The functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods

Redfern, William S.; Dymond, Angela W.; Strang, Isobel; Storey, Sharon; Grant, Claire; Marks, Louise; Barnard, Claire; Heys, Clive; Moyser, Katherine; Greenwood, Katherine; Cobey, Des; Moore, Nick; Karp, Natasha A.; Prior, Helen

doi:10.1016/j.vascn.2019.106591

Cited by 23 publications

(13 citation statements)

References 51 publications

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“…Relatively low doses of amphetamine (3 mg/kg) increase spontaneous activity and affect a number of FOB endpoints in the autonomic, neuromuscular, sensorimotor, and behavioral domains in rats. 30 Nirmatrelvir did not affect any FOB endpoints up to 1,000 mg/kg. Although plasma exposures were not directly measured in this study, safety margins were calculated using the maximum plasma concentrations achieved on Day 1 of the corresponding 14-day toxicity study in rats, which was conducted at the same dose levels.…”

Section: Discussionmentioning

confidence: 85%

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

et al. 2022

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COVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death. Nonclinical safety studies with nirmatrelvir are essential in informing benefit-risk of Paxlovid and were conducted to support clinical development. In vivo safety pharmacology assessments included a nervous system/pulmonary study in rats and a cardiovascular study in telemetered monkeys. Potential toxicities were assessed in repeat dose studies of up to 1 month in rats and monkeys. Nirmatrelvir administration (1,000 mg/kg, p.o.) to male rats produced transient increases in locomotor activity and respiratory rate but did not affect behavioral endpoints in the functional observational battery. Cardiovascular effects in monkeys were limited to transient increases in blood pressure and decreases in heart rate, observed only at the highest dose tested (75 mg/kg per dose b.i.d; p.o.). Nirmatrelvir did not prolong QTc-interval or induce arrhythmias. There were no adverse findings in repeat dose toxicity studies up to 1 month in rats (up to 1,000 mg/kg daily, p.o.) or monkeys (up to 600 mg/kg daily, p.o.). Nonadverse, reversible clinical pathology findings without clinical or microscopic correlates included prolonged coagulation times at ≥60 mg/kg in rats and increases in transaminases at 600 mg/kg in monkeys. The safety pharmacology and nonclinical toxicity profiles of nirmatrelvir support clinical development and use of Paxlovid for treatment of COVID-19.

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Section: Discussionmentioning

confidence: 85%

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

et al. 2022

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“…This includes sensory, locomotor, and cognitive functions such as learning, memory and problem solving. 154 Sensory recovery and feedback are important in controlling motor functions, while motor recovery is responsible for initiating muscle fibers to achieve limb movements. 155 Common sensory tests include Von Frey Hair (VFH) microfilament tactile sensory test 156 and heat and cold sensation tests.…”

Section: Summary and Suggestions For Future Workmentioning

confidence: 99%

Injectable hydrogels in stroke and spinal cord injury treatment: a review on hydrogel materials, cell–matrix interactions and glial involvement

2021

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“…Принципиальных различий, касающихся набора определяемых параметров, между батареями тестов Ирвина и НФТ нет, хотя НФТ несколько превосходит тесты Ирвина более детальной оценкой сенсомоторных рефлексов и количественного измерения спонтанной активности [15]. В свою очередь, тест Ирвина в авторской интерпретации предусматривает использование большего количества точек регистрации эффектов с учетом времени максимального накопления соединения в плазме крови (T max ) [16].…”

Section: набор функциональных тестов и тесты ирвина применительно к задачам доклинических исследований безопасностиunclassified

“…Можно лишь полагать, что этот тест будет основан на исследовании in vivo, поскольку рассмотрение любого токсического эффекта в отсутствие нейроэндокринной регуляции a priori является неполным и неадекватным. Эта позиция нашла отражение в рекомендациях ICH, подчеркивающих необходимость регистрации эффектов на «функциональном» уровне, а не на уровне функции рецептора 15 .…”

Section: обобщение результатов исследований нейротоксичности в практике доклинических исследованийunclassified

Preclinical in vivo Neurotoxicity Studies of Drug Candidates

Еремина

Колик

Ostrovskaia

et al. 2020

Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo pr

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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 functional observational battery and modified Irwin test as global neurobehavioral assessments in the rat: Pharmacological validation data and a comparison of methods

Cited by 23 publications

References 51 publications

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

Comprehensive Nonclinical Safety Assessment of Nirmatrelvir Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™

Injectable hydrogels in stroke and spinal cord injury treatment: a review on hydrogel materials, cell–matrix interactions and glial involvement

Preclinical in vivo Neurotoxicity Studies of Drug Candidates

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