use, overdose, and use in pregnant women were identified. In 35.5% of spontaneous reports, the reporter was identified, in 89.5%, the patient’s sex was known, and in 36.3%, the patient’s age was known.CONCLUSIONS. The findings show that the monitoring of VKontakte social network is a promising source of data on drug safety approved in the Russian Federation. The study confirms the fundamental possibility of validating the entries from the social network users as spontaneous reports.
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. In the Russian Federation, risk-based approaches/methods to assess the safety of medicinal products have been used since 2016, but existing models based on them are few and applicable mainly to healthcare organizations. This underscores the need to systematise risk assessment procedures for medicinal products within pharmacovigilance frameworks by pharmacovigilance specialists using a risk-based approach in the risk management system. AIM. This study aimed to analise of the key tools of the risk-based approach and optimise their application in medicinal product risk management systems. RESULTS. A four-stage risk management framework for medicinal products was developed using a risk-based methodology: identification of risks associated with medicinal product use, determination of risk factors specific to individual medicinal products, correlation and evaluation of data for each risk factor with each of the identified risks and a conclusion on the benefit-risk ratio of medicinal products use. Key tools for implementing this approach include: 1) organization of work with information about adverse drug reactions; 2) active monitoring of drug safety; 3) development, implementation, and evaluation of risk mitigation measures; 4) targeted communication of safety issues to healthcare professionals, patients, and caregivers. Spontaneous reports, reports of adverse drug reactions received on request from the holder of the registration certificate, data from pharmacoepidemiological studies, information published in the scientific medical literature, as well as Internet resources are used as sources of information to identify the risks of adverse drug reactions at the post-registration stage of medicinal products circulation. Risk factors for the development of adverse drug reactions in the use of medicinal products are physiological changes in the patient's body, gender, age, presence of comorbidities, genetic predisposition, differences in pharmacokinetics and pharmacodynamics of medicinal products depending on the patient's age, use of off-label medicinal products. A five-step algorithm for medicinal product risk assessment was developed: parameters and objectives of risk evaluation, data sources, potential risks, severity and probability of risks, and benefit-risk ratio assessment. Additional risk minimisation measures are summarised. CONCLUSIONS. The proposed variant of the risk-based approach using available tools can be used by pharmacovigilance specialists in drug risk management.
INTRODUCTION. Both low-molecular-weight and unfractionated heparins are frequently used to prevent and treat COVID-19-associated thrombosis, placing patients at an increased risk of developing heparin-induced thrombocytopenia (HIT) as an adverse reaction. Vaccination has played a key role in combating the COVID-19 pandemic, yet careful consideration is needed for potential adverse events following immunisation, in particular, for vaccine-induced immune thrombotic thrombocytopenia (VITT) associated with adenoviral vector vaccines.AIM. This study aimed to conduct a comparative analysis of HIT and VITT prevalence, pathogenetic mechanisms, clinical manifestation patterns, and treatment considerations in order to select the most effective therapeutic strategies for each condition and optimise them for clinical use.DISCUSSION. This comparative analysis covers full-text systematic reviews, meta-analyses, clinical trial reports, review articles, and case reports in Russian and English published from 1992 to March 2024 and retrieved from bibliographic databases, including PubMed.gov, Lens.org, and eLIBRARY.RU. According to the analysis, HIT incidence is higher in women who had previous cardiovascular or orthopaedic surgery, women on extracorporeal membrane oxygenation, and critically ill patients with COVID-19, whereas VITT is more common in women under 55 taking oral contraceptives and immunised with an adenoviral vector vaccine. The first signs of HIT usually show 5–10 days after heparin initiation, and the time of VITT onset varies from 4 days to 1 month. In contrast to HIT, VITT is characterised by atypical localisation of thrombosis. In HIT, platelet-activating anti-heparin/platelet factor 4 IgG antibodies bind to FcγRIIA receptors, which leads to platelet activation and aggregation. In VITT, the polyanion that triggers the immune system is either hexon protein or adenoviral vector DNA from neutrophil extracellular traps. Potential treatments for HIT include heparin discontinuation or switching from unfractionated heparins to low-molecular-weight heparins, fondaparinux sodium, or non-heparin anticoagulants (direct thrombin inhibitors and oral anticoagulants). Treatment options for VITT include non-heparin anticoagulants, fondaparinux sodium, and intravenous immunoglobulins. Switching to non-heparin anticoagulants in VITT is optional. Venous thrombosis is the main cause of death in both adverse reactions.CONCLUSIONS. Medical professionals should be alert to the potential development of VITT after vaccination with adenoviral COVID-19 vaccines and HIT during the use of heparins. Patients with suspected adverse reactions require prompt hospital admission, haematologist consultation, and laboratory and instrument testing.
INTRODUCTION. Valsartan+sacubitril (a combination of neprilysin inhibitor and angiotensin II receptor blocker) effectively reduces blood pressure (BP) and has the potential to improve metabolic parameters. However, despite this class of drugs being included in clinical guidelines, the specific indications in patients with arterial hypertension are not clearly defined, thus requiring a more detailed study.AIM. This study aimed to assess valsartan+sacubitril combination used for treatment of arterial hypertension in adults in outpatient settings, specifically regarding its efficacy, safety, and impact on overall clinical outcomes and quality of life.MATERIALS AND METHODS. The study is an open prospective longitudinal observation with active control. The study was conducted at State Autonomous Healthcare Institution “City Polyclinic No. 12” (city of Tyumen, Tyumen region). Patients were recruited from 01.10.2022 till 31.03.2025. For each patient, the observation period was 3 months for stage 1 (n=550) and 1 year for stage 2 (n=160). BP was controlled at the inclusion, at the end of stage 1, and after 3, 6, and 12 months of treatment. At stage 1, patients were divided into 4 groups: angiotensin-converting-enzyme inhibitor (ACE) + diuretic (n=189), ACE inhibitor + calcium channel blocker (CCB) (n=121), angiotensin II receptor blocker (ARB) + diuretic (n=119), ARB + CCB (n=121). At stage 2, patients not achieving target BP ≤140/90 mmHg (n=160) were randomised into 2 groups: study group (n=80), patients receiving valsartan+sacubitril + diuretic/CCB; and control group (n=80), receiving a triple combination of ARB + diuretic + CCB or ACE inhibitor + diuretic + CCB.RESULTS. At stage 2, the rate of patients achieving target BP was 93% in the study group vs. 83% in the control group after 3 months; 94% vs. 88% after 6 months; and 99% vs. 98% after 12 months, respectively. Average daily systolic blood pressure and diastolic blood pressure after 3 months of treatment had a statistically significant difference in favour of the study group (p<0.05). Noteworthy is the positive effect on the reduction of peak average daily systolic, diastolic, as well as pulse BP, and blood pressure load (p<0.001). After 6 months, the difference between the groups remained the same for all the decreasing parameters (according to 24-h blood pressure monitoring). Only after 12 months did patients in the control group receive a comparable reduction in the parameters; no statistically significant differences were revealed (p>0.05). EQ-5D showed higher quality of life in the study group after 12 months, the average score being 0.82±0.08 vs. 0.69±0.10 in the control group (change +0.17 vs. +0.05; p<0.05). All adverse reactions for valsartan+sacubitril were predictable; the differences in the frequency of treatment discontinuation between the groups were not statistically significant.CONCLUSIONS. Valsartan+sacubitril has demonstrated efficacy and safety in hypertension in adults. This combination can be recommended as a second-line treatment in case of ineffective two-component regimens of the first-line antihypertensive therapy.
INTRODUCTION. Mathematical models are actively used in biomedical research, including efficacy and safety prediction of medicinal products. Scientific Centre for Expert Evaluation of Medicinal Products has developed and implemented a method for preclinical benefit-risk assessment of medicinal products. The method is based on the binary classification of variables used to calculate WoE (Weight of Evidence) and IV (Information Value) predictors. Calculation algorithms for WoE and IV are based on Bayesian model of prior probability, which allows for risk prediction and informed decision-making regarding pharmacotherapy and its ability to reduce the genotoxic and embryotoxic effects of environmental teratogens. However, confirmed predictive ability warrants pharmacological validation of a potential corrector and the predictive system computation quality.AIM. This study aimed to validate preclinical assessment method of the benefit-risk ratio by correcting reprotoxic effects of peat smoke in rats with pharmacotherapy as a case study.MATERIALS AND METHODS. The study used experimental and statistical analysis. A method developed by Scientific Centre for Expert Evaluation of Medicinal Products was used to confirm predictive significance of preclinical benefit-risk assessment for pharmacotherapeutic correction of peat smoke-induced embryotoxic effects. In order to validate benefit-risk assessment mathematical model and the corrective pharmacological properties of fabomotizole in genotoxicity and embryotoxicity models induced by peat smoke in rats, logistic regression and ROC analysis methods were applied.RESULTS. AUC analysis (0.701; 0.617–0.786) within pharmacological validation showed that fabomotizole corrective capacity in rats was predicted in the range from “unsatisfactory” to “good” (0.500; 0.239–0.761). This corresponds to WOE/IV estimates, from “low” to “moderate” weight (0.34; –0.99) and “weak” to “strong” information value (0.02; 0.45). Computation quality test for genotoxicity showed an AUC of 0.554 for the predicted probability and 0.432 for the predicted group (random guessing). For embryotoxicity, AUC was 0.701 and 0.782, indicating good predictive ability of the model.CONCLUSIONS. The validation study has confirmed the predictive value of WoE and IV. The benefit-risk model based on Bayesian prior probability has shown high convergence with ROC analysis in assessing genotoxicity and embryotoxicity of peat smoke, as well as corrective capacity of fabomotizole.
INTRODUCTION. Ophthalmotoxicity assessment of potential drugs is a highly meaningful element of preclinical trials that reflects modes of action and pharmacological effects of a chemical compound on the eyes in topical and systemic use. However, there is no relevant common algorithm for ophthalmotoxicity assessment, suggesting expediency of summarising Russian and foreign experience.AIM. This study aimed to develop an algorithm assessing ophthalmotoxicity of medicinal products in preclinical in vivo studies based on Russian and international guidelines.DISCUSSION. Study approaches of chemical compound ophthalmotoxicity were analysed in Russian and international regulatory documents (Guidelines for conducting preclinical studies of medicines, GOST 34658-2020, Guidelines of Organisation for Economic Co-operation and Development (OECD) No. 450 and No. 263). The recommended methods prove to be applicable in preclinical studies and make it possible to study the effect of chemical compounds on the structure (ophthalmoscopy, biomicroscopy, optical coherence tomography) and functions (electroretinography) of the eyes. The study included basic information on the comparative eye anatomy and physiology in mice, rats, and rabbits, crucial for studying irritant and retinotoxic effects and translating the results into clinical trials. Ophthalmotoxicity research methods and their practical application in typical laboratory animals were described in detail considering their anatomy and physiology. Based on generalised study data, a comprehensive differential approach is proposed for ophthalmotoxicity study of the developed medicinal products.CONCLUSIONS. The proposed algorithm assessing ocular toxicity of ophthalmic and systemic drugs makes it possible to optimise the design and schedule of preclinical studies in animals and improve the safety of drug use in humans.
Modern psychopharmacological research complements traditional monoamine theories by adopting new data on the role of neuroinflammation, the microbiome, and impaired neuroplasticity in the development of mental disorders. An insider perspective (an interview with a practicing specialist) is essential for assessing the real risks and prospects at an expert level, as well as understanding the complex ethical, medical, and social challenges associated with the development of new psychotropic medications. Renad N. Alyautdin, Dr. Sci. (Med.), Editor-in-Chief, Safety and Risk of Pharmacotherapy, Department for Medicine Safety Evaluation, Scientific Centre for Expert Evaluation of Medicinal Products, and Marina A. Kinkulkina, Dr. Sci. (Med.), Corresponding Member of RAS, Head of the Department of Psychiatry and Narcology, I.M. Sechenov First Moscow State Medical University, discussed the search for new therapeutic targets, the challenges of developing and implementing innovative drugs, and the options for minimising treatment risks for personalised medicine within the context of mental health treatment in the era of evolving psychopharmacotherapy.
INTRODUCTION. Despite its relatively low share in the structure of oncological incidence, cutaneous melanoma (CM) is one of the most cost-intensive nosologies. The emerging new combination treatment regimens require regular pharmacoeconomic monitoring.AIM. This study aimed to evaluate the current structure, dynamics, and costs of drug therapy in Moscow region over 2020–2022 based on pharmacoepidemiological and pharmacoeconomic analysis of subsidised drug provision in order to identify key regional trends.MATERIALS AND METHODS. Primary depersonalised data were obtained from patient medical records in the Unified Medical Information and Analytical System (EMIAS). The analysis included total number of patients and their clinical profile (gender, age, diagnosis code); for the drugs, international non-proprietary name, dosage form, dosage, number of packages sold, and total cost was analysed. Cost analysis considered both total cost and structure in terms of selected international non-proprietary names. An additional analysis was conducted for a three-year period.RESULTS. Data from 1,522 patients diagnosed with ICD-10 C43.0–43.9 were examined (465 patients in 2020, 526 patients in 2021, and 531 patients in 2022). Over the study period, the number of patients increased by 14%, with gender structure gradually changing and the ratio of men decreasing from 44.3% to 39.9%. Two-thirds of the patients received drug therapy for the primary disease. Total outpatient costs ranged from 407.6 million rubles in 2020 to 615.3 million rubles in 2022. CM share of drug therapy averaged 98% of the total cost. Over 2020–2022, the highest patient coverage, number of packages, and cost level was attributed to dabrafenib+trametinib and vemurafenib+cobimetinib combinations. They accounted for an average of 85% of all patients and almost 99% of all costs. Over the 3-year period, there was a twofold cost increase for dabrafenib and trametinib, with a comparable twofold cost decrease for vemurafenib and cobimetinib.CONCLUSIONS. Pharmacotherapy structure, dynamics, and cost has been evaluated in CM patients of Moscow region over 2020–2022. The obtained data can be used to optimise pharmacotherapy of CM patients at the regional level by widely introducing both clinical and pharmacoeconomic evaluation principles of treatment approaches.
INTODUCTION. On 1 March 2025, an updated Pharmacovigilance procedure of medicinal products came into force complying with order of Roszdravnadzor No. 3518 as of 17 June 2024. Analysing reports submitted to Roszdravnadzor is a method that allows to adapt pharmacovigilance of a healthcare facility to the new requirements.AIM. This study aimed to assess completeness and accuracy of reporting adverse drug reactions (ADR) to Roszdravnadzor. These data are essential to draft recommendations for filling out “Adverse drug reaction / no effect” form.MATERIALS AND METHODS. The authors performed a post-hoc analysis of ADR reporting forms over 2009–2019 taken from Irkutsk region Safety monitoring centre and local data from Roszdravnadzor Automated Information System (2019–2023). Naranjo scale was used to assess the accuracy of the causal relationship between ADRs and medicinal product.RESULTS. During the study period, medical facilities of Irkutsk region have submitted 2,655 spontaneous reports. The reporting deadlines were met in 91.3% of the cases. The ADR summary fully described the patient and medicinal products in 87.1% of the cases. Of the 2,655 ADRs, 72.3% described the underlying disease. The most common mistake (3.1%) was incomplete patient information (weight, allergic reactions, and laboratory findings). Lack of therapeutical effect was described in 2.0% of the cases. Drug misuse was reported in 21.5% of spontaneous reports (mostly prescribing antibacterials for viral infections). Causal relationship between the ADR and medicinal products was found in most of the cases (94.5%), the accuracy being classified as certain (25.0%), probable (23.2%), possible (23.2%), and doubtful (3.5%).CONCLUSIONS. The analysis showed that most ADR reports were submitted in due time and in the scope stipulated by regulatory documents. In order to correctly assess the accuracy of ADR reports, the form should include as much data on the patient, medicinal products, and ADR as possible. Regularly improving staff awareness of pharmacovigilance procedure and reporting deadlines will increase pharmacovigilance effectiveness of a medical organisation.
INTRODUCTION. Actual effectiveness and safety of dual antiplatelet therapy (DAPT) can be evaluated only when patients genuinely adhere to prescribed therapy. Investigating the causes of non-adherence to DAPT inevitably involves a comprehensive analysis of adverse drug reactions (ADR), their clinical management, and the occurrence of clinically significant ischemic events in patients surviving acute myocardial infarction (AMI).AIM. This study aimed to analyse the adherence dynamics to DAPT in the context of haemorrhagic complications, their pharmacological management, and clinically significant cardiac events in patients over the first year following AMI. The data were provided by Unified Medical Information Analysis System (EMIAS), Moscow, for the years 2021-2023. MATERIALS AND METHODS. A retrospective analysis was performed using EMIAS data on patients who were under outpatient follow-up by cardiologists at a Moscow polyclinic for one year following AMI. "Method based on assessment of all medical records" (WHO) was used to register ADRs. Patient medication adherence was evaluated by tracking prescripton claims for individual DAPT components and in total. Only patients who demonstrated adherence to DAPT during the first six months of therapy (n=168) were included in the analysis.RESULTS. Upon hospital discharge, patients received acetylsalicylic acid 100 mg (97.6%) in combination with a P2Y12 platelet inhibitor, predominantly ticagrelor (76.2%). During the second six-month period, 73 (44.5%) patients lost adherence to DAPT (non-adherent). Haemorrhages of any severity were recorded in 24.4% of patients over the year (total ADRs — 57); and in 15.5% in the first six months. Within 6–12 months, compared to non-adherent patients, the severity of bleeding according to the BARC scale was higher among those who maintained adherence (p=0.035), with serious haemorrhagic ADRs observed only in this group. DAPT adjustment by cardiologists was performed in 29.3% of patients with bleeding, more often in the first half of the year than in the second (22% vs 7.3%; p=0.029). The number of hospitalisations for cardiac reasons in 6–12 months was higher in the non-adherent group (p=0.047), who mainly discontinued acetylsalicylic acid (PDC 52.9±26.9%) for an average of 111.7±37.7 days (“therapy interruption”).CONCLUSIONS. Among patients initially adherent to DAPT in the first six months, only 56.5% maintained adherence in the second half of the year following AMI. The annual incidence of haemorrhagic ADRs was 24.4%. These ADRs were more severe among those who maintained adherence (p=0.035), however, more non-adherent patients were hospitalised for cardiac reasons (p=0.047). Benefit-risk balance of haemorrhages and thrombosis should be monitored for long-term DAPT; personalised approach is feasible in clinical practice, including risk stratification of haemorrhages using PRECISE-DAPT/BARC scales; high-risk patients require early switch to monotherapy (such as clopidogrel after 3–6 months) focusing on the balance between anti-ischaemic effectiveness and risk of haemorrhage.
INTRODUCTION. Following acute coronary syndrome (ACS), patients are at high risk of repeated cardiovascular accidents. They receive intensive lipid-lowering and antiplatelet therapy according to clinical recommendations. However, therapy intensification may entail increased risks of adverse drug reactions. The clinical case describes fatal rhabdomyolysis associated with high-dose rosuvastatin therapy. The risk factors of this adverse reaction have been analysed; knowing the factors can help prevent similar events in patients.CASE REPORT. A 68-year-old patient, male, received continuous therapy with rosuvastatin 10 mg per day for 3 years with good tolerability. After the ACS, rosuvastatin dose was increased to a maximum of 40 mg per day, dual antiplatelet therapy with ticagrelor was prescribed, as well as bisoprolol, amlodipine, omeprazole, perindopril, and spironolactone. Within a month, the patient developed muscle pain and acute renal failure, with clinical and laboratory evidence confirming rhabdomyolysis. Despite intensive therapy, the patient died. An analysis was performed for genetic markers of individual rosuvastatin pharmacokinetics, showing: CYP2C9 *1*1 (normal activity), SLCO1B1 *5*15 (reduced activity for homozygous state), ABCG2 c.421 C/C (normal activity). Literature analysis of drug interaction revealed possible additional increase in rosuvastatin concentrations (up to 2.6 times) associated with ticagrelor inhibiting breast cancer resistant protein transporter activity.CONCLUSIONS. In the present case, fatal statin-associated rhabdomyolysis developed due to two significant factors — pharmacogenetic predisposition and a significant drug-drug interaction of rosuvastatin with ticagrelor, which disrupted the functions of two carrier proteins that determine medicine bioavailability (breast cancer resistant protein) and its transport through the hepatocyte membrane (OATPB1). Pharmacogenetic testing and active monitoring of laboratory values is indicated in such patients in the first days of drug therapy for the timely diagnosis of possible complications; such situations are crucial for the prognosis in patients after ACS following high-dose statin therapy and other medicines with the potential for significant drug interactions.
