Melioidosis: Milestones of the Scientific Studies

Anniversary of melioidosis agent discovery. Discussed are the key advances of world science in the sphere of Burkholderia pseudomallei ecology, epidemiology, clinical picture, and treatment of the disease. Apart from this, summarized are the data on the 50-years long study of melioidosis, carried out by the specialists of Plague Control Agency of the Russian Federation

Risk Management Plan: An Expert Analysis of Changes to the EAEU Good Pharmacovigilance Practice Requirements for the Content and Submission of the Document

The Council of the Eurasian Economic Commission published Decision No. 81 “On Amendments to the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union” on 19 June 2022 and enacted it on 6 December 2022. A risk management plan (RMP) is a key component of pharmacovigilance system documentation to be submitted in the marketing authorisation dossier for a medicinal product.The aim of the study was to review the changes to the requirements for the RMP structure, content, and submission from a regulatory expert’s perspective.Significant changes have been introduced to the requirements set by the regulatory authorities of the Eurasian Economic Union for RMPs for medicinal products. In particular, the requirements for the content of parts and modules of RMPs have been clarified and expanded. Furthermore, the amendments have introduced a new mandatory requirement that the information in parts and modules of the RMP and the dossier for a medicinal product should be consistent. Marketing authorisation holders have been provided with a detailed description of the conditions, procedures, and exceptional situations for submitting RMPs in dossiers. The updated requirements will help marketing authorisation holders improve and streamline their risk management processes

Critical Overview of the Contents of Risk Management Plans for Medicines

The pharmacovigilance system plays one of the key roles in ensuring safety and efficacy of medicine use. The risk management process helps to ensure the most favourable benefit/risk ratio of a medicine or combination of medicines both for the target populations and the general public. Unavailability of a risk management process for medicines may adversely affect the health of the general population. One of the major documents in medicine risk management is the risk management plan (RMP).The aim of the study was to analyse compliance of RMPs submitted as part of registration dossiers with the requirements of the Eurasian Economic Union (EAEU), and to analyse problems arising during their preparation.Materials and methods: the authors analysed 200 RMPs submitted from January 1 until August 31, 2021.Results: it was determined that the most frequent mistakes made by pharmacovigilance officers are related to medicine summaries in RMPs covering several medicines, medicine safety specification parts of RMPs, description of risks in the pharmacovigilance plan and description of risk minimisation measures, and insufficient representation of the key elements of the medicine efficacy and safety overview in the RMP summary. For instance, RMPs often lack information on the epidemiology of indications for target populations in the EAEU, or RMPs may lack some of the major risks reflected in the patient information leaflets, or lack assessment of safety risk minimisation actions, etc.Conclusions: proper preparation of RMPs that would comply with the EAEU Good Pharmacovigilance Practice is inconceivable without further professional training of pharmacovigilance officers

SURVIVAL OF BURKHOLDERIA PSEUDOMALLEI IN CELLS OF TETRAHYMENA PYRIFORMIS CILIATE INFUZORIAN: EFFECT ON TETRAHYMENA ENCYSTMENT ACTIVITY

Objective of the study was to model the interaction of Burkholderia pseudomallei with Tetrahymena pyriformis in vitro and investigate the changes in the population composition of the protozoa when co-cultured with a microorganism.Materials and methods. B. pseudomallei 110, C141, 57576, 107 strains differing in virulence for BALB/c mice were used. The axenic culture of T. pyriformis was incubated with microorganisms in 100 to 1 ratio, at 28 °C, in LB. Samples of co-cultures were examined using light microscopy, by counting the number of trophozoites and cysts in the population. Dynamics of multiplication of B. pseudomallei cultures associated with T. pyriformis was determined through seeding bacteria on a dense nutrient medium to count the grown colonies.Results and conclusions. B. pseudomallei in association with T. pyriformis is ingested by protozoan cells; it multiplies in them and stimulates protozoa encystment. Hereby virulent strain B. pseudomallei 110 induces encystment of T. pyriformis on days 2–4 and complete cell destruction within 7–8 days. Avirulent strain, B. pseudomallei 107, induces full encystment on day 7; significant part of the cysts remains intact on day10. Dynamics of B. pseudomallei growth, co-cultured with T. pyriformis is characterized on day 1 by distinct decrease in the number of viable bacterial cells and increase in it within following 24 hours. Bacteria concentration curves depend on the virulence of the strain: maximum level of B. pseudomallei 110 replication is observed after 48 hours, while that of B. pseudomallei 107 – not less than after 7–8 days

Safety of Antibacterial and Antiprotozoal Medicinal Products

The experts of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on the recalls of antibacterial and antiprotozoal medicinal products and/or the need for labelling updates due to changes in the safety profile. The analysis revealed 16 decisions containing information on the following medicines registered in Russia: ertapenem, сeftriaxone, cefazolin, аmoxicillin, сefoperazone+sulbactam, piperacillin+tazobactam, сlindamycin, teicoplanin, rifampin, co-trimoxazole, hydroxychloroquine

Ivermectin: Evaluation of Efficacy and Safety in COVID-19

The search for an effective and safe COVID-19 therapy involves, among other things, assessment of efficacy of medicines already used for the treatment of other diseases, and having potential antiviral activity against SARS-CoV-2. The relevance of the presented study stems from ambiguous data on the off-label use of the antiparasitic medicine ivermectin for the treatment of COVID-19 patients. The aim of the study was to analyse ivermectin efficacy and safety for COVID-19 treatment, as reflected in the scientific literature. Ivermectin, an antiparasitic medicine from the group of macrocyclic lactones produced by Streptomyces avermitilis, stimulates release of the inhibitory neurotransmitter gamma-aminobutyric acid, which leads to impaired transmission of nerve impulses, paralysis and death of parasites. The results of preclinical studies show ivermectin’s inhibitory activity against a number of RNA and DNA viruses, including SARS-CoV-2. The results of ivermectin clinical studies are ambiguous: a number of studies demonstrated a positive effect on the condition of COVID-19 patients, however, there is currently no convincing evidence of the validity and efficacy of ivermectin use for the prevention and treatment of COVID-19 patients. The safety profile of ivermectin is relatively favourable. Large randomised controlled trials are needed to fully assess the feasibility of using ivermectin in COVID-19

Drug Safety Monitoring—International Information

Experts of the Department for Evaluation of Medicinal Products’ Safety of the Scientific Centre for Expert Evaluation of Medicinal Products analysed administrative decisions of foreign regulatory authorities on limiting the use of some medicinal products and/or the need to introduce changes in patient information leaflets due to changes in the medicines’ safety profiles. The analysis helped to identify 16 administrative decisions that contain information on the following medicines registered in Russia: duloxetine, sertraline, paroxetine, сitalopram, desvenlafaxine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, venlafaxine, vortioxetine, mirtazapine, risperidone, clozapine, aripiprazole, quetiapine, olanzapine, lacosamide, gabapentin, pregabalin

Immune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agents

The introduction into clinical practice of immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1), has improved the prognosis of patients with malignant neoplasms of diff erent localisation. The antitumour eff ect of immune checkpoint inhibitors is based on blocking CTLA-4 and PD-1/PD-L1 signaling pathways and enhancing lymphocyte antitumour activity. However, inhibition of immune checkpoints may lead to dysregulation of immune responses and appearance of a new type of adverse reactions resulting from changes in the activity of immunocompetent cells. The aim of the study was to analyse adverse reactions associated with the use of immune checkpoint inhibitors. It was demonstrated that the structure of immune-mediated adverse reactions varied depending on the class of immune checkpoint inhibitors. The incidence of immune-mediated adverse reactions was higher with CTLA-4 inhibitors as compared with PD-1/PD-L1 inhibitors, and increased signifi cantly in the case of combination therapy. The treatment with CTLA-4 inhibitors most often resulted in skin reactions (rash, itching), gastrointestinal tract reactions (diarrhea, colitis), and endocrine gland problems (hypophysitis). The treatment with PD-1 inhibitors most often led to respiratory disorders (pneumonitis), and in some cases to gastrointestinal disorders (diarrhea, colitis), skin reactions (rash, itching), and endocrine gland problems (hypothyroidism), but they were less common. The treatment with PD-L1 inhibitors was associated with the development of pneumonitis. The development of immune-mediated adverse reactions may require discontinuation of treatment and administration of immunosuppressants, therefore early diagnosis and timely treatment of complications are important prerequisites for successful antitumour therapy. Further study of the mechanisms of immune-mediated adverse reaction development will optimise antitumour therapy with immune checkpoint inhibitors

Assessment of Pharmacovigilance Reporting in Russia

The risk-based approach to pharmacovigilance control implemented in Russia since January 1, 2018 increases the responsibility of manufacturers and developers of medicines. The purpose of the work is to assess the system of Express reporting and Periodic reporting on the safety of drugs in accordance with the relevant requirements of the legislation of the Russian Federation and the Eurasian Economic Union. The article continues a series of publications on recommendations for the preparation of reporting forms on pharmacovigilance. The article presents the results of the assessment of the state of elements of the system of drug safety control in Russia in terms of the preparation of reporting forms in accordance with the current regulatory requirements of national and international legislation for holders of registration certificates of medicines for medical use and developers of medicines. Recommendations for proper preparation of periodic reporting are proposed. The range of problems requiring additional assessment, in particular, the state of the system of regional centers for monitoring the safety of medicines in Russia is highlighted. The article is addressed to clinical pharmacologists, pharmacovigil commissioners, pharmacovigilance specialists, heads of medical and pharmaceutical organizations and medical authors

Drug Safety Monitoring Information

Analysis of administrative decisions of foreign regulatory authorities on the recall of medicines and/or the need for changes in the instructions for their medical use due to changes in the safety profile, conducted by experts of the Scientific Centre for Expert Evaluation of Medicinal Products revealed 19 administrative decisions. These decisions contained information on the following medicines registered in Russia: amikacin, tobramycin, gentamicin, neomycin, ciprofloxacin, delafloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, сeftriaxone, ceftaroline, rifapentine, tigecycline, bacitracin, ertapenem, daptomycin, erythromycin, fosfomycin, ampicillin+sulbactam, chloroquine, hydroxychloroquine