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’)10.30895/1991-2919-2020-10-3-164-176vedomostiregmed-312Research ArticleОБЗОРЫREVIEWSДоклинические исследования нейротоксических свойств новых лекарственных препаратов in vivoPreclinical in vivo Neurotoxicity Studies of Drug Candidateshttps://orcid.org/0000-0002-7226-5505ЕреминаН. В.EreminaN. V.

Еремина Наталья Вахитовна, канд. биол. наук

Балтийская ул., д. 8, Москва, 125315

Natalia V. Eremina, Cand. Sci. (Biol.)

8 Baltiyskaya St., Moscow 125315

neremina@panacelalabs.comhttps://orcid.org/0000-0002-9847-8058КоликЛ. Г.KolikL. G.

Колик Лариса Геннадьевна, д-р биол. наук, профессор РАН

Балтийская ул., д. 8, Москва, 125315

Larisa G. Kolik, Dr. Sci. (Biol.), Professor of RAS

8 Baltiyskaya St., Moscow 125315

lgkolik@mail.ruhttps://orcid.org/0000-0002-3654-6182ОстровскаяР. У.OstrovskayaR. U.

Островская Рита Ушеровна, д-р мед. наук, профессор

Балтийская ул., д. 8, Москва, 125315

Rita U. Ostrovskaya, Dr. Sci. (Med.), Professor

8 Baltiyskaya St., Moscow 125315

rita.ostrovskaya@gmail.comhttps://orcid.org/0000-0003-0218-8580ДурневА. Д.DurnevA. D.

Дурнев Андрей Дмитриевич, д-р мед. наук, профессор, член-корр. РАН

Балтийская ул., д. 8, Москва, 125315

Andrey D. Durnev, Dr. Sci. (Med.), Professor, Corresponding Member of RAS

8 Baltiyskaya St., Moscow 125315

addurnev@mail.ruФедеральное государственное бюджетное научное учреждение «Научно-исследовательский институт фармакологии имени В.В. Закусова»РоссияZakusov Research Institute оf PharmacologyRussian Federation202028062020103164176Copyright © Еремина Н.В., Колик Л.Г., Островская Р.У., Дурнев А.Д., 20202020Еремина Н.В., Колик Л.Г., Островская Р.У., Дурнев А.Д.Eremina N.V., Kolik L.G., Ostrovskaya R.U., Durnev A.D.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/312

Нейротоксические эффекты являются одной из частых причин прекращения доклинических и/или клинических исследований лекарственных препаратов. Их доклиническая оценка сложна в связи с широким спектром проявлений и степеней выраженности эффектов. Существующие экспериментальные подходы к оценке нейротоксичности громоздки, трудоемки и недостаточно адаптированы к доклиническим исследованиям лекарственных средств на ранних этапах разработок. Цель работы — анализ существующих подходов к экспериментальной оценке нейротоксического потенциала новых лекарственных препаратов с обсуждением необходимости и возможности создания и применения интегративных экспресс-тестов на нейротоксичность для ранней оценки перспективности фармакологических разработок. На основании обзора данных литературы и методических документов проведен сравнительный анализ современных подходов к оценке нейротоксичности химических соединений на лабораторных животных. Рассмотрены основные проблемы оценки нейротоксичности применительно к новым лекарственным препаратам, сопоставлены батарея тестов Ирвина и набор функциональных тестов. Проанализированы вопросы исследования влияния лекарственных препаратов на развитие и становление функций центральной нервной системы в периоды внутриутробного и постнатального развития. Констатировано, что существующая практика недостаточна в отношении оценки возможных негативных влияний на когнитивные функции. Сделана оценка факторов, влияющих на когнитивные функции грызунов в ходе исследований. Тесты «Острое угашение исследовательско-ориентировочной реакции» и «Экстраполяционное избавление» предложены к валидации в качестве возможных экспресс-тестов для выявления совокупности органических и функциональный нейротоксических нарушений на ранних этапах доклинических исследований лекарственных препаратов.

Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.

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