vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2024-14-3-265-282vedomostiregmed-630Research ArticleБЕЗОПАСНОСТЬ ЛЕКАРСТВЕННЫХ СРЕДСТВSAFETY OF MEDICINESПрактические аспекты функциональной оценки токсических поражений периферической нервной системы в доклинических исследованиях на грызунах: обзорPractical Aspects of Assessing Toxic Lesions of the Peripheral Nervous System in Preclinical Studies in Rodents: A Reviewhttps://orcid.org/0000-0001-7406-753XИльинскийН. С.IlinskiiN. S.

Ильинский Никита Сергеевич, канд. мед. наук

ул. Лесопарковая, д. 4, Санкт-Петербург, 195043

Nikita S. Ilinskii, Cand. Sci. (Med.)

4 Lesoparkovaya St., St Petersburg 195043

gniiivm_7@mil.ruhttps://orcid.org/0000-0002-6974-5583ТюнинМ. А.TyuninM. A.

Тюнин Михаил Александрович, канд. мед. наук

ул. Лесопарковая, д. 4, Санкт-Петербург, 195043

Mikhail A. Tyunin, Cand. Sci. (Med.)

4 Lesoparkovaya St., St Petersburg 195043

gniiivm_7@mil.ruhttps://orcid.org/0000-0002-5324-512XЧепурС. В.ChepurS. V.

Чепур Сергей Викторович, д-р мед. наук, профессор

ул. Лесопарковая, д. 4, Санкт-Петербург, 195043

Sergey V. Chepur, Dr. Sci. (Med.), Professor

4 Lesoparkovaya St., St Petersburg 195043

gniiivm_7@mil.ruhttps://orcid.org/0000-0003-4290-350XПугачВ. А.PugachV. A.

Пугач Виктория Александровна, канд. биол. наук

ул. Лесопарковая, д. 4, Санкт-Петербург, 195043

Viktoria A. Pugach, Cand. Sci. (Biol.)

4 Lesoparkovaya St., St Petersburg 195043

gniiivm_7@mil.ruhttps://orcid.org/0000-0002-6524-9371МясниковВ. А.MyasnikovV. A.

Мясников Вадим Александрович, канд. мед. наук

ул. Лесопарковая, д. 4, Санкт-Петербург, 195043

Vadim A. Myasnikov, Cand. Sci. (Med.)

4 Lesoparkovaya St., St Petersburg 195043

gniiivm_7@mil.ruФедеральное государственное бюджетное учреждение «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны Российской ФедерацииРоссияState Scientific Research Testing Institute of Military MedicineRussian Federation202420062024143265282Copyright © Ильинский Н.С., Тюнин М.А., Чепур С.В., Пугач В.А., Мясников В.А., 20242024Ильинский Н.С., Тюнин М.А., Чепур С.В., Пугач В.А., Мясников В.А.Ilinskii N.S., Tyunin M.A., Chepur S.V., Pugach V.A., Myasnikov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/630ВВЕДЕНИЕ

ВВЕДЕНИЕ. В практике доклинических исследований безопасности фармакологически активных веществ стандартные процедуры оценки нейротоксичности в основном нацелены на диагностику расстройств высшей нервной деятельности и поведения. Однако именно структуры периферической нервной системы ввиду большей уязвимости представляют собой доступную мишень, что обусловливает высокую распространенность нейротоксичных побочных эффектов лекарственных средств. Указанные обстоятельства определяют актуальность уточнения методических подходов к оценке токсических поражений периферической нервной системы.

ЦЕЛЬ

ЦЕЛЬ. Анализ современного методического уровня клинико-функциональных тестов для оценки токсического действия фармакологически активных веществ на структуры периферической нервной системы и формулирование практических рекомендаций по их применению при проведении доклинических исследований на грызунах.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Оптимальной тест-системой для доклинических исследований фармакологически активных веществ считаются грызуны, однако используя этих животных невозможно воспроизвести весь объем неврологического осмотра, применяемого для выявления клинических эквивалентов нейротоксичности. В работе представлено описание системного подхода к использованию доступных диагностических тестов для повышения транслируемости данных. Дана краткая характеристика неврологического дефицита, вызванного побочными действиями лекарственных средств у людей, и описаны основные токсиндромы, которые также могут быть выявлены у животных. На основании обзора литературы и собственного опыта в соответствующих разделах представлены практические рекомендации по выполнению основных тестов, позволяющих исследовать силу и тонус мышц, состояние физиологических рефлексов, координацию движений и разные виды чувствительности у грызунов. Приведены краткие сведения о возможностях электрофизиологической диагностики искомых поражений. В качестве минимального перечня методик первичного скрининга нейротоксических побочных эффектов рекомендованы следующие тесты: оценка позы животного в покое и при ходьбе «Сужающаяся дорожка», «Подтягивание на горизонтальной перекладине», шкала отведения пальцев, «Тест отдергивания хвоста», рефлекс Прейера.

ВЫВОДЫ

ВЫВОДЫ. Анализ результатов комплексной оценки неврологического дефицита в экспериментах на грызунах рекомендовано проводить клинически релевантным способом, то есть с позиций топической диагностики и общности звеньев патологического процесса. Целесообразно выполнять верификацию патологического процесса на уровне периферической нервной системы при помощи комплекса электрофизиологических методик.

INTRODUCTION

INTRODUCTION. In the current practice of preclinical safety studies of pharmacologically active substances, standard neurotoxicity assessment procedures are mainly aimed at diagnosing higher nervous activity and behavioural disorders. However, it is the structures of the peripheral nervous system that are particularly susceptible to drug-induced neurotoxicity, which renders these structures an easy target and leads to a high incidence of neurotoxic side effects. These circumstances dictate the importance of refining methodological approaches to the assessment of toxic injury in the peripheral nervous system.

AIM

AIM. The study aimed to analyse the current methodological level of clinical and functional tests for assessing the toxic effects of pharmacologically active substances on the structures of the peripheral nervous system, as well as to formulate practical recommendations for using these tests in preclinical studies in rodents.

DISCUSSION

DISCUSSION. Rodents are considered the optimal test system for preclinical studies of pharmacologically active substances, but it is impossible to reproduce the entire neurological examination that is conducted to identify clinical equivalents of neurotoxicity in humans using these animals. This article presents a systematic approach to using available diagnostic tests to increase the translatability of data. The article briefly describes the neurological deficits due to adverse drug reactions in humans, as well as the main toxidromes that can also occur in animals. Based on a literature review and experience, the authors provide practical recommendations for performing basic tests to study the strength and tone of muscles, the state of physiological reflexes, the coordination of movements, and various types of sensitivities in rodents. The article provides a brief overview of the diagnostic utility of electrophysiological testing for identifying toxic damage to the peripheral nervous system. The following tests are recommended as a minimum list of primary screening techniques for detecting neurotoxic side effects in study animals: a resting posture assessment, the beam walking test, the horizontal bar test, the digit abduction score assay, the tail flick test, and the Preyer reflex test.

CONCLUSIONS

CONCLUSIONS. The results of a comprehensive assessment of neurological deficits in rodent experiments should be analysed from a clinically relevant perspective— that is, with a focus on topical diagnosis and common pathological process components. It is advisable to verify the pathological process at the level of the peripheral nervous system using a set of electrophysiological techniques.

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The authors declare that there are no conflicts of interest present.